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English Pages [2588] Year 2019
USMLE Step 1 ®
LECTURE NOTES
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Copyright © 2019 Kaplan, Inc. ISBN: 978-1-5062-4266-8 All rights reserved. The text of this publication, or any part thereof, may not be reproduced in any manner whatsoever without written permission from the publisher. This book may not be duplicated or resold, pursuant to the terms of your Kaplan Enrollment Agreement. USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
USMLETM* STEP 1 ANATOMY USMLETM* STEP 1 BEHAVIORAL SCIENCE USMLETM* STEP 1 BIOCHEMISTRY AND MEDICAL GENETICS USMLETM* STEP 1 IMMUNOLOGY AND MICROBIOLOGY USMLETM* STEP 1 PATHOLOGY USMLETM* STEP 1 PHARMACOLOGY USMLETM* STEP 1 PHYSIOLOGY
USMLE
®
Step 1
Lecture Notes
2019 Anatomy
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USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the National Board of Medical Examiners (NBME), which neither sponsor nor endorse this product. This publication is designed to provide accurate information in regard to the subject matter covered as of its publication date, with the understanding that knowledge and best practice constantly evolve. The publisher is not engaged in rendering medical, legal, accounting, or other professional service. If medical or legal advice or other expert assistance is required, the services of a competent professional should be sought. This publication is not intended for use in clinical practice or the delivery of medical care. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. © 2019 by Kaplan, Inc. Published by Kaplan Medical, a division of Kaplan, Inc. 750 Third Avenue New York, NY 10017 10 9 8 7 6 5 4 3 2 1 Course ISBN: 978-1-5062-3646-9 All rights reserved. The text of this publication, or any part thereof, may not be reproduced in any manner whatsoever without written permission from the publisher. This book may not be duplicated or resold, pursuant to the terms of your Kaplan Enrollment Agreement. Retail ISBN: 978-1-5062-3606-3 Kaplan Publishing print books are available at special quantity discounts to use for sales promotions, employee premiums, or educational purposes. For more information or to purchase books, please call the Simon & Schuster special sales department at 866-506-1949.
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Editors James White, PhD Assistant Professor of Cell Biology School of Osteopathic Medicine Rowan University Stratford, NJ Adjunct Assistant Professor of Cell and Developmental Biology University of Pennsylvania School of Medicine Philadelphia, PA
David Seiden, PhD Professor of Neuroscience and Cell Biology Rutgers–Robert Wood Johnson Medical School Piscataway, NJ
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Table of Contents
Part I: Early Embryology and Histology: Epithelia
Chapter 1: Gonad Development ����������������������������������������������������������������������3
Chapter 2: First 8 Weeks of Development ������������������������������������������������������7
Chapter 3: Histology: Epithelia������������������������������������������������������������������������13
Part II: Gross Anatomy
Chapter 1: Back and Autonomic Nervous System����������������������������������������21
Chapter 2: Thorax��������������������������������������������������������������������������������������������35
Chapter 3: Abdomen, Pelvis, and Perineum������������������������������������������������� 85
Chapter 4: Upper Limb���������������������������������������������������������������������������������� 179
Chapter 5: Lower Limb����������������������������������������������������������������������������������195
Chapter 6: Head and Neck����������������������������������������������������������������������������207
Part III: Neuroscience
Chapter 1: Nervous System Organization and Development������������������� 225
Chapter 2: Histology of the Nervous System ��������������������������������������������� 235
Chapter 3: Ventricular System��������������������������������������������������������������������� 245
Chapter 4: The Spinal Cord��������������������������������������������������������������������������251
Chapter 5: The Brain Stem����������������������������������������������������������������������������275
Chapter 6: The Cerebellum ������������������������������������������������������������������������� 309
Chapter 7: Basal Ganglia ������������������������������������������������������������������������������ 317
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Chapter 8: Visual Pathways��������������������������������������������������������������������������� 325
Chapter 9: Diencephalon������������������������������������������������������������������������������� 335
Chapter 10: Cerebral Cortex������������������������������������������������������������������������� 341
Chapter 11: Limbic System ��������������������������������������������������������������������������� 359
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Additional resources available at www.kaptest.com/usmlebookresources
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PART I
Early Embryology and Histology: Epithelia
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Gonad Development
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Learning Objectives ❏❏ Explain information related to indifferent gonad ❏❏ Interpret scenarios on testis and ovary ❏❏ Answer questions about meiosis ❏❏ Interpret scenarios on spermatogenesis ❏❏ Solve problems concerning oogenesis
GONAD DEVELOPMENT Although sex is determined at fertilization, the gonads initially go through an indifferent stage weeks 4–7 when there are no specific ovarian or testicular characteristics. The indifferent gonads develop in a longitudinal elevation or ridge of intermediate mesoderm called the urogenital ridge. The components of the indifferent gonads are as follows: • Primordial germ cells provide a critical inductive influence on gonad development, migrating in at week 4. They arise from the lining cells in the wall of the yolk sac. • Primary sex cords are finger-like extensions of the surface epithe-
lium which grow into the gonad that are populated by the migrating primordial germ cells.
• Mesonephric (Wolffian) and the paramesonephric (Mullerian)
ducts of the indifferent gonad contribute to the male and female genital tracts, respectively.
The indifferent gonads develop into either the testis or ovary. Development of the testis and male reproductive system is directed by the following: • Sry gene on the short arm of the Y chromosome, which encodes for testis-determining factor (TDF) • Testosterone, which is secreted by the Leydig cells • Müllerian-inhibiting factor (MIF), which is secreted by the Sertoli
cells
• Dihydrotestosterone (DHT): external genitalia
Development of the ovary and female reproductive system requires estrogen. Ovarian development occurs in the absence of the Sry gene and in the presence of the WNT4 gene.
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Part I Anatomy
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Early Embryology and Histology: Epithelia Immunology
MIF: Müllerian-inhibiting factor TDF: testis-determining factor Pharmacology
Primordial germ cells
Biochemistry
Yolk sac Physiology
Urogenital ridge
Medical Genetics
Mesonephric duct (Wolffian)
MIF: Müllerian-inhibiting factor TDF: testis-determining factor Pathology
Paramesonephric duct (Müllerian) Indifferent gonad
Behavioral Science/Social Sciences
Microbiology
TDF Testosterone MIF
No factors
Testis and male genital system
Ovary and female genital system
Figure I-1-1. Development of Testis and Ovary Figure I-1-1. Development of Testis and Ovary
GAMETOGENESIS Meiosis Meiosis, occurring within the testis and ovary, is a specialized process of cell division that produces the male gamete (spermatogenesis) and female gamete (oogenesis). There are notable differences between spermatogenesis and oogenesis. Two cell divisions take place in meiosis. In meiosis I, the following events occur: • Synapsis: pairing of 46 homologous chromosomes • Crossing over: exchange of segments of DNA • Disjunction: separation of 46 homologous chromosome pairs
(no centromere-splitting) into 2 daughter cells, each containing 23 chromosome pairs
In meiosis II, synapsis does not occur, nor does crossing over. Disjunction does occur with centromere-splitting.
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Chapter 1
Type B Spermatogonia Oogonia
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Gonad Development
(46, 2n) (Diploid) Meiosis I
Primary spermatocyte
DNA replication (46, 4n)
Primary oocyte
Synapsis
Crossover
Cell division Alignment and disjunction Centromeres do not split Secondary spermatocyte Secondary oocyte
(23, 2n) Meiosis II Cell division Alignment and disjunction Centromeres split
Gamete
(23, 1n) (Haploid) Figure I-1-2. Meiosis Figure I-1-2. Meiosis
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Part I Anatomy
Pharmacology
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Early Embryology and Histology: Epithelia Immunology
Biochemistry
Spermatogenesis At week 4, primordial germ cells arrive in the indifferent gonad and remain dormant until puberty. • When a boy reaches puberty, primordial germ cells differentiate into type A spermatogonia, which serve as stem cells throughout adult life. • Some type A spermatogonia differentiate into type B spermatogonia.
Physiology
Medical Genetics
• Type B spermatogonia enter meiosis I to form primary spermatocytes. • Primary spermatocytes form 2 secondary spermatocytes. • Secondary spermatocytes enter meiosis II to form 2 spermatids.
Pathology
Behavioral Science/Social Sciences
• Spermatids undergo spermiogenesis, which is a series of morphologi-
cal changes resulting in the mature spermatozoa.
Oogenesis Microbiology
At week 4, primordial germ cells arrive in the indifferent gonad and differentiate into oogonia. Oogonia enter meiosis I to form primary oocytes. All primary oocytes are formed by month 5 of fetal life; they are arrested the first time in prophase (diplotene) of meiosis I and remain arrested until puberty. • Primary oocytes arrested in meiosis I are present at birth. • When a girl reaches puberty, during each monthly cycle a primary
oocyte becomes unarrested and completes meiosis I to form a secondary oocyte and polar body.
• The secondary oocyte becomes arrested the second time in metaphase
of meiosis II and is ovulated.
• At fertilization within the uterine tube, the secondary oocyte c ompletes
meiosis II to form a mature oocyte and polar body.
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First 8 Weeks of Development
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Learning Objectives ❏❏ Solve problems concerning beginning of development
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❏❏ Demonstrate understanding of the formation of the bilaminar embryo ❏❏ Solve problems concerning embryonic period
EARLY EMBRYOLOGY Week 1: Beginning of Development Fertilization occurs in the ampulla of the uterine tube when the male and female pronuclei fuse to form a zygote. At fertilization, the secondary oocyte rapidly completes meiosis II. sis mito : e g va ea l C Day 2 2-cell Blastula
Day 3
Embryoblast (forms embryo)
4-cell Blastula Day 4 Morula
Trophoblast (forms placenta) Day 5
(46, 2N) Zygote
Blastocyst
Day 1 Day 6 (Implantation begins)
Fertilization
Ovary Zona pellucida
Corona radiata cells
Secondary oocyte arrested in metaphase of meiosis II
Ampulla of oviduct
Cytotrophoblast Blastocyst cavity Embryoblast Syncytiotrophoblast
FigureFigure I-2-1. Week I-2-1.1Week 1
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Prior to fertilization, spermatozoa undergo 2 changes in the female genital tract: • Capacitation consists of the removal of several proteins from the
Pharmacology
Biochemistry
plasma membrane of the acrosome of the spermatozoa. It occurs over about 7 hours in the female reproductive tract.
• Hydrolytic enzymes are released from the acrosome used by the sperm
Physiology
Pathology
Medical Genetics
Behavioral Science/Social Sciences
to penetrate the zona pellucida. This results in a cortical reaction that prevents other spermatozoa penetrating the zona pellucida thus preventing polyspermy.
During the first 4–5 days of week 1, the zygote undergoes rapid mitotic division (cleavage) in the oviduct to form a blastula, consisting of increasingly smaller blastomeres. This becomes the morula (32-cell stage). A blastocyst forms as fluid develops in the morula. The blastocyst consists of an inner cell mass known as the embryoblast, and the outer cell mass known as the trophoblast, which becomes the placenta.
Microbiology
At the end of week 1, the trophoblast differentiates into the cytotrophoblast and syncytiotrophoblast and then implantation begins.
Clinical Correlate Ectopic Pregnancy Tubal (most common form) usually occurs when the blastocyst implants within the ampulla of the uterine tube because of delayed transport. Risk factors include endometriosis, pelvic inflammatory disease, tubular pelvic surgery, and exposure to diethylstilbestrol (DES.) Clinical signs include abnormal or brisk uterine bleeding, sudden onset of abdominal pain that may be confused with appendicitis, missed menstrual period (e.g., LMP 60 days ago), positive human chorionic gonadotropin test, culdocentesis showing intraperitoneal blood, and positive sonogram. Abdominal form usually occurs in the rectouterine pouch (pouch of Douglas).
For implantation to occur, the zona pellucida must degenerate. The blastocyst usually implants within the posterior wall of the uterus. The embryonic pole of blastocyst implants first. The blastocyst implants within the functional layer of the endometrium during the progestational phase of the menstrual cycle.
Week 2: Formation of the Bilaminar Embryo In week 2, the embryoblast differentiates into the epiblast and hypoblast, forming a bilaminar embryonic disk. The epiblast forms the amniotic cavity and hypoblast cells migrate to form the primary yolk sac. The prechordal plate, formed from fusion of epiblast and hypoblast cells, is the site of the future mouth.
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Chapter 2 Hypoblast Epiblast
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First 8 Weeks of Development
Clinical Correlate
Bilaminar disk Endometrial blood vessel Lacuna spaces Endometrial gland Syncytiotrophoblast • Implantation • hCG
Prechordal plate Chorionic cavity Yolk sac
Connecting stalk
Amniotic cavity
Primary villi
Human chorionic gonadotropin (hCG), a glycoprotein produced by the syncytiotrophoblast, stimulates progesterone production by the corpus luteum. hCG can be assayed in maternal blood or urine and is the basis for early pregnancy testing. hCG is detectable throughout pregnancy. • Low hCG may predict a spontaneous abortion or ectopic pregnancy. • High hCG may predict a multiple pregnancy, hydatidiform mole, or gestational trophoblastic disease.
Chorion Extraembryonic mesoderm Cytotrophoblast
FigureI-3-1. I-2-2.Week Week22 Figure
Extraembryonic mesoderm is derived from the epiblast. Extraembryonic somatic mesoderm lines the cytotrophoblast, forms the connecting stalk, and covers the amnion. Extraembryonic visceral mesoderm covers the yolk sac. The connecting stalk suspends the conceptus within the chorionic cavity. The wall of the chorionic cavity is called the chorion, consisting of extraembryonic somatic mesoderm, the cytotrophoblast, and the syncytiotrophoblast. The syncytiotrophoblast continues its growth into the endometrium to make contact with endometrial blood vessels and glands. No mitosis occurs in the syncytiotrophoblast. The cytotrophoblast is mitotically active. Hematopoiesis occurs initially in the mesoderm surrounding the yolk sac (up to 6 weeks) and later in the fetal liver, spleen, thymus (6 weeks to third trimester), and bone marrow.
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Part I Anatomy
Pharmacology
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Biochemistry
Weeks 3–8: Embryonic Period All major organ systems begin to develop during the weeks 3–8. By the end of this period, the embryo begins to look human, and the nervous and cardiovascular systems start to develop. Week 3 corresponds to the first missed menstrual period. Dorsal View
Physiology
Cranial
Medical Genetics
Prechordal plate Pathology
Primitive node
Behavioral Science/Social Sciences
Primitive pit
B
Primitive streak
Microbiology
Cloacal membrane Caudal
A
Sectional View Cranial
Primitive node & streak Epiblast (ectoderm) Amnion Notochord
Yolk sac Mesoderm B
Endoderm
Hypoblast
Figure 3 I-2-3. Week 3 Figure I-4-1. Week
During this time gastrulation also takes place; this is the process by which the 3 primary germ layers are produced: ectoderm, mesoderm, and endoderm. It begins with the formation of the primitive streak within the epiblast. • Ectoderm forms neuroectoderm and neural crest cells. • Mesoderm forms paraxial mesoderm (35 pairs of somites), intermedi-
ate mesoderm, and lateral mesoderm.
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Chapter 2
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First 8 Weeks of Development
Clinical Correlate Sacrococcygeal teratoma: a tumor that arises from remnants of the primitive streak; often contains various types of tissue (bone, nerve, hair, etc) Chordoma: a tumor that arises from remnants of the notochord, found either intracranially or in the sacral region Hydatidiform mole: results from the partial or complete replacement of the trophoblast by dilated villi • In a complete mole, there is no embryo; a haploid sperm fertilizes a blighted ovum and reduplicates so that the karyotype is 46,XX, with all chromosomes of paternal origin. In a partial mole, there is a haploid set of maternal chromosomes and usually 2 sets of paternal chromosomes so that the typical karyotype is 69,XXY. • Molar pregnancies have high levels of hCG, and 20% develop into a malignant
trophoblastic disease, including choriocarcinoma.
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Immunology
Table I-2-1. Germ Layer Derivatives Ectoderm Surface ectoderm
Pharmacology
Physiology
Pathology
Muscle Biochemistry
Epidermis
Smooth
Hair
Cardiac
Nails
Skeletal
Endoderm Forms epithelial lining of: GI track: foregut, midgut, and hindgut Lower respiratory system: larynx, trachea, bronchi, and lung
Inner ear, external ear Medical Genetics
Connective tissue
Enamel of teeth
All serous membranes
Genitourinary system: urinary bladder, urethra, and lower vagina
Lens of eye
Bone and cartilage
Pharyngeal pouches:
Anterior pituitary (Rathke’s pouch)
Blood, lymph, cardiovascular organs
Parotid gland
Behavioral Science/Social Sciences
Anal canal below pectinate line Microbiology
Mesoderm
Neuroectoderm Neural tube
Adrenal cortex Gonads and internal reproductive organs Spleen Kidney and ureter
• Auditory tube and middle ear • Palatine tonsils • Parathyroid glands • Thymus Forms parenchyma of:
Central nervous system
Dura mater
• Liver
Retina and optic nerve
Notochord
• Pancreas
Pineal gland Neurohypophysis Astrocytes
Nucleus pulposus
• Submandibular and sublingual glands • Follicles of thyroid gland
Oligodendrocytes Neural crest ectoderm Adrenal medulla Ganglia Sensory—Pseudounipolar Neurons Autonomic—Postganglionic Neurons Pigment cells Schwann cells Meninges Pia and arachnoid mater Pharyngeal arch cartilage Odontoblasts Parafollicular (C) cells Aorticopulmonary septum Endocardial cushions Extra embryonic structures Yolk sac derivatives: Primordial germ cells Early blood cells and blood vessels
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Histology: Epithelia
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Learning Objectives ❏❏ Demonstrate understanding of epithelial cells
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❏❏ Use knowledge of epithelium ❏❏ Interpret scenarios on cytoskeletal elements ❏❏ Explain information related to cell adhesion molecules ❏❏ Answer questions about cell surface specializations
Histology is the study of normal tissues. Groups of cells make up tissues, tissues form organs, organs form organ systems, and systems make up the organism. Each organ consists of 4 types of tissue: epithelial, connective, nervous, and muscular.
Note Only certain aspects of epithelia will be reviewed here; other aspects of histology appear elsewhere in this book.
EPITHELIUM Epithelial cells are often polarized: the structure, composition, and function of the apical surface membrane differ from those of the basolateral surfaces. The polarity is established by the presence of tight junctions that separate these 2 regions. Internal organelles are situated symmetrically in the cell. Membrane polarity and tight junctions are essential for the transport functions of epithelia. Many simple epithelia transport substances from one side to the other (kidney epithelia transport salts and sugars; intestinal epithelia transport nutrients, antibodies, etc.). There are 2 basic mechanisms used for these transports: • Transcellular pathway through which larger molecules and a combina-
tion of diffusion and pumping in the case of ions that pass through the cell
• Paracellular pathway that permits movement between cells
Tight junctions regulate the paracellular pathway, because they prevent backflow of transported material and keep basolateral and apical membrane components separate. Epithelial polarity is essential to the proper functioning of epithelial cells; when polarity is disrupted, disease can develop. For example, epithelia lining the trachea, bronchi, intestine, and pancreatic ducts transport chloride from basolateral surface to lumen via pumps in the basolateral surface and channels in
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Part I
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Early Embryology and Histology: Epithelia
Anatomy
Immunology
Pharmacology
Biochemistry
Physiology
Medical Genetics
the apical surface. The transport provides a driving force for Na by producing electrical polarization of the epithelium. Thus NaCl moves across, and water follows. In cystic fibrosis the apical Cl channels do not open. Failure of water transport results in thickening of the mucous layer covering the epithelia. Transformed cells may lose their polarized organization, and this change can be easily detected by using antibodies against proteins specific for either the apical or basolateral surfaces. Loss of polarity in the distribution of membrane proteins may eventually become useful as an early index of neoplasticity. Epithelia are always lined on the basal side by connective tissue containing blood vessels. Since epithelia are avascular, interstitial tissue fluids provide epithelia with oxygen and nutrients.
Pathology
Microbiology
Behavioral Science/Social Sciences
Epithelia modify the 2 compartments that they separate. The epithelial cells may either secrete into or absorb from each compartment, and may selectively transport solutes from one side of the barrier to the other. Epithelia renew themselves continuously, some very rapidly (skin and intestinal linings), some at a slower rate. This means that the tissue contains stem cells that ivision continuously proliferate. The daughter cells resulting from each cell d either remain in the pool of dividing cells or differentiate.
Epithelial Subtypes The epithelial subtypes are as follows: • Simple cuboidal epithelium (e.g., renal tubules, salivary gland acini) • Simple columnar epithelium (e.g., small intestine) • Simple squamous epithelium (e.g., endothelium, mesothelium, epithe-
lium lining the inside of the renal glomerular capsule)
• Stratified squamous epithelium: nonkeratinized (e.g., esophagus) and
keratinizing (e.g., skin)
• Pseudostratified columnar epithelium (e.g., trachea, epididymis) • Transitional epithelium (urothelium) (e.g., ureter and bladder) • Stratified cuboidal epithelium (e.g., salivary gland ducts)
CYTOSKELETAL ELEMENTS Microfilaments Microfilaments are actin proteins. They are composed of globular monomers of G-actin that polymerize to form helical filaments of F-actin. Actin polymerization is ATP dependent. The F-actin filaments are 7-nm-diameter filaments that are constantly ongoing assembly and disassembly. F-actin has a distinct polarity. The barbed end (the plus end) is the site of polymerization and the pointed end is the site of depolymerization. Tread milling is the balance in the activity at the 2 ends.
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Chapter 3
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Histology: Epithelia
In conjunction with myosin, actin microfilaments provide contractile and motile forces of cells including the formation of a contractile ring that provides a basis for cytokinesis during mitosis and meiosis. Actin filaments are linked to cell membranes at tight junctions and at the zonula adherens, and form the core of microvilli.
Intermediate Filaments Intermediate filaments are 10-nm-diameter filaments that are usually stable once formed. These filaments provide structural stability to cells. There are 4 types: • Type I: keratins (keratins are found in all epithelial cells) • Type II: intermediate filaments comprising a diverse group • Type III: intermediate filaments forming neurofilaments in neurons • Type IV: 3 types of lamins forming a meshwork rather than individual
filaments inside the nuclear envelope of all cells
Clinical Correlate A first step in the invasion of malignant cells through an epithelium results from a loss of expression of cadherins that weakens the epithelium.
Clinical Correlate Changes in intermediate filaments are evident in neurons in Alzheimer’s and cirrhotic liver disease.
Microtubules Microtubules consist of 25-nm-diameter hollow tubes. Like actin, microtubules undergo continuous assembly and disassembly. They provide “tracks” for intracellular transport of vesicles and molecules. Such transport exists in all cells but is particularly important in axons. Transport requires specific ATPase motor molecules; dynein drives retrograde transport and kinesin drives anterograde transport. Microtubules are found in true cilia and flagella, and utilize dynein to convey motility to these structures. Microtubules form the mitotic spindle during mitosis and meiosis.
Clinical Correlate Colchicine prevents microtubule polymerization and is used to prevent neutrophil migration in gout. Vinblastine and vincristine are used in cancer therapy because they inhibit the formation of the mitotic spindle.
CELL ADHESION MOLECULES Cell adhesion molecules are surface molecules that allow cells to adhere to one another or to components of the extracellular matrix. The expression of adhesion molecules on the surface of a given cell may change with time, altering its interaction with adjacent cells or the extracellular matrix. Cadherin and selectin are adhesion molecules that are calcium ion-dependent. The extracellular portion binds to a cadherin dimer on another cell (trans binding). The cytoplasmic portions of cadherins are linked to cytoplasmic actin filaments by the catenin complex of proteins. Integrins are adhesion molecules that are calcium-independent. They are transmembrane surface molecules with extracellular domains that bind to fibronectin and laminin, which are components of extracellular basement membrane. The cytoplasmic portions of integrins bind to actin filaments. Integrins form a portion of hemidesmosomes but are also important in interactions between leukocytes and endothelial cells.
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Anatomy
Immunology
Pharmacology
Biochemistry
CELL SURFACE SPECIALIZATIONS Cell Adhesion
• Painful flaccid bullae (blisters) in oropharynx and skin that rupture easily Behavioral Science/Social Sciences
A cell must physically interact via cell surface molecules with its external environment, whether it be the extracellular matrix or basement membrane. The basement membrane is a sheet-like structure underlying virtually all epithelia, which consists of basal lamina (made of type IV collagen, glycoproteins [e.g., laminin], and proteoglycans [e.g., heparin sulfate]), and reticular lamina (composed of reticular fibers). Cell junctions anchor cells to each other, seal boundaries between cells, and form channels for direct transport and communication between cells. The 3 types of junctional complex include anchoring, tight, and gap junctions.
• Postinflammatory hyperpigmentation
Cell Junctions
Clinical Correlate Pemphigus Vulgaris
Physiology
Pathology
• Autoantibodies against Medical Genetics desmosomal proteins in skin cells
• Treatment: corticosteroids Microbiology
Bullous Pemphigoid • Autoantibodies against basement-membrane hemidesmosomal proteins • Widespread blistering with pruritus • Less severe than pemphigus vulgaris • Rarely affects oral mucosa • Can be drug-induced (e.g., middle-aged or elderly patient on multiple medications) • Treatment: corticosteroids
Tight junctions (zonula occludens) function as barriers to diffusion and determine cell polarity. They form a series of punctate contacts of adjacent epithelial cells near the apical end or luminal surface of epithelial cells. The major components of tight junctions are occludens (ZO-1,2,3) and claudin proteins. These proteins span between the adjacent cell membranes and their cytoplasmic parts bind to actin microfilaments. Zonula adherens forms a belt around the entire apicolateral circumference of the cell, immediately below the tight junction of epithelium. Cadherins span between the cell membranes. Like the tight junctions immediately above them, the cytoplasmic parts of cadherins are associated with actin filaments. Desmosomes (macula adherens) function as anchoring junctions. Desmosomes provide a structural and mechanical link between cells. Cadherins span between the cell membranes of desmosomes and internally desmosomes are anchored to intermediate filaments in large bundles called tonofilaments. Hemidesmosomes adhere epithelial cells to the basement membrane. The basement membrane is a structure that consists of the basal membrane of a cell and 2 underlying extracellular components, the basal lamina and the reticular lamina. The basal lamina is a thin felt-like extracellular layer composed of predominantly of type IV collagen associated with laminin, proteoglycans, and fibronectin that are secreted by epithelial cells. Fibronectin binds to integrins on the cell membrane, and fibronectin and laminin in turn bind to collagen in the basal lamina. Internally, like a desmosome, the hemidesmosomes are linked to intermediate filaments. Below the basal lamina is the reticular lamina, composed of reticular fibers. Through the binding of extracellular components of hemidesmosomes to integrins, and thus to fibronectin and laminin, the cell is attached to the basement membrane and therefore to the extracellular matrix components outside the basement membrane. These interactions between the cell cytoplasm and the extracellular matrix have implications for permeability, cell motility during embryogenesis, and cell invasion by malignant neoplasms. Gap junctions (communicating junctions) function in cell-to-cell communication between the cytoplasm of adjacent cells by providing a passageway for ions such as calcium and small molecules such as cyclic adenosine monophosphate (cAMP). The transcellular channels that make up a gap junction consist
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Histology: Epithelia
of connexons, which are hollow channels spanning the plasma membrane. Each connexon consists of 6 connexin molecules. Unlike other intercellular junctions, gap junctions are not associated with any cytoskeletal filament. Apical surface
Microvilli
Plasma membrane Tight junction
Actin microfilaments Intermediate filaments (keratin)
Zonula adherens Desmosome Cell A
Cell B
Cell C
Gap junction Cell D Hemidesmosome
Basal lamina Figure I-3-1. Junctions
Connexon
ace r sp l A a l u l cel cel Intra layer of bi Lipid ll B f ce o r e bilay ace Lipid r sp a l u l cel Intra
2–4 nm
1.5 nm 7 nm Figure I-3-2. Gap Junction
Microvilli Microvilli contain a core of actin microfilaments and function to increase the absorptive surface area of an epithelial cell. They are found in columnar epithelial cells of the small and large intestine, cells of the proximal tubule of the kidney and on columnar epithelial respiratory cells. Stereocilia are long, branched microvilli that are found in the male reproductive tract (e.g., epididymis). Short stereocilia cap all sensory cells in the inner ear.
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Early Embryology and Histology: Epithelia
Anatomy
Immunology
Glycocalyx Pharmacology
Microvilli
Biochemistry
Zonula occludens (tight junction) Physiology
Medical Genetics
Zonula adherens Desmosome
Pathology
Behavioral Science/Social Sciences
Microbiology
Figure I-3-3. Apical Cell Surface/Cell Junctions
Clinical Correlate
Cilia
Kartagener syndrome is characterized by immotile spermatozoa and infertility. It is due to an absence of dynein that is required for flagellar motility. It is usually associated with chronic respiratory infections because of similar defects in cilia of respiratory epithelium.
Cilia contain 9 peripheral pairs of microtubules and 2 central microtubules. The microtubules convey motility to cilia through the ATPase dynein. Cilia bend and beat on the cell surface of pseudostratified ciliated columnar respiratory epithelial cells to propel overlying mucous. They also form the core of the flagella, the motile tail of sperm cells.
B = Basal body IJ = Intermediat M = Microvillus OJ = Occluding
B: basal body IJ: intermediate junction M: microvillus OJ: occluding junction
Copyright LippincottLippincott Williams &Williams Wilkins. Used with permission. Copyright & Wilkins. Used with permission.
Figure I-3-4. Cilia
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Gross Anatomy
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1
Learning Objectives ❏❏ Solve problems concerning vertebral column ❏❏ Demonstrate understanding of spinal meninges ❏❏ Use knowledge of spinal nerves ❏❏ Use knowledge of autonomic nervous system
VERTEBRAL COLUMN Embryology During week 4, sclerotome cells of the somites (mesoderm) migrate medially to surround the spinal cord and notochord. After proliferation of the caudal portion of the sclerotomes, the vertebrae are formed, each consisting of the caudal part of one sclerotome and the cephalic part of the next.
Vertebrae The vertebral column is the central component of the axial skeleton which functions in muscle attachments, movements, and articulations of the head and trunk. • The vertebrae provide a flexible support system that transfers the
weight of the body to the lower limbs and also provides protection for the spinal cord.
• The vertebral column is composed of 32–33 vertebrae (7 cervical,
12 thoracic, 5 lumbar, and the fused 5 sacral, and 3–4 coccygeal), intervertebral disks, synovial articulations (zygapophyseal joints) and ligaments.
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Gross Anatomy
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Anatomy
Immunology
Pharmacology
Biochemistry
~33 vertebrae
~33 vertebrae
31 spinal nerves
31 spinal nervesMedical Genetics
Physiology
Anterior view Atlas (C1)Behavioral Science/Social Sciences
Pathology
Axis (C2)
Lateral view
Posterior view
Cervical curvature C7 T1
C7 T1
Microbiology
Intervertebral disk Intervertebral foramen T12
L1
Thoracic curvature
Cervical vertebrae (7)
Thoracic vertebrae (12)
T12 L1
Lumbar vertebrae (5) L5
Lumbar curvature
L5
Sacrum (S1–5) Coccyx
Interlaminar space Sacrum (5)
Sacral curvature
Sacral hiatus (caudal block) Coccyx
Figure II-1-1. Vertebral Column Figure II-1-1. Vertebral Column
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A typical vertebra consists of an anterior body and a posterior vertebral arch consisting of 2 pedicles and 2 laminae. The vertebral arch encloses the vertebral (foramen) canal that houses the spinal cord. Vertebral notches of adjacent pedicles form intervertebral foramina that provide for the exit of the spinal nerves. The dorsal projecting spines and the lateral projecting transverse processes provide attachment sites for muscles and ligaments.
Spinous process Lamina Transverse process Vertebral foramen
Pedicle Body
Facet on superior articular process
A
Pedicle
Body Inferior vertebral notch B
Spinous process
Superior and inferior articular processes
Figure II-1-2. Typical Vertebra
Figure II-1-2. Typical Vertebra
Intervertebral Disks The intervertebral disks contribute to about 25% of the length of the vertebral column. They form the cartilaginous joints between the vertebral bodies and provide limited movements between the individual vertebrae. • Each intervertebral disk is numbered by the vertebral body above the
disk.
• Each intervertebral disk is composed of the following:
–– Anulus fibrosus consists of the outer concentric rings of fibrocartilage and fibrous connective tissue. The anuli connect the adjacent bodies and provide limited movement between the individual vertebrae. –– Nucleus pulposus is an inner soft, elastic, compressible material that functions as a shock absorber for external forces placed on the vertebral column. The nucleus pulposus is the postnatal remnant of the notochord.
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Gross Anatomy
Anatomy
Immunology
Intervertebral disk Intervertebral foramen Biochemistry Ventral
Pharmacology
Pedicle
Anterior longitudinal ligament Physiology
Medical Genetics
Annulus fibrosus Pathology
Nucleus pulposus
L4
Spinal nerve
Behavioral Science/Social Sciences
Posterolateral herniation
Posterior longitudinal ligament
Posterior longitudinal ligament
Microbiology
Dorsal
A. Intervertebral Disk
Zygapophyseal joint
Anterior longitudinal ligament B. Intervertebral Foramen
Figure II-1-3. Intervertebral Disks Figure II-1-3. Intervertebral Disks
Clinical Correlate
Ligaments of the Vertebral Column
The herniation of a nucleus pulposus is most commonly in a posterolateral direction due to the strength and position of the posterior longitudinal ligament (Figure II-1-3-A).
The vertebral bodies are strongly supported by 2 longitudinal ligaments. Both ligaments are firmly attached to the intervertebral disks and to the bodies of the vertebrae. • Anterior longitudinal ligament forms a broad band of fibers that
connects the anterior surfaces of the bodies of the vertebrae between the cervical and sacral regions. It prevents hyperextension of the vertebrae and is often involved in “whiplash” accidents.
• Posterior longitudinal ligament connects the posterior surfaces of the
vertebral bodies and is located in the vertebral canal. It limits flexion of the vertebral column. This ligament causes the herniation of a disk to be positioned posterolaterally.
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Herniated Disk The nucleus pulposus may herniate through the anulus fibrosus. The herniated nucleus pulposus may compress the spinal nerve roots, resulting in pain along the involved spinal nerve (sciatica). • Herniation usually occurs in the lower lumbar (L4/L5 or L5/S1) or
lower cervical (C5/C6 or C6/C7) parts of the vertebral column.
• The herniated disk will usually compress the spinal nerve roots one
number below the involved disk (e.g., the herniation of the L4 disk will compress the L5 roots, or herniation of the C7 disk will compress the C8 nerve roots). 4th lumbar spinal nerve
Nucleus pulposus L4 Herniation of the L4 nucleus pulposus into vertebral canal
Compresses roots of 5th lumbar spinal nerve
L5
S1
Figure II-1-4. Herniated Intervertebral Figure II-1-4. Herniated Intervertebral DiskDisk
Intervertebral Foramen The intervertebral foramina are formed by successive intervertebral notches and provide for the passage of the spinal nerve. The boundaries of the foramina are: • Anterior: bodies of the vertebrae and intervertebral disks • Posterior: zygapophyseal joint and articular processes • Superior and inferior: pedicles of the vertebrae
SPINAL MENINGES The spinal cord is protected and covered by 3 connective tissue layers within the vertebral canal: the dura mater, arachnoid, and pia mater.
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Gross Anatomy Immunology
Epidural space Vertebral body
Pia mater Pharmacology
Biochemistry
Epidural fat
Arachnoid mater Dura mater
Subarachnoid space
Ventral root of spinal nerve Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Spinal nerve
Dorsal root of spinal nerve
Intervertebral foramen Denticulate ligament
Microbiology
Internal vertebral venous plexus Figure II-1-5. Cross-Section of Vertebral Canal Figure II-1-5. Cross-Section of Vertebral Canal
Dura Mater The dura mater is a tough, cylindrical covering of connective tissue forming a dural sac which envelops the entire spinal cord and cauda equina. • The dura mater and dural sac terminate inferiorly at the second sacral
vertebra level.
• Superiorly, the dura mater continues through the foramen magnum
and is continuous with the meningeal layer of the cranial dura.
Arachnoid The arachnoid is a delicate membrane which completely lines the inner surface of the dura mater and dural sac. It continues inferiorly and terminates at the second sacral vertebra.
Pia Mater The pia mater is tightly attached to the surface of the spinal cord and provides a delicate covering of the cord. • The spinal cord, with its covering of pia mater, terminates at the L1 or
L2 vertebral levels in the adult.
• There are 2 specializations of the pia mater that are attached to the
spinal cord:
–– The denticulate ligaments are bilateral thickenings of pia mater that run continuously on the lateral sides of the midpoint of the cord. They separate the ventral and dorsal roots of the spinal nerves and anchor to the dura mater.
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–– The filum terminale is a continuation of the pia mater distal to the lower end of the spinal cord. The filum terminale is part of the cauda equina which is composed of ventral and dorsal roots of lumbar and sacral nerves that extend below the inferior limit of the spinal cord. etween There are 2 spaces related to the meninges. The epidural space is located b the inner walls of the vertebral canal and the dura mater. It contains fat and the internal vertebral venous plexus. The venous plexus runs the e ntire length of the epidural space and continues superiorly through the foramen magnum to connect with dural venous sinuses in the cranial cavity. The subarachnoid space is a pressurized space located between the arachnoid and pia mater layers. It contains cerebrospinal fluid (CSF), which bathes the spinal cord and spinal nerve roots within the dural sac, and terminates at the second sacral vertebral level.
Clinical Correlate The internal vertebral venous plexus is valveless and connects with veins of the pelvis, abdomen, and thorax. It provides a route of metastasis of cancer cells to the vertebral column and the cranial cavity.
There are 2 important vertebral levels. The L1 or L2 vertebrae is the inferior limit of the spinal cord in adults (conus medullaris). S2 vertebra is the inferior limit of the dural sac and the subarachnoid space (cerebrospinal fluid).
Thoracic vertebrae L2 vertebra Lumbar vertebrae S2 vertebra Sacrum A
Coccyx
Epidural anesthesia
Lumbar puncture
Pia mater
Skin
Lamina
Fascia
Epidural space
Ligamentum flavum
Conus medullaris
End of dural sac
Subarachnoid space containing CSF Dura mater Epidural space B
L1
L2
L3
L4
L5
S1
Filum terminale (Pia mater)
S4 S5 S2 S3 Sacrum
Arachnoid
Coccyx
Figure II-1-6. Important Vertebral Levels
Figure II-1-6. Important Vertebral Levels
SPINAL NERVES There are 31 pairs of spinal nerves attached to each segment of the spinal cord: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. The spinal nerves with the cranial nerves form part of the peripheral nervous system.
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Gross Anatomy
Anatomy
Pharmacology
Immunology
Dorsal ramus (mixed)
Arachnoid White matter
Supplies: • Skin of back and dorsal neck • Deep intrinsic back muscles (Erector spinae)
Biochemistry Dura mater
Gray matter
Pia mater Dorsal root (sensory)
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Dorsal root ganglion
Ventral root (motor) Microbiology
Spinal nerve (mixed)
Ventral ramus (mixed) Sympathetic ganglion
Supplies: • Skin of anterolateral trunk and limbs • Skeletal muscles of anterolateral trunk and limbs
Figure II-1-7. Cross Section Spinal Cord and Nerve Figure II-1-7. Cross Section of Spinal Cord of and Parts of Spinal Parts of Spinal Nerve
Each spinal nerve is formed by the following components: • Dorsal root carries sensory fibers from the periphery into the dorsal
aspect of the spinal cord; on each dorsal root there is a dorsal root ganglion (sensory) containing the pseudounipolar cell bodies of the nerve fibers that are found in the dorsal root
• Ventral root arises from the ventral aspect of the spinal cord and car-
ries axons of motor neurons from the spinal cord to the periphery; the cell bodies of the axons in the ventral root are located in the ventral or lateral horns of the spinal cord gray matter
• Spinal nerve is formed by the union of the ventral and dorsal roots;
it exits the vertebral column by passing through the intervertebral foramen
• Dorsal rami innervate the skin of the dorsal surface of the back, neck,
zygapophyseal joints, and intrinsic skeletal muscles of the deep back
• Ventral rami innervate the skin of the anterolateral trunk and limbs,
and the skeletal muscles of the anterolateral trunk and limbs (ventral rami form the brachial and lumbosacral plexuses)
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The spinal nerves exit the vertebral column by a specific relationship to the vertebrae. The cervical nerves C1–C7 exit the intervertebral foramina superior to the pedicles of the same-numbered vertebrae. The C8 nerve exits the intervertebral foramen inferior to the C7 pedicle. This is the transition point. All nerves beginning with T1 and below will exit the intervertebral foramina inferior to the pedicle of the same-numbered vertebrae.
Lumbar Puncture A lumbar puncture is used to inject anesthetic material in the epidural space or to withdraw CSF from the subarachnoid space. • A spinal tap is typically performed at the L4-L5 interspace. • A horizontal line drawn at the top of the iliac crest marks the level of
the L4 vertebra.
• When a lumbar puncture is performed in the midline, the needle
passes through the interlaminar space of the vertebral column found between the laminae of the lumbar vertebrae.
• The interlaminar spaces are covered by the highly elastic ligamenta
flava.
Clinical Correlate
Lumbar vertebrae Interlaminar spaces (covered by ligamentum flavum)
During a lumbar puncture, a needle is passed through the interlaminar space while the vertebral column is flexed. The needle passes through the following layers: • Skin • Superficial fascia • Deep fascia • Supraspinous ligament
Sacrum
• Interspinous ligament • Interlaminar space
Coccyx Figure II-1-8. Interlaminar Spaces Figure II-1-8. Interlaminar Spaces
• Epidural space • Dura • Arachnoid • Subarachnoid space
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Pharmacology
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Gross Anatomy Immunology
Biochemistry
AUTONOMIC NERVOUS SYSTEM The autonomic nervous system (ANS) is concerned with the motor innervation of smooth muscle, cardiac muscle, and glands of the body. Anatomically and functionally, it is composed of 2 motor divisions: sympathetic and parasympathetic. In both divisions, 2 neurons form an autonomic pathway. • Preganglionic neurons have their neuronal cell bodies in the CNS
Physiology
(formed by neuroectoderm); their axons exit in cranial and spinal nerves.
Medical Genetics
• Postganglionic neurons have cell bodies in autonomic ganglia in the
peripheral nervous system (PNS) (formed by neural crest cells)
Pathology
Behavioral Science/Social Sciences
Central nervous system (CNS)
Motor ganglion
Preganglionic nerve fiber
Microbiology
Postganglionic nerve fiber
Target
Figure II-1-9. Autonomic Nervous Figure II-1-9. Autonomic Nervous System System
Sympathetic Nervous System The preganglionic cell bodies of the sympathetic nervous system are found in the lateral horn gray matter of spinal cord segments T1–L2 (14 segments). The postganglionic cell bodies of the sympathetic system are found in one of 2 types of motor ganglia in the PNS: • Chain or paravertebral • Collateral or prevertebral (found only in abdomen or pelvis)
Table II-1-1. Sympathetic = Thoracolumbar Outflow Origin (Preganglionic)
Site of Synapse (Postganglionic)
Innervation (Target)
Spinal cord levels T1–L2
Sympathetic chain ganglia (paravertebral ganglia)
Smooth muscle, cardiac muscle and glands of body wall and limbs (T1–L2), head (T1–2) and thoracic viscera (T1–5).
Thoracic splanchnic nerves T5–T12
Prevertebral ganglia (collateral) (e.g., celiac, aorticorenal, superior mesenteric ganglia)
Smooth muscle and glands of the foregut and midgut
Lumbar splanchnic nerves L1–L2
Prevertebral ganglia (collateral) (e.g., inferior mesenteric and pelvic ganglia)
Smooth muscle and glands of the pelvic viscera and hindgut
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Back and Autonomic Nervous System
Head (sweat glands, dilator pupillae m., superior tarsal m.)
III IV V VI
Internal carotid a. External carotid a.
IX X XI
X C1
(Periarterial carotid nerve plexus) Superior cervical ganglion Middle cervical ganglion
T1
m: muscle a: artery
Lesions at arrows result in ipsilateral Horner syndrome (ptosis, miosis, and anhydrosis).
Cervicothoracic ganglion Heart, trachea, bronchi, lungs (thorax)
* Thoracic *Splanchnic * nerves (T5–T12)
L1 L2 Prevertebral ganglia Sympathetic chain
Smooth muscle and glands of the foregut and midgut Prevertebral ganglia
*Gray rami carry postganglionic sympathetic axons from the sympathetic ganglion to the spinal nerve.
Lumbar splanchnic nerves (L1-L2) Smooth muscle and glands of the hindgut and pelvic viscera
Preganglionic Postganglionic
Figure II-1-10. Overview of Sympathetic Outflow Figure II-1-10. Overview of Sympathetic Outflow
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Preganglionic
Postganglionic Pharmacology
Biochemistry
Physiology
Medical Genetics
Lateral horn (T1–L2) Dorsal ramus
Pathology
Ventral ramus
Behavioral Science/Social Sciences
Spinal nerve Gray ramus communicans– postganglionics (31) (to body wall)
Microbiology
White ramus communicans– preganglionics (14)
To smooth muscles and glands of body wall and limbs
Sympathetic chain ganglion
Figure II-1-11. Cross Section of Section Spinal Cord Showing Sympathetic OutflowOutflow Figure II-1-11. Cross of Spinal Cord Showing Sympathetic
Note
Parasympathetic Nervous System
White rami are preganglionic sympathetics that all enter the sympathetic trunk of ganglia. They may synapse with ganglion at point of entry or go up or down and synapse above or below point of entry. If a white ramus does not synapse, it passes through ganglion and becomes a root of a thoracic or lumbar splanchnic nerve.
The preganglionic cell bodies of the parasympathetic nervous system are found in the CNS in one of 2 places: • Gray matter of brain stem associated with cranial nerves III, VII, IX, and X, or • Spinal cord gray in sacral segments S2 3, and 4 (pelvic splanchnics)
The postganglionic cell bodies of the parasympathetic nervous system are found in terminal ganglia in the PNS that are usually located near the organ innervated or in the wall of the organ.
Table II-1-2. Parasympathetic = Craniosacral Outflow Origin (Preganglionic)
Site of Synapse (Postganglionic)
Innervation (Target)
Cranial nerves III, VII, IX
4 cranial ganglia
Glands and smooth muscle of the head
Cranial nerve X
Terminal ganglia (in or near the walls of viscera)
Viscera of the neck, thorax, foregut, and midgut
Pelvic splanchnic nerves S 2, 3, 4
Terminal ganglia (in or near the walls of viscera)
Hindgut and pelvic viscera (including the bladder, rectum, and erectile tissue)
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Parasympathetic Nervous System
Ciliary Pupillary sphincter Ciliary m.
ganglion
Submandibular
III
ganglion Submandibular gland V Pterygopalatine Sublingual gland Head ganglion VII Lacrimal gland Nasal and oral IX mucosal glands X Otic Parotid gland ganglion Viscera of the Terminal thorax and abdomen ganglia (foregut and midgut)
Midbrain Pons
Medulla C1
T1
Preganglionic Postganglionic
L1
Hindgut and pelvic viscera (including the bladder, erectile tissue, and rectum)
Terminal ganglia
Pelvic splanchnics
S2 S3 S4
Figure II-1-12. Overview Outflow Figure II-1-12. OverviewofofParasympathetic Parasympathetic Outflow
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N II
Thorax
2
Learning Objectives ❏❏ Solve problems concerning the chest wall ❏❏ Use knowledge of embryology of lower respiratory system ❏❏ Use knowledge of pleura and pleural cavity ❏❏ Interpret scenarios on respiratory histology ❏❏ Use knowledge of alveolar ducts, alveolar sacs, and the alveoli ❏❏ Answer questions about embryology of the heart ❏❏ Solve problems concerning the mediastinum ❏❏ Interpret scenarios on heart histology ❏❏ Solve problems concerning the diaphragm
CHEST WALL Breast The breast (mammary gland) is a subcutaneous glandular organ of the superficial pectoral region. It is a modified sweat gland, specialized in women for the production and secretion of milk. A variable amount of fat surrounds the glandular tissue and duct system and is responsible for the shape and size of the female breast. • Cooper ligaments are suspensory ligaments that attach the mammary
gland to the skin and run from the skin to the deep fascia.
• There is an extensive blood supply to the mammary tissues. The 2
prominent blood supplies are:
–– Internal thoracic artery (internal mammary), a branch of the subclavian artery which supplies medial aspect of the gland –– Lateral thoracic artery, a branch of the axillary artery which contributes to the blood supply to lateral part of the gland; lateral aspect of the chest wall, the lateral thoracic artery courses with the long thoracic nerve, superficial to serratus anterior muscle
Clinical Correlate The presence of a tumor within the breast can distort Cooper ligaments, which results in dimpling of the skin (orange-peel appearance).
Clinical Correlate During a radical mastectomy, the long thoracic nerve (serratus anterior muscle) may be lesioned during ligation of the lateral thoracic artery. A few weeks after surgery, the patient may present with a winged scapula and weakness in abduction of the arm above 90°. The thoracodorsal nerve supplying the latissimus dorsi muscle may also be damaged during mastectomy, resulting in weakness in extension and medial rotation of the arm.
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Anatomy
Gross Anatomy Immunology
• The lymphatic drainage of the breast is critical due to its important
role in metastasis of breast cancer. The lymphatic drainage of the breast follows 2 primary routes:
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
(Parasternal) internal thoracic nodes
Microbiology
–– Laterally, most of the lymphatic flow (75%) drains from the nipple and the superior, lateral, and inferior quadrants of the breast to the axillary nodes, initially to the pectoral group. –– From the medial quadrant, most lymph drains to the parasternal nodes, which accompany the internal thoracic vessels. It is also through this medial route that cancer can spread to the opposite breast.
Subclavian nodes Interpectoral nodes
Sagittal View of Breast
Axillary nodes Subcutaneous fat
Brachial nodes Subscapular nodes Pectoral nodes
Suspensory ligaments (Cooper) Gland lobules Lactiferous duct Lactiferous sinus
Figure II-2-1. Breast Figure II-2-1. Breast
EMBRYOLOGY OF LOWER RESPIRATORY SYSTEM During week 4 of development, the lower respiratory system (trachea, bronchi, and lungs) begins to develop as a single respiratory (laryngotracheal) diverticulum of endoderm from the ventral wall of the foregut. The respiratory epithelium develops from endoderm while the muscles, connective tissues, and cartilages develop from mesoderm. • The respiratory diverticulum enlarges distally to form the lung bud. • The diverticulum and lung bud then bifurcate into the 2 bronchial
buds, which then undergo a series of divisions to form the major part of the bronchial tree (main, secondary, and tertiary bronchi) by month 6.
• The tertiary segmental bronchi are related to the bronchopulmonary
segments of the lungs.
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Thorax
• To separate the initial communication with foregut, the
tracheoesophageal septum forms to separate the esophagus from the trachea.
• A critical time in lung development is the 25–28th weeks. By this time,
the Type I and II pneumocytes are present and gas exchange and surfactant production are possible. Premature fetuses born during this time can survive with intensive care. The amount of surfactant production is critical. Tracheoesophageal septum Foregut
Esophagus
Respiratory diverticulum Lung bud
Trachea
Esophagus
Bronchial buds Figure II-2-2. Development the Lower Respiratory Figure II-2-2. Development of theofLower Respiratory System System
A tracheoesophageal fistula is an abnormal communication between the trachea and esophagus caused by a malformation of the tracheoesophageal septum. It is generally associated with the following: • Esophageal atresia and polyhydramnios (increased volume of amni-
otic fluid)
• Regurgitation of milk • Gagging and cyanosis after feeding • Abdominal distention after crying • Reflux of gastric contents into lungs causing pneumonitis
The fistula is most commonly (90% of cases) located between the esophagus and distal third of the trachea.
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Immunology
Clinical Correlate Trachea
Pulmonary hypoplasia occurs when lung development is stunted. This Pharmacology condition has 2 congenitalBiochemistry causes: • Congenital diaphragmatic hernia (a herniation of abdominal contents into the thorax, which affects Physiology Medical Genetics development of the left lung) • Bilateral renal agenesis (this causes oligohydramnios, which increases pressure on fetal thorax and Potter’s Pathology Behavioral Science/Social Sciences sequence [one feature of Potter’s sequence is bilateral pulmonary hypoplasia]) Microbiology
Tracheoesophageal fistula
Esophagus
Bronchi
Gastric acids Figure II-2-3. Tracheoesophageal Fistula Fistula(Most (MostCommon Common Type) Figure II-2-3. Tracheoesophageal Type)
ADULT THORACIC CAVITY The thoracic cavity is kidney-shaped on cross section and is bounded anterolaterally by the bony thorax (sternum, ribs, and intercostal spaces) and posteriorly by the thoracic vertebrae. Superiorly, the thoracic cavity communicates through the thoracic inlet with the base of the neck. (Note, however, that clinically this region is usually called the thoracic outlet.) Inferiorly, the thoracic outlet is closed by the diaphragm which separates the thoracic from the abdominal cavity. The thoracic cavity is divided into 2 lateral compartments: the lungs and their covering of serous membranes, and a central compartment called the mediastinum which contains most of the viscera of the thorax.
Clinical Correlate Passage of instruments through the intercostal space is done in the lower part of the space to avoid the intercostal neurovascular structures (as during a thoracentesis). An intercostal nerve block is done in the upper portion of the intercostal space.
Intercostal Spaces • There are 11 intercostal spaces within the thoracic wall (Figure II-
2-4A). The spaces are filled in by 3 layers of intercostal muscles and their related fasciae and are bounded superiorly and inferiorly by the adjacent ribs.
• The costal groove is located along the inferior border of each rib
(upper aspect of the intercostal space) and provides protection for the intercostal nerve, artery, and vein which are located in the groove. The vein is most superior and the nerve is inferior in the groove (VAN).
• The intercostal arteries are contributed to anteriorly from branches of
the internal thoracic artery (branch of the subclavian artery) and posteriorly from branches of the thoracic aorta. Thus, the intercostal arteries can provide a potential collateral circulation between the subclavian artery and the thoracic aorta.
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First rib Clavicle
Sternum
Second rib Scapula
Rib 2 Rib 6 Rib 8
Posterior mediastinum
T12
Body of sternum
Anterior mediastinum
Esophagus Left lung Right lung Thoracic vertebra
Costochondral junction A. Thoracic Wall
Thorax
Middle mediastinum
Manubrium of sternum Sternal angle (of Louis)
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Descending aorta
B. (Transverse section) thoracic cavity Figure II-2-4. Thoracic Cavity
Figure II-2-4. Thoracic Cavity
PLEURA AND PLEURAL CAVITY
Clinical Correlate
Within the thoracic and abdominal cavities there are 3 serous mesodermalderived membranes which form a covering for the lungs (pleura), heart (pericardium), and abdominal viscera (peritoneum).
Respiratory distress syndrome is caused by a deficiency of surfactant (type II pneumocytes). This condition is associated with premature infants, infants of diabetic mothers, and prolonged intrauterine asphyxia. Thyroxine and cortisol treatment increase the production of surfactant.
Each of these double-layered membranes permits friction-reducing movements of the viscera against adjacent structures. The outer layer of the serous membranes is referred to as the parietal layer; and the inner layer which is applied directly to the surface of the organ is called the visceral layer. The 2 layers are continuous and there is a potential space (pleural cavity) between the parietal and visceral layers containing a thin layer of serous fluid.
Pleura The pleura is the serous membrane that invests the lungs in the lateral compartments of the thoracic cavity (Figure II-2-5). The external parietal pleura lines and attaches to the inner surfaces of the chest wall, diaphragm, and mediastinum. The innermost visceral layer reflects from the parietal layer at the hilum of the lungs and is firmly attached to and follows the contours of the lung. Visceral and parietal pleura are continuous at the root of the lung.
Surfactant deficiency may lead to hyaline membrane disease, whereby repeated gasping inhalations damage the alveolar lining. Hyaline membrane disease is characterized histologically by collapsed alveoli (atelectasis) and eosinophilic (pink) fluid covering the alveoli.
The parietal pleura is regionally named by its relationship to the thoracic wall and mediastinum (Figure II-2-5): • Costal parietal pleura is lateral and lines the inner surfaces of the ribs
and intercostal spaces
• Diaphragmatic parietal pleura lines the thoracic surface of the dia-
phragm
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• Mediastinal parietal pleura is medial and lines the mediastinum. The
mediastinal pleura reflects and becomes continuous with the visceral pleura at the hilum.
Pharmacology
Biochemistry
Clinical Correlate Inflammation of the parietal pleural sharp Physiologylayers (pleurisy) produces Medical Geneticspain upon respiration. Costal inflammation produces local dermatome pain of the chest wall via the intercostal nerves; whereby mediastinal irritation Pathology Behavioral Science/Social Sciences produces referred pain via the phrenic nerve to the shoulder dermatomes of C3–5.
• Cervical parietal pleura extends into the neck above the first rib
where it covers the apex of the lung.
The visceral pleura tightly invests the surface of the lungs, following all of the fissures and lobes of the lung.
Innervation of Pleura The parietal pleura has extensive somatic sensory innervation provided by nerves closely related to different aspects of the pleura. • The intercostal nerves supply the costal and peripheral portions of the
diaphragmatic pleura.
• The phrenic nerve supplies the central portion of the diaphragmatic
Microbiology
Clinical Correlate Open pneumothorax occurs when air enters the pleural cavity following a penetrating wound of the chest cavity. Air moves freely through the wound during inspiration and expiration. • During inspiration, air enters the chest wall and the mediastinum will shift toward other side and compress the opposite lung. • During expiration, air exits the wound and the mediastinum moves back toward the affected side. Tension pneumothorax occurs when a piece of tissue covers and forms a flap over the wound. • During inspiration, air enters the chest cavity, which results in a shift of the mediastinum toward the other side, compressing the opposite lung. • During expiration, the piece of tissue prevents the air from escaping the wound, which increases the pressure and the shift toward the opposite side is enhanced. This severely reduces the opposite lung function and venous return to the heart and can be life-threatening.
pleura and the mediastinal pleura.
The visceral pleura is supplied by visceral sensory nerves that course with the autonomic nerves. Cervical pleura
Hilum Mediastinal pleura
Lung
Costal pleura Parietal pleura Visceral pleura Pleural cavity
Diaphragm Costodiaphragmatic recess
8th rib Diaphragmatic pleura 10th rib
Figure II-2-5. Layers of the Pleura Figure II-2-5. Layers of the Pleura
The pleural cavity is the potential space between the parietal and visceral layers of the pleura. It is a closed space which contains a small amount of serous fluid that lubricates the opposing parietal and visceral layers. The introduction of air into the pleural cavity may cause the lung to collapse, resulting in a pneumothorax which causes shortness of breath and painful respiration. The lung collapses due to the loss of the negative pressure of the pleural cavity during a pneumothorax.
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Pleural Reflections Pleural reflections are the areas where the parietal pleura abruptly changes direction from one wall to the other, outlining the extent of the pleural cavities. • The sternal line of reflection is where the costal pleura is continuous
with the mediastinal pleura posterior to the sternum (from costal cartilages 2–4). The pleural margin then passes inferiorly to the level of the sixth costal cartilage.
• Around the chest wall, there are 2 rib interspaces separating the
inferior limit of parietal pleural reflections from the inferior border of the lungs and visceral pleura: between ribs 6–8 in the midclavicular line, ribs 8–10 in the midaxillary line, and ribs 10–12 at the vertebral column (paravertebral line), respectively.
Midclavicular line
Costomediastinal recesses
Midaxillary line
Paravertebral line
Rib 8
Rib 8 Rib 10
Rib 10 Costodiaphragmatic recesses
Costodiaphragmatic recesses
Anterior View
Posterior View
Costodiaphragmatic recesses Lateral View
Figure II-2-6. Pleural Reflections and Recesses
Figure II-2-6. Pleural Reflections and Recesses
Pleural Recesses
Note
Pleural recesses are potential spaces not occupied by lung tissue except during deep inspiration.
Visceral Pleura
Parietal Pleura
Midclavicular line
6th rib
8th rib
Midaxillary line
8th rib
10th rib
Paravertebral line
10th rib
12th rib
• Costodiaphragmatic recesses are spaces below the inferior borders of
the lungs where costal and diaphragmatic pleura are in contact.
• The costomediastinal recess is a space where the left costal and
mediastinal parietal pleura meet, leaving a space caused by the cardiac notch of the left lung. This space is occupied by the lingula of the left lung during inspiration.
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LUNGS The lungs and the pleural membranes are located in the lateral compartment of the thoracic cavity. The lungs are separated from each other in the midline by the mediastinum. The hilum of the lung is on the medial surface and serves for passage of structures in the root of the lung: the pulmonary vessels, primary bronchi, nerves, and lymphatics.
Surfaces and Regions Each lung has 3 surfaces: • The costal surface is smooth and convex and is related laterally to the
Pathology
Behavioral Science/Social Sciences
ribs and tissues of the chest wall.
• The mediastinal surface is concave and is related medially to the
Microbiology
middle mediastinum and the heart. The mediastinal surfaces contain the root of the lung and a deep cardiac impression, more pronounced on the left lung.
• The diaphragmatic surface (base) is concave and rests on the superior
surface of the diaphragm. It is more superior on the right owing to the presence of the liver.
Clinical Correlate A tumor at the apex of the lung (Pancoast tumor) may result in thoracic outlet syndrome.
Apex Hilum
Lung
Costal surface
Mediastinal surface
Diaphragm
8th rib
Costodiaphragmatic recess 10th rib
Diaphragmatic surface
Figure II-2-7. Surfaces of the Lung Figure II-2-7. Surfaces of the Lung
The apex (cupola) of the lung projects superiorly into the root of the neck above the level of the first rib and is crossed anteriorly by the subclavian artery and vein.
Lobes and Fissures The right lung is divided into 3 lobes (superior, middle, inferior) separated by 2 fissures, the horizontal and oblique fissures. The horizontal fissure separates the superior from the middle lobe and the oblique fissure separates the middle from the inferior lobe.
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The left lung is divided into 2 lobes (superior, inferior) separated by an oblique fissure. The lingula of the upper lobe of the left lung corresponds to the middle lobe of the right lung. • The oblique fissure of both lungs projects anteriorly at approximately
the 5th intercostal space in the midclavicular line, ending medially deep to the 6th costal cartilage.
• The horizontal fissure runs horizontally from the oblique fissure in
the right 5th intercostal space to the right 4th costal cartilage.
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Clinical Correlate The superior lobe of the right lung projects anteriorly on the chest wall above the 4th rib and the middle lobe projects anteriorly below the 4th rib. A small portion of the inferior lobe of both lungs projects below the 6th rib anteriorly but primarily projects to the posterior chest wall.
Clinical Correlate • T o listen to breath sounds of the superior lobes of the right and left lungs, the stethoscope is placed on the superior area of the anterior chest wall (above the 4th rib for the right lung).
Horizontal fissure
Trachea
Right lung
Left lung
Superior lobe
Superior lobe
Middle lobe
Oblique fissure Inferior lobe
Oblique fissure Inferior lobe
Diaphragm
Mediastinum
Figure II-2-8. Lobes and Fissures Fissures ofofLungs Figure II-2-8. Lobes and Lungs
Lymphatic System
• F or breath sounds from the middle lobe of the right lung, the stethoscope is placed on the anterior chest wall inferior to the 4th rib and medially toward the sternum. • F or the inferior lobes of both lungs, breath sounds are primarily heard on the posterior chest wall.
Clinical Correlate Aspiration of a foreign body will more often enter the right primary bronchus, which is shorter, wider, and more vertical than the left primary bronchus. When the individual is vertical, the foreign body usually falls into the posterior basal segment of the right inferior lobe.
The lymphatic system consists of an extensive network of lymph capillaries, vessels, and nodes that drain extracellular fluid from most of the body tissues and organs. The lymph flow will return to the blood venous system by 2 major lymphatic vessels, the right lymphatic duct and the thoracic duct on the left (Figure II-2-10A). These 2 vessels drain into the junction of the internal jugular and the subclavian veins on their respective sides.
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• The thoracic duct carries all lymphatic drainage from the body below
the diaphragm and on the left side of the trunk and head above the diaphragm (Figure II-2-10B).
Pharmacology
Biochemistry
• The right lymphatic duct drains lymph flow from the right head and
neck and the right side of the trunk above the diaphragm (Figure II2-10B).
Physiology
Pathology
Medical Genetics
Behavioral Science/Social Sciences
Lymphatic Drainage The lymphatic drainage of the lungs is extensive and drains by way of superficial and deep lymphatic plexuses. The superficial plexus is immediately deep to the visceral pleura. The deep plexus begins deeply in the lungs and drains through pulmonary nodes which follow the bronchial tree toward the hilum. The major nodes involved in the lymphatic drainage of these 2 plexuses are:
Microbiology
• Bronchopulmonary (hilar) nodes are located at the hilum of the
lungs. They receive lymph drainage from both superficial and deep lymphatic plexuses, and they drain into the tracheobronchial nodes.
• Tracheobronchial nodes are located at the bifurcation of the trachea,
and they drain into the right and left bronchomediastinal nodes and trunk.
• Bronchomediastinal nodes and trunk are located on the right and
left sides of the trachea, and they drain superiorly into either the right lymphatic duct or the thoracic duct on the left. Right Lung
Clinical Correlate The lymphatic drainage from the lower lobe of the left lung also drains across the midline into the right bronchomediastinal lymphatic trunk and nodes, then continues along the right pathway to the right lymphatic duct. This is important to consider with metastasis of lung cancer.
To right lymphatic duct
Trachea
Bronchomediastinal nodes
Left Lung To thoracic duct
Tracheobronchial nodes
Tracheobronchial nodes
Bronchopulmonary nodes
Bronchopulmonary nodes Diaphragm
Figure II-2-9. Lymphatics Lungs Figure II-2-9. Lymphaticsofofthe the Lungs
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From head and neck Right lymphatic duct
Thoracic duct
From upper limb & neck
Right bronchomediastinal trunk
Left internal jugular vein
Area draining to right lymphatic duct
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Area draining to thoracic duct
From upper limb and neck
Left subclavian vein Left bronchomediastinal trunk
A. Right lymphatic and thoracic ducts
B. General lymphatic drainage
Figure II-2-10. Drainage Figure II-2-10. Lymphatic
RESPIRATORY HISTOLOGY The lung is an organ that functions in the intake of oxygen and exhaling of CO2. Approximately 14 times each minute, we take in about 500 mL of air per breath. Inspired air will be spread over 120 square meters of the surface area of the lungs. The air–blood barrier has to be thin enough for air to pass across but tough enough to keep the blood cells inside their capillaries. Because lungs are opened to the outside world, they are susceptible to environmental insults in the form of pollution and infectious bacteria. The lungs receive the entire cardiac output and are positioned to modify various blood components. The pulmonary endothelium plays an active role in the metabolic transformation of lipoproteins and prostaglandins. The enzyme that converts angiotensin I to angiotensin II is produced by the lung endothelial cells.
Clinical Correlate Any disease that affects capillaries also affects the extensive capillary bed of the lungs. Bacteria which colonize the lungs may damage the barriers between the alveoli and the capillaries, gaining access to the bloodstream (a common complication of bacterial pneumonia). • With allergies, smooth-muscle constriction reduces the diameter of air tubes and results in reduced air intake. • Lung cancers commonly develop from bronchi (smoking, asbestos, and excessive radiation are the main causes). • Mesothelioma is a malignant tumor of the pleura (causative agent: asbestos dust).
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Paranasal sinuses Pharmacology
Biochemistry
Frontal sinus Physiology
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Olfactory area Pathology
Sphenoid sinus Pharyngeal tonsil
Behavioral Science/Social Sciences
Nasal conchae
Nasopharynx
Microbiology
Oropharynx
Larynx Laryngopharynx
Trachea
Figure II-2-11. RespiratoryPathways Pathways Figure II-2-11. Respiratory Table II-2-1. Histologic Features of Trachea, Bronchi, and Bronchioles Trachea
Bronchi
Bronchioles
Epithelia
Pseudostratified ciliated columnar (PCC) cells, goblet cells
PCC to simple columnar cells
Ciliated, some goblet cells, Clara cells in terminal bronchioles
Cartilage
16–20 C-shaped cartilaginous rings
Irregular plates
None
Glands
Seromucous glands
Fewer seromucous glands
None
Smooth muscle
Between open ends of C-shaped cartilage
Prominent
Highest proportion of smooth muscle in the bronchial tree
Elastic fibers
Present
Abundant
Abundant
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TRACHEA The trachea is a hollow tube, about 10 cm in length (and about 2 cm in diameter), extending from the larynx to its bifurcation at the carina to form a primary bronchus for each lung. The most striking structures of the trachea are the C-shaped hyaline cartilage rings. In the human there are 16–20 of them distributed along the length of the trachea. The rings overlap in the anterior part of the trachea. The free posterior ends of the C-shaped cartilages are interconnected by smooth-muscle cells.
Copyright McGraw-Hill Used permission. Copyright McGraw-HillCompanies. Companies. Usedwith with permission.
Figure II-2-12. Trachea with a hyaline cartilage ring (arrow) Figure II-2-12. Trachea with a hyaline cartilage ring (arrow) and and pseudostratified columnar epithelium pseudostratified columnar epithelium
The trachea is composed of concentric rings of mucosa, submucosa, an incomplete muscularis, and an complete adventitia. • The mucosa has 3 components: a pseudostratified epithelium, an
underlying vascularized loose connective tissue (lamina propria) that contains immune cells, and a thin layer of smooth-muscle cells (muscularis mucosa).
• The submucosa is a vascular service area containing large blood ves-
sels. Collagen fibers, lymphatic vessels and nerves are also present in this layer.
• The outside covering of the trachea, the adventitia, is composed of
several layers of loose connective tissue.
The epithelial lining of the trachea and bronchi is pseudostratified columnar in which all cells lie on the same basal membrane but only some reach the luminal surface. The only other place in the body with this epithelium is the male reproductive tract.
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Clinical Correlate If mucosal clearance is ineffective, or the mechanism overwhelmed, Pharmacology Biochemistryor infection (pathogenic bacteria) pneumoconiosis (dust-related disease) may follow. In cystic fibrosis, the secreted mucous Medical Genetics is thick or viscous and the cilia have a difficult time moving it toward the pharynx. Patients with this disease have frequent infections of the Pathologyrespiratory system. Behavioral Science/Social Sciences
Physiology
Microbiology
Copyright McGraw-Hill Companies. Used with permission. Copyright McGraw-Hill Companies. Used with permission.
Figure II-2-13. Pseudostratified columnar epithelium with goblet Figure II-2-13. Pseudostratified Columnar Epithelium with Goblet Cells cells (arrowhead) surrounded by ciliated cells (arrow) (arrowhead) Surrounded by Ciliated Cells (arrow)
Clinical Correlate Patients lacking dynein have immotile cilia or Kartagener syndrome. With immotile cilia, patients are subject to many respiratory problems because their cilia cannot move this mucous layer with its trapped bacteria. Males also possess immotile sperm.
Tracheal Epithelial Cell Types Columnar cells extend from the basal membrane to the luminal surface. These cells contain 200–300 apical cilia per cell that are intermingled with microvilli. The cilia are motile and beat to help move the secreted mucous layer over the lining of the trachea and out of the respiratory system. Goblet cells secrete a polysaccharide mucous material into the lumen of trachea. Mucous production is supplemented by secretions of the submucosal mixed glands. The mucous layer of the respiratory system traps particulate substances (dust, bacteria, and viruses) and absorbs noxious water-soluble gases such as ozone and sulfur dioxide. The mucous sticky layer is moved by the beating cilia toward the pharynx where it is swallowed. This movement is known as the mucociliary escalator system. Most material (dust and bacteria) is trapped in the mucous layer, and is removed and digested. Pulmonary neuroendocrine (PNE) cells are comparable to the endocrine cells in the gut. These epithelial neuroendocrine cells have been given various names: • APUD cells (Amino-Precursor-Uptake-Decarboxylase), DNES cells
(Diffuse Neuro Endocrine System) and K (Kulchitsky) cells. These cells occur in clusters and are often located at airway branch points.
• Brush cells may represent goblet cells that have secreted their products
or intermediate stages in the formation of goblet or the tall ciliated cells. They have short microvilli on their apical surfaces. Some of these cells have synapses with intraepithelial nerves, suggesting that these cells may be sensory receptors.
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Basal cells are stem cells for the ciliated and goblet cells. The stem cells lie on the basal membrane but do not extend to the lumen of the trachea. These cells, along with the epithelial neuroendocrine cells, are responsible for the pseudostratified appearance of the trachea.
BRONCHI The bronchial tree forms a branching airway from the trachea to the bronchioles. When the primary bronchi enter the lung, they give rise to 5 secondary or lobar bronchi—3 for the right lung and 2 for the left. The 5 lobes are further subdivided into 10 tertiary or segmental bronchi in each lung, which form bronchopulmonary segments.
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Clinical Correlate The columnar and goblet cells are sensitive to irritation. The ciliated cells become taller, and there is an increase in the number of goblet cells and submucosal glands. Intensive irritation from smoking leads to a squamous metaplasia where the ciliated epithelium becomes a squamous epithelium. This process is reversible.
Clinical Correlate Bronchial metastatic tumors arise from Kulchitsky cells.
Copyright McGraw-Hill McGraw-Hill Companies. permission. Copyright Companies.Used Usedwith with permission.
Figure II-2-14. Bronchus with a plate of cartilage (arrow) Figure II-2-14. Bronchus with a Plate of Cartilage (arrow)
The epithelial lining of the bronchi is also pseudostratified. It consists of c iliated columnar cells, basal cells, mucous cells, brush cells and neuroendocrine (APUD, DNES, or K) cells. There are also seromucous glands in the submucosa that empty onto the epithelial surface via ducts. The walls of bronchi c ontain irregular plates of cartilage and circular smooth-muscle fascicles bound together by elastic fibers. The number of goblet cells and submucosa glands d ecreases from the trachea to the small bronchi.
BRONCHIOLES The wall of a bronchiole does not contain cartilage or glands. The smooth-muscle fascicles are bound together by elastic fibers. The epithelium is still ciliated, but is a simple cuboidal or columnar epithelium rather than pseudostratified. The epithelial lining of the airway is composed of ciliated cells (goblet and basal cells are absent in the terminal bronchioles) and an additional type called the Clara cell.
Clinical Correlate Cystic fibrosis can result in abnormally thick mucous, in part due to defective chloride transport by Clara cells.
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Clara cells (also called bronchiolar secretory cells) are nonciliated and secrete a serous solution similar to surfactant. They aid in the detoxification of airborne toxins, and serve as a stem cell for the ciliated cells and for themselves. The number of Clara cells increases in response to increased levels of pollutants like cigarette smoke. Clara cells are most abundant in the terminal bronchioles, where they make up about 80% of the epithelial cell lining; they are also involved with chloride ion transport into the lumens of the terminal bronchioles.
Clinical Correlate Chronic obstructive pulmonary disease Behavioral Science/Social Sciences (COPD) affects the bronchioles and includes emphysema and asthma.
Pathology
Microbiology
• Emphysema is caused by a loss of elastic fibers and results in chronic airflow obstruction. • Asthma is a chronic process characterized by a reversible narrowing of airways. • Asthma is reversible; emphysema is not. Copyright McGraw-Hill Used with permission. Copyright McGraw-HillCompanies. Companies. Used with permission.
Figure II-2-15. Terminal bronchiole lumen (asterisk) with epithelium Figure II-2-15. Terminal lumen with epithelium containcontainingbronchiole ciliated cells and(asterisk) Clara cells (arrows) ing ciliated cells and Clara cells (arrows)
The terminal bronchiole is the last conducting bronchiole. This bronchiole is followed by respiratory bronchioles which are periodically interrupted by alveoli in their walls. The goblet cells are absent from the epithelial lining of the respiratory bronchioles; however, this epithelium is still lined with a sparse ciliated cuboidal epithelium which prevents the movement of mucous into the alveoli. After the last respiratory bronchiole, the wall of the airway disappears and air enters the alveoli.
ALVEOLAR DUCTS, ALVEOLAR SACS, AND THE ALVEOLI The alveolar ducts and sacs have little or no walls and consist almost entirely of alveoli. The alveoli constitute 80–85% of the volume of the normal lung. There are 300 million alveoli in the lungs, each ~200 microns in diameter. The cuboidal epithelium of the respiratory bronchioles and the alveolar ducts are continuous with the squamous cells lining the alveoli.
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Alveolar macrophage
Type I cell Alveolus
Alveolar macrophage
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Connective tissue Surfactant Type II cells
Capillary
Red blood cell
Alveolus
Endothelial cell
Type I cell Basal lamina Endothelial cell
Capillary Figure II-2-16. Alveolus andand Blood–Air Barrier Figure II-2-16. Alveolus blood–air barrier
The type I pneumocyte is the major cell lining cell of the alveolar surfaces (also called small alveolar cell or alveolar type I cell). • Represent only 40% of the alveolar lining cells, but are spread so thinly
they cover 90–95% of the surface
• Primarily involved in gas exchange • Post-mitotic
The type II pneumocyte is the other major alveolar cell (also called great alveolar cell [because of its size], granular pneumocyte, septal cell, corner cell, niche cell, or alveolar type II). • Constitute 60% of the cell lining the alveoli, but form only 5–10% of
the surface
• Produce and secrete surfactant • Large, round cells with “myelin figures” in their apical cytoplasm which
represent the remnants of surfactant after histological processing
• Serve as stem cells for themselves and the type I cell
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Figure II-2-17. Alveoli with type I pneumocytes (arrowhead), type II Figure II-2-17. Alveoli with Type I Pneumocytes (arrowhead), Type II Pneumopneumocytes (arrow), and alveolar macrophage (curved arrow) cytes (arrow), and Alveolar Macrophage (curved in the alveolar wall.arrow) in the Alveolar Wall
Surfactant Clinical Correlate Corticosteroids induce the fetal synthesis of surfactant. High insulin levels in diabetic mothers antagonize the effects of corticosteroids. Infants of diabetic mothers have a higher incidence of respiratory distress syndrome.
Surfactant is essential to maintain the normal respiratory mechanics of the alveoli. Production of surfactant in the fetus is essential for the survival of the neonate as it takes its first breath. Surfactant is composed of a mixture of phospholipids and surfactant proteins whose function is to aid in the spreading of the surfactant at the alveolar air–water interface. The phospholipids act as a detergent which lowers the surface tension of the alveoli and prevents alveolar collapse during expiration. Most surfactant is recycled back to Type II cells for reutilization; some of it undergoes phagocytosis by macrophages.
Alveolar Wall In the alveolar wall under the alveolar epithelium is a rich network of capillaries arising from pulmonary arteries. The alveolar wall contains a variety of cells and extracellular fibers. The cells include fibroblasts, macrophages, myofibroblasts, smooth-muscle cells, and occasional mast cells. Type I and II collagens, as well as elastic fibers, are in the septa. Type I collagen is present primarily in the walls of the bronchi and bronchioles. Twenty percent of the mass of the lung consists of collagen and elastic fibers. Elastic fibers are responsible for the stretching and recoiling activities of the alveoli during respiration. These microscopic elements are responsible for the recoil of the lungs during expiration. Gas exchange occurs between capillary blood and alveolar air across the blood– gas barrier. This barrier consists of surfactant, the squamous Type I pneumocytes, a shared basal lamina, and capillary endothelium. The distance between the lumen of the capillary and the lumen of the alveolus can be as thin as 0.1 microns. There are openings in the wall of most alveoli that form the pores of Kohn. These pores are thought to be important in collateral ventilation. The diameter of these alveolar pores can be as large as 10–15 microns.
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Alveolar Macrophages
Clinical Correlate
The alveolar macrophages are derived from monocytes that exit the blood vessels in the lungs. The resident alveolar macrophages can undergo limited mitoses to form additional macrophages. These cells can reside in the interalveolar septa as well as in the alveoli. Alveolar macrophages that patrol the alveolar surfaces may pass through the pores of Kohn.
Alveolar macrophages have several other names: dust cells because they have phagocytosed dust or cigarette particles, and heart failure cells because they have phagocytosed blood cells that have escaped into the alveolar space during congestive heart failure.
There are ~1–3 macrophages per alveolus. Alveolar macrophages vary in size, 15–40 microns in diameter. These macrophages represent the last defense mechanism of the lung. Macrophages can pass out of the alveoli to the bronchioles and enter the lymphatics or become trapped in the moving mucous layer and propelled toward the pharynx to be swallowed and digested.
EMBRYOLOGY OF THE HEART Formation of Heart Tube The heart begins to develop from splanchnic mesoderm in the latter half of week 3 within the cardiogenic area of the cranial end of the embryo. Neural crest cells migrate into the developing heart and play an important role in cardiac development. The cardiogenic cells condense to form a pair of primordial heart tubes which will fuse into a single heart tube during body folding. • The heart tube undergoes dextral looping (bends to the right) and
rotation.
• The upper truncus arteriosus (ventricular) end of the tube grows more
rapidly and folds downward and ventrally and to the right.
• The atria and sinus venosus lower part of the tube fold upward and
dorsally and to the left. These foldings begin to place the chambers of the heart in their postnatal anatomic positions.
The primitive heart tube forms 4 dilatations and a cranial outflow tract, the truncus arteriosus. The fates of these are shown below.
Arterial (outflow)
Blood flow
Truncus arteriosus Bulbus cordis
Ventral Dorsal
Primitive ventricle
Atria
Primitive atrium
Sinus venosus Venous (Inflow)
Ventricles
Figure II-2-18. Development of the Heart Tube Figure II-2-18. Development of the Heart Tube
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Table II-2-2. Adult Structures Derived From the Dilatations of the Primitive Heart Embryonic Dilatation
Adult Structure
Truncus arteriosus (neural crest)
Aorta; Pulmonary trunk; Semilunar values
Bulbus cordis
Smooth part of right ventricle (conus arteriosus)
Biochemistry
Smooth part of left ventricle (aortic vestibule) Physiology
Primitive ventricle Medical Genetics
Trabeculated part of right ventricle Trabeculated part of left ventricle
Primitive atrium* Pathology
Microbiology
Trabeculated part of right atrium (pectinate muscles)
Behavioral Science/Social Sciences
Trabeculated part of left atrium (pectinate muscles)
Sinus venosus (the only dilation that does not become subdivided by a septum)
Right—Smooth part of right atrium (sinus venarum) Left—Coronary sinus and oblique vein of left atrium
*The smooth-walled part of the left atrium is formed by incorporation of parts of the pulmonary veins into its wall. The smooth-walled part of the right atrium is formed by the incorporation of the right sinus venosus.
Fetal Circulation There are 3 major venous systems that flow into the sinus venosus end of the heart tube: • Vitelline (omphalomesenteric) veins drain deoxygenated blood from the yolk stalk; they will coalesce and form the veins of the liver (sinusoids, hepatic portal vein, hepatic vein) and part of the inferior vena cava. • Umbilical vein carries oxygenated blood from the placenta. • Cardinal veins carry deoxygenated blood from the body of the
embryo; they will coalesce and contribute to some of the major veins of the body (brachiocephalic, superior vena cava, inferior vena cava, azygos, renal).
During fetal circulation, oxygenated blood flood from the placenta to the fetus passes through the umbilical vein. Three vascular shunts develop in the fetal circulation to bypass blood flow around the liver and lungs: • The ductus venosus allows oxygenated blood in the umbilical vein to bypass the sinusoids of the liver into the inferior vena cava and to the right atrium. From the right atrium, oxygenated blood flows mostly through the foramen ovale into the left atrium then left ventricle and into the systemic circulation. • The foramen ovale develops during atrial septation to allow oxygen-
ated blood to bypass the pulmonary circulation. Note that this is a right-to-left shunting of blood during fetal life.
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• During fetal circulation, the superior vena cava drains deoxygenated
blood from the upper limbs and head into the right atrium. Most of this blood flow is directed into the right ventricle and into the pulmonary trunk. The ductus arteriosus opens into the underside of the aorta just distal to the origin of the left subclavian artery and shunts this deoxygenated blood from the pulmonary trunk to the aorta to bypass the pulmonary circulation.
The shunting of blood through the foramen ovale and through the ductus arteriosus (right to left) during fetal life occurs because of a right-to-left pressure gradient. 65%
Ductus arteriosus becomes ligamentum 3 arteriosum
Superior vena cava 40%
Left atrium
50%
R → L Postnatal
Pulmonary artery Left ventricle
Right atrium
Inferior vena cava
Fetal
L → R
Foramen ovale becomes 2 fossa ovalis
Right ventricle
Pressure Gradients
Aorta
67%
60% 26%
26%
Liver From placenta
80%
Ductus venosus 1 becomes ligamentum venosum Portal vein Umbilical vein becomes ligamentum teres of liver
To placenta
Right and left umbilical arteries become medial umbilical ligament Figure II-2-19. FetalCirculation Circulationand and Shunts Figure II-2-19. Fetal Shunts
Following birth, these 3 shunts, labelled 1, 2, and 3, will close because of changes in the pressure gradients and in oxygen tensions. The umbilical vein closes and reduces blood flow into the right atrium. The ductus venosus also closes. Lung expansion reduces pulmonary resistance and results in increased flow to the lungs and increased venous return to the left atrium.
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• Closure of the foramen ovale occurs as a result of the increase in left
atrial pressure and reduction in right atrial pressure.
• Closure of the ductus venosus and ductus arteriosus occurs over the Pharmacology
Biochemistry
next several hours as a result of the contraction of smooth muscles in its wall and increased oxygen tension.
• The release of bradykinin and the immediate drop of prostaglandin E
at birth also facilitate the closure of the ductus arteriosus.
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
The changes which occur between pre- and postnatal circulation are summarized below.
Table II-2-3. Adult Vestiges Derived from the Fetal Circulatory System Changes After Birth
Remnant in Adult
Closure of right and left umbilical arteries
Medial umbilical ligaments
Closure of the umbilical vein
Ligamentum teres of liver
Closure of ductus venosus
Ligamentum venosum
Closure of foramen ovale
Fossa ovalis
Closure of ductus arteriosus
Ligamentum arteriosum
SEPTATION OF THE HEART TUBE Except for the sinus venosus of the embryonic heart tube that initially develops into right and left horns, the ventricular, atrial, and truncus parts of the heart tube, which are originally a common chamber, will undergo septation into a right and left heart structure. The septation of the atria and ventricles occurs simultaneously beginning in week 4 and is mostly finished in week 8. Most of the common congenital cardiac anomalies result from defects in the formation of these septa.
Atrial Septation During fetal life, blood is shunted from the right to the left atrium via the foramen ovale (FO). Note that during fetal circulation, right atrial pressure is higher than left due to the large bolus of blood directed into the right atrium from the placenta and to high pulmonary resistance. The FO has to remain open and functional during the entire fetal life to shunt oxygenated blood from the right atrium into the left atrium.
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R
+
l
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Septum primum (SP)
L
–
Foramen primum (FP) Endocardial cushions (EC) (neural crest)
Septum secundum (SS) (rigid) +
Foramen secundum (FS)
–
SP Septum primum (SP) (flexible) EC
SS +
–
EC
FO
Foramen ovale (FO)
SP FS
–
+ Membranous part Interventricular septum Muscular part
Figure II-2-20. Formation AtrialSeptum Septum Figure II-2-20. Formation ofof Atrial
Beginning week 4, the common atrium is divided into right and left atria by a series of events involving 2 septa and 2 foramina. • The flexible septum primum (SP) grows inferiorly from the roof of the
common atrium toward the endocardial cushions, a centrally located mass of mesoderm in the developing heart. Initially, the SP does not reach and fuse with the endocardial cushions. The endocardial cushions form the right and left atrioventricular canals and contribute to the formation of the atrioventricular valves, membranous part of the interventricular septum, and aorticopulmonary septum. Neural crest cells migrate into the cushions and facilitate their development.
• The foramen primum (FP) is located between the inferior edge of the
SP and the endocardial cushion; it is obliterated when the SP later fuses with the endocardial cushions.
• The foramen secundum (FS) forms within the upper part of the SP
just before the FP closes to maintain the right-to-left shunting of oxygenated blood that entered the right atrium via the inferior vena cava.
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• The rigid septum secundum (SS) forms to the right of the SP from the
roof of the atrium, descends, and partially covers the FS. It does not fuse with the endocardial cushions.
Pharmacology
Biochemistry
• The foramen ovale (FO) is the opening between SP and SS.
Closure of the FO normally occurs immediately after birth; it is caused by increased left atrial pressure resulting from changes in pulmonary circulation and decreased right atrial pressure due to the closure of the umbilical vein. Physiology
Pathology
Medical Genetics
Aorta Superior vena cava
Behavioral Science/Social Sciences
Microbiology
Sinus venarum
Septum secundum Limbus
Fossa ovalis (septum primum) Coronary sinus Inferior vena cava
Tricuspid valve
Pectinate muscles
Figure II-2-21. Postnatal Atrial AtrialSeptum Septum Figure II-2-21. Postnatal
Atrial Septal Defects Atrial septal defect (ASD) is one of several congenital heart defects. It is more common in female births than in male. Postnatally, ASDs result in left-to-right shunting and are non-cyanotic conditions. Two clinically important ASDs are the secundum and primum types. • Secundum-type ASD is the most common ASD. It is caused by either
an excessive resorption of the SP or an underdevelopment and reduced size of the SS or both. This ASD results in variable openings between the right and left atria in the central part of the atrial septum above the limbus. If the ASD is small, clinical symptoms may be delayed as late as age 30.
Note Postnatal Shunts Right-to-left shunts are cyanotic conditions. Left-to-right shunts are non-cyanotic conditions.
• Primum type ASD is less common than secundum ASD and results
from a failure of the septum premium to fuse with the endocardial cushions, and may be combined with defects of the endocardial cushions. Primum ASDs occur in the lower aspect of the atrial wall, usually with a normal formed fossa ovalis. If the endocardial cushion is involved, a primum ASD can also be associated with a defect of the membranous interventricular septum and the atrioventricular valves.
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Aorta Superior vena cava
Tricuspid valve
Secundum ASD
Clinical Correlate
Fossa ovalis Primum ASD Inferior vena cava Figure II-2-22. Secundum and andPrimum PrimumAtrial AtrialSeptal Septal Defect Figure II-2-22. Secundum Defect
Ventricular Septation The development of the interventricular (IV) septum begins in week 4 and is usually completed by the end of week 7. Unlike atrial septation, the IV septum will develop and close completely by week 8 without any shunting between the ventricles. The adult IV septum consists of 2 parts: a large, muscular component forming most of the septum and a thin, membranous part forming a small component at the superior aspect of the septum. • The muscular IV septum develops in the floor of the ventricle,
ascends, and partially separates the right and left ventricles, leaving the IV foramen.
• The membranous IV septum closes the IV foramen. It forms by the
fusion of the right conotruncal ridge, the left conotruncal ridge, endocardial cushion (neural crest cells are associated with the endocardial cushion and conotruncal ridges).
Ventricular septal defect (VSD) is the most common of the congenital heart defects, and more common in males than in females. The most common form is a membranous VSD, associated with the failure of neural crest cells to migrate into the endocardial cushions. A membranous VSD is caused by the failure of the membranous interventricular (IV) septum to develop, and it results in left-to-right shunting of blood through the IV foramen. Patients with left-to-right shunting complain of excessive fatigue upon exertion. Left-to-right shunting of blood is noncyanotic but causes increased blood flow and pressure to the lungs (pulmonary hypertension). Pulmonary hypertension causes marked proliferation of the tunica intima and media of pulmonary muscular arteries and arterioles. Ultimately, the pulmonary resistance becomes higher than systemic resistance and causes right-to-left shunting of blood and late cyanosis. At this stage, the condition is called Eisenmenger complex.
Foramen ovale
Interventricular foramen A
–
+
Endocardial cushion Muscular septum
–
+
Membranous part Muscular part
Interventricular septum
B Figure II-2-23. Interventricular Septum
Figure II-2-23. Interventricular Septum
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Patent Ductus Arteriosus A patent ductus arteriosus (PDA) occurs when the ductus arteriosus (a connection between the pulmonary trunk and aorta) fails to close after birth. PDA is common in premature infants and in cases of maternal rubella infection. • Postnatally, a PDA causes a left-to-right shunt (from aorta to pul-
monary trunk) and is non-cyanotic. The newborn presents with a machine-like murmur.
Physiology
Pathology
Medical Genetics
Behavioral Science/Social Sciences
• Normally, the ductus arteriosus closes within a few hours after birth
via smooth-muscle contraction to form the ligamentum arteriosum. Prostaglandin E (PGE) and low oxygen tension sustain patency of the ductus arteriosus in the fetal period.
• PGE is used to keep the PDA open in certain heart defects (transposi-
tion of great vessels).
• PGE inhibitor (e.g., indomethacin), acetylcholine, histamine, and catMicrobiology
echolamines promote closure of the ductus arteriosus in a premature birth.
Ligamentum arteriosum Patent ductus arteriosus Left pulmonary artery A. Normal obliterated ductus arteriosus
B. Patent ductus arteriosus
Figure II-2-24. Ductus Arteriosus
Figure II-2-24. Ductus Arteriosus
Septation of the Truncus Arteriosus The septation of the truncus arteriosus occurs during week 8. Neural crest cells migrate into the conotruncal and bulbar ridges of the truncus arteriosus, which grow in a spiral fashion and fuse to form the aorticopulmonary (AP) septum. The AP septum divides the truncus arteriosus into the aorta and pulmonary trunk.
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Aorticopulmonary septum
l
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Aorta
Pulmonary Trunk
RV
LV
Figure II-2-25. Formation of the Aorticopulmonary Septum Figure II-2-25. Formation of the Aorticopulmonary Septum
There are 3 classic cyanotic congenital heart abnormalities that occur with defects in the development of the aorticopulmonary septum. They are related to the failure of neural crest cells to migrate into the truncus arteriosus: • Tetralogy of Fallot (most common) occurs when the AP septum fails to
align properly and shifts anteriorly to the right. This causes right-to-left shunting of blood with resultant cyanosis that is usually present sometime after birth. Imaging typically shows a boot-shaped heart due to the enlarged right ventricle. There are 4 major defects in tetralogy of Fallot: –– Pulmonary stenosis (most important) –– Membranous interventricular septal defect –– Right ventricular hypertrophy (develops secondarily) –– Overriding aorta (receives blood from both ventricles) Aorta
1
1. Pulmonary stenosis 2. Ventricular septal defect
Pulmonary trunk
3. Hypertrophied right ventricle
RA
LA
4. Overriding aorta
2 4
RV
LV
3 Figure II-2-26. Tetralogy of Fallot Figure II-2-26. Tetralogy of Fallot
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• Transposition of the great vessels occurs when the AP septum fails
to develop in a spiral fashion and results in the aorta arising from the right ventricle and the pulmonary trunk arising from the left ventricle. This causes right-to-left shunting of blood with resultant cyanosis.
Biochemistry
–– Transposition is the most common cause of severe cyanosis that persists immediately at birth. Transposition results in producing 2 closed circulation loops. Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
–– Infants born alive with this defect usually have other defects (PDA, VSD, ASD) that allow mixing of oxygenated and deoxygenated blood to sustain life. ASD
1. Aorta arises from right ventricle Microbiology
Aorta
2. Pulmonary trunk arises from left ventricle
RA
3. Usually associated with a VSD, ASD, or patent ductus arteriosus
Pulmonary trunk
LA
VSD RV 1
LV 2 3
Figure II-2-27. Transposition of of the the Great GreatVessels Vessels Figure II-2-27. Transposition • Persistent truncus arteriosus occurs when there is only partial develop-
ment of the AP septum. This results in a condition where only one large vessel leaves the heart that receives blood from both the right and left ventricles. This causes right-to-left shunting of blood with resultant cyanosis. This defect is always accompanied by a membranous VSD.
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Note Non-cyanotic congenital (left-to-right) heart defects at birth: • Atrial septal defect
Pulmonary artery
• Ventricular septal defects • Patent ductus arteriosus
Truncus arteriosus
Cyanotic congenital (right-to-left) heart defects at birth: • Transposition of great vessels • Tetralogy of Fallot
Interventricular septal defect
• Persistent truncus arteriosus
Figure II-2-28. Persistent Truncus Arteriosus Figure II-2-28. Persistent Truncus Arteriosus
MEDIASTINUM The mediastinum is the central, midline compartment of the thoracic cavity. It is bounded anteriorly by the sternum, posteriorly by the 12 thoracic vertebrae, and laterally by the pleural cavities. • Superiorly, the mediastinum is continuous with the neck through the
thoracic inlet; and inferiorly, is closed by the diaphragm. The mediastinum contains most of the viscera of the thoracic cavities except from the lungs (and pleura) and the sympathetic trunk.
• The sympathetic trunks are primarily located paravertebrally, just out-
side the posterior mediastinum. However, the greater, lesser, and least thoracic splanchnic nerves, which convey preganglionic sympathetic fibers to the collateral (prevertebral) ganglia below the diaphragm, enter the posterior mediastinum after leaving the sympathetic trunks.
• The mediastinum is divided into superior and inferior mediastina by a
plane passing from the sternal angle (of Louis) anteriorly to the intervertebral disc between T4 and T5 posteriorly. The sternal angle and plane are important clinical landmarks. The inferior mediastinum is classically subdivided into anterior, middle, and posterior mediastina.
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Thoracic inlet T1 Pharmacology
Physiology
Pathology
Biochemistry
Medical Genetics
Sternal angle (second rib) Anterior mediastinum (thymus)
First rib
T4
Middle mediastinum T9
Behavioral Science/Social Sciences
Superior mediastinum Inferior mediastinum Aorta
Horizontal plane of sternal angle
Esophagus Posterior mediastinum
Left atrium Microbiology
T12
Figure II-2-29. Divisions of the Mediastinum Figure II-2-29. Divisions of the Mediastinum
Anterior Mediastinum The anterior mediastinum is the small interval between the sternum and the anterior surface of the pericardium. It contains fat and areolar tissue and the inferior part of the thymus gland. A tumor of the thymus (thymoma) can develop in the anterior or superior mediastinum.
Posterior Mediastinum The posterior mediastinum is located between the posterior surface of the pericardium and the T5-T12 thoracic vertebrae. Inferiorly, it is closed by the diaphragm. There are 4 vertically oriented structures coursing within the posterior mediastinum: • Thoracic (descending) aorta
–– Important branches are the bronchial, esophageal, and posterior intercostal arteries –– Passes through the aortic hiatus (with the thoracic duct) at the T12 vertebral level to become the abdominal aorta • Esophagus
–– Lies immediately posterior to the left primary bronchus and the left atrium, forming an important radiological relationship
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–– Covered by the anterior and posterior esophageal plexuses, which are derived from the left and right vagus nerves, respectively –– Passes through the esophageal hiatus (with the vagal nerve trunks) at the T10 vertebral level –– Is constricted (1) at its origin from the pharynx, (2) posterior to the arch of the aorta, (3) posterior to the left primary bronchus, and (4) at the esophageal hiatus of the diaphragm • Thoracic duct
–– Lies posterior to the esophagus and between the thoracic aorta and azygos vein –– Ascends the posterior and superior mediastina and drains into the junction of the left subclavian and internal jugular veins –– Arises from the cisterna chyli in the abdomen (at vertebral level L1) and enters the mediastinum through the aortic hiatus of the diaphragm • Azygos system of veins
–– Drains the posterior and thoracic lateral wall –– Communicates with the inferior vena cava in the abdomen and terminates by arching over the root of the right lung to empty into the superior vena cava above the pericardium –– Forms a collateral venous circulation between the inferior and superior vena cava
Middle Mediastinum The middle mediastinum contains the heart and great vessels and pericardium, which will be discussed later.
Superior Mediastinum The superior mediastinum is located between the manubrium of the sternum, anteriorly, and the thoracic vertebrae 1-4, posteriorly. As with all mediastina, the parietal pleura and the lungs form the lateral boundary. The thoracic inlet connects superiorly with the neck and the horizontal plane through the sternal angle forms the inferior boundary. • The superior mediastinum contains the thymus, great arteries and
veins associated with the upper aspect of the heart, trachea, and esophagus.
• The vagus and phrenic nerves and the thoracic duct also course
through the mediastinum.
• The pulmonary trunk and arteries are located completely in the middle
mediastinum and are not found in the superior mediastinum.
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Esophagus
Pharmacology
Left vagus nerve (X)
Trachea Biochemistry Right vagus nerve (X)
Left internal jugular vein
Right subclavian artery and vein Physiology
Left phrenic nerve Left subclavian artery and vein
Medical Genetics
Right brachiocephalic vein Pathology
Left brachiocephalic vein
Brachiocephalic Superior artery mediastinum Behavioral Science/Social Sciences Middle mediastinum
Microbiology
Left common carotid artery
Left vagus nerve (X)
Right phrenic nerve
Left recurrent laryngeal nerve
Superior vena cava
Ligamentum arteriosum
Aortic arch
Pulmonary trunk
Ascending aorta
Figure II-2-30. Structuresofofthe theMediastinum Mediastinum Figure II-2-30. Structures
The relationships of these structures in the superior mediastinum are best visualized in a ventral to dorsal orientation between the sternum anteriorly and the vertebrae posteriorly: • Thymus: located posterior to the manubrium, usually atrophies in the
adult and remains as fatty tissue
• Right and left brachiocephalic veins: right vein descends almost verti-
cally and left vein obliquely crosses the superior mediastinum posterior to the thymic remnants –– The 2 veins join to form the superior vena cava posterior to the right first costal cartilage. –– The superior vena cava descends and drains into the right atrium deep to the right third costal cartilage.
• Aortic arch and its 3 branches: aortic arch begins and ends at the plane
of the sternal angle and is located just inferior to the left brachiocephalic vein.
–– As a very important radiological landmark, the origins of the 3 branches of the aortic arch (brachiocephalic, left common carotid, and left subclavian) are directly posterior to the left brachiocephalic vein.
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• Trachea: lies posterior to the aortic arch and bifurcates at the level of
T4 vertebra to form right and left primary bronchi
–– The carina is an internal projection of cartilage at the bifurcation. • Esophagus: lies posterior to the trachea and courses posterior to left
primary bronchus to enter the posterior mediastinum
ln addition to these structures, the superior mediastinum also contains the right and left vagus and phrenic nerves and the superior end of the thoracic duct.
Clinical Correlate
• The thoracic duct is the largest lymphatic channel in the body. It
The left recurrent laryngeal nerve (Figure II-2-30) curves under the aortic arch distal to the ligamentum arteriosum where it may be damaged by pathology (e.g., malignancy or aneurysm of the aortic arch), resulting in paralysis of the left vocal folds. The right laryngeal nerve is not affected because it arises from the right vagus nerve in the root of the neck and passes under the subclavian artery.
• Phrenic nerves arise from the ventral rami of cervical nerves 3, 4, and
Either the right or the left recurrent laryngeal nerve may be lesioned with thyroid gland surgery.
• Right and left vagus nerves contribute to the pulmonary and cardiac
plexuses. In the neck, the right vagus nerve gives rise to the right recurrent laryngeal nerve, which passes under the right subclavian artery to ascend in the groove between the esophagus and the trachea to reach the larynx. Note: The right recurrent laryngeal nerve is not in the mediastinum. The left vagus nerve gives rise to the left recurrent laryngeal nerve in the superior mediastinum, which passes under the aortic arch and ligamentum arteriosum to ascend to the larynx. returns lymph to the venous circulation at the junction of the left internal jugular vein and the left subclavian vein. 5. The nerves are the sole motor supply of the diaphragm and convey sensory information from the central portion of both the superior and inferior portions of the diaphragm and parietal pleura. Both phrenic nerves pass through the middle mediastinum lateral between the fibrous pericardium and pleura, and anterior to the root of the lung.
Coarctation of the Aorta Coarctation of the aorta is a narrowing of the aorta distal to the origin of the left subclavian artery. Two types are usually identified based on if the constriction is found proximal or distal to the opening of the ductus arteriosus (DA). • Preductal coarctation (infantile type) is less common and occurs
proximal to the DA (Figure II-2-31A). The DA usually remains patent and provides blood flow via the DA to the descending aorta and the lower parts of the body.
• Postductal coarctation (adult type) is more common and occurs distal
to the DA (Figure II-2-31B). The DA usually closes and obliterates.
–– This results in the intercostal arteries providing collateral circulation between the internal thoracic artery and the thoracic aorta to provide blood supply to the lower parts of the body (Figure II-2-31C). –– Patients will be hypertensive in the upper body (head, neck, and upper limbs) and hypotensive with weak pulses in the lower limbs. –– Enlargement of the intercostal arteries results in costal notching on the lower border of the ribs, evident in imaging.
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Subclavian artery Common carotid Biochemistry arteries
Pharmacology
Subscapular artery
Postductal coarctation
Patent ductus arteriosus Medical Genetics
Physiology
Pulmonary artery Pathology
Ligamentum arteriosum
Behavioral Science/Social Sciences
A
Microbiology
Intercostal arteries
B
C
Inferior epigastric artery
Figure II-2-31. Coarctation of the Aorta: (A) Preductal; (B) Postductal; (C) Collateral Circulation Figure II-2-31. Coarctation of the Aorta: (A) Preductal; (B) Postductal; (C) Collateral Circulation
Middle Mediastinum The middle mediastinum contains the pericardium, the heart, parts of the great vessels, and the phrenic nerves. The pericardium is the serous sac covering the heart. It is the only one of the serous membranes that has 3 layers: an outer fibrous layer and a double-layered parietal and visceral serous layers.
Position of transverse pericardial sinus Heart Fibrous pericardium Serous pericardium Parietal layer Visceral layer (epicardium) Pericardial cavity Diaphragm Figure II-2-32. Layers of the Pericardium Figure II-2-32. Layers of the Pericardium
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The fibrous pericardium surrounds the entire heart and the great vessels at the upper aspect of the heart. It is firmly attached below to the central tendon of the diaphragm and superiorly to the adventitia of the great vessels at the plane of the sternal angle (level of the second rib). The fibrous pericardium is very strong and maintains the position of the heart within the middle mediastinum. The serous pericardium is double-layered and formed by the outer parietal layer that lines the inner aspect of the fibrous pericardium and the inner visceral layer (epicardium) that covers the surface of the heart. The reflection between these 2 serous layers is at the base of the great vessels. The pericardial cavity is the potential space between the parietal and visceral layers containing a small amount of serous fluid that allows free movement of the beating heart. The pericardial cavity is expanded to form 2 sinuses: • The transverse pericardial sinus is a space posterior to the ascend-
ing aorta and pulmonary trunk and anterior to the superior vena cava and pulmonary veins. Note that it separates the great arteries from the great veins. The transverse sinus is useful in cardiac surgery to allow isolation of the aorta and pulmonary trunk.
• The oblique pericardial sinus is the blind, inverted, U-shaped space
posterior to the heart and bounded by reflection of serous pericardium around the 4 pulmonary veins and the inferior vena cava as they enter the heart.
HEART
Clinical Correlate Cardiac tamponade is the pathological accumulation of fluids (serous or blood) within the pericardial cavity. The fluid compresses the heart and restricts venous filling during diastole and reduces cardiac output. To remove the fluid, pericardiocentesis is performed with a needle at the left infrasternal angle through the cardiac notch of the left lung.
The heart lies obliquely within the middle mediastinum, mostly posterior to the sternum. Externally, the heart can be described by its borders and surfaces.
Borders of the Heart • The right border is formed by the right atrium. • The left border is mainly formed by the left ventricle. • The apex is the tip of the left ventricle, and is found in the left fifth
intercostal space.
• The superior border is formed by the right and left auricles plus the
conus arteriosus of the right ventricle.
• The inferior border is formed at the diaphragm, mostly by the right
ventricle.
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Aorta
Superior vena cava Pharmacology
Physiology
Pathology
Biochemistry
Medical Genetics
Ligamentum arteriosum Left pulmonary artery
Right pulmonary artery
Pulmonary trunk Left atrium
Right pulmonary veins
Left pulmonary veins
Behavioral Science/Social Sciences
Left ventricle (Left border)
Right atrium (Right border)
Right ventricle
Microbiology
Inferior vena cava
Apex Figure II-2-33. SternocostalView Viewofofthe theHeart Heart Figure II-2-33. Sternocostal
Surfaces of the Heart • The anterior (sternocostal) surface is formed primarily by the right
ventricle.
• The posterior surface is formed primarily by the left atrium. • The diaphragmatic surface is formed primarily by the left ventricle.
There are 3 main sulci (coronary and the anterior and posterior interventricular) that course on the surfaces of the heart; they contain the major vessels of the heart and epicardial fat.
Coronary sulcus Anterior interventricular sulcus
RA RV
LA RA
LV LV
Anterior (Sternocostal surface)
Posterior interventricular sulcus
RV
Posterior surface Diaphragmatic surface
Posterior
Figure II-2-34. Surfaces of Heart with Sulci Figure II-2-34. Surfaces of Heart with Sulci
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Surface Projections of the Heart Surface projections of the heart may be traced on the anterior chest wall. • The upper right aspect of the heart is deep to the third right costal
cartilage.
• The lower right aspect of the heart is deep to the sixth right costal
cartilage.
• The upper left aspect of the heart is deep to the left second costal
cartilage
• The apex of the heart is in the left fifth intercostal space at the
midclavicular line.
• The right border extends between the margin of the third right costal
cartilage to the sixth right costal cartilage just to the right of the sternum.
• The left border extends between the fifth left intercostal space to the
second left costal cartilage.
• The inferior border extends from the sixth right costal cartilage to the
fifth left intercostal space at the midclavicular line.
• The superior border extends from the inferior margin of the second
left costal cartilage to the superior margin of the third right costal cartilage.
Rib 2 Upper Left
Rib 3 Upper Right
Rib 5 Lower Right
Apex
Rib 6
Figure II-2-35. Surface Projections of the Heart Figure II-2-35. Surface Projections of the Heart
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Chambers of the Heart The right atrium receives venous blood from the entire body with the exception of blood from the pulmonary veins.
Pharmacology
Biochemistry
• The auricle is derived from the fetal atrium; it has rough myocardium
known as pectinate muscles.
• The sinus venarum is the smooth-walled portion of the atrium, which Physiology
Medical Genetics
receives blood from the superior and inferior venae cavae. It developed from the sinus venosus.
• The crista terminalis is the vertical ridge that separates the smooth Pathology
Behavioral Science/Social Sciences
from the rough portion (pectinate muscles) of the right atrium; it extends longitudinally from the superior vena cava to the inferior vena cava. The SA node is in the upper part of the crista terminalis.
• The fossa ovalis is close to the foramen ovale, an opening in the interMicrobiology
atrial septum which allows blood entering the right atrium from the inferior vena cava to pass directly to the left side of the heart.
• The right AV (tricuspid) valve communicates with the right ventricle. Aorta Superior vena cava
Crista terminalis Tricuspid valve
Sinus venarum
Pectinate muscles
Fossa ovalis
Coronary sinus Inferior vena cava
Tricuspid valve
Figure II-2-36. Inside the the Right RightAtrium Atrium Figure II-2-36. Inside
The left atrium receives oxygenated blood from the lungs via the pulmonary veins. There are 4 openings: upper right and left, and lower right and left pulmonary veins. The left AV orifice is guarded by the mitral (bicuspid) valve; it allows oxygenated blood to pass from the left atrium to the left ventricle. The right ventricle receives blood from the right atrium via the tricuspid valve; outflow is to the pulmonary trunk via the pulmonary semilunar valve. • The trabeculae carneae are ridges of myocardium in the ventricular wall. • The papillary muscles project into the cavity of the ventricle and
attach to cusps of the AV valve by the strands of the chordae tendineae.
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• The chordae tendineae are fibrous cords between the papillary muscles
and the valve leaflets that control closure of the valve during contraction of the ventricle.
• The infundibulum is the smooth area of the right ventricle leading to
the pulmonary valve.
• The septomarginal trabecula (moderator band) is a band of cardiac
muscle between interventricular septum and anterior papillary muscle which conducts part of the cardiac conduction system.
In the left ventricle, blood enters from the left atrium through the mitral valve and is pumped out to the aorta through the aortic valve. • The trabeculae carneae are ridges of myocardium in the ventricular
wall, normally thicker than those of the right ventricle.
• The papillary muscles, usually 2 large ones, are attached by the chor-
dae tendineae to the cusps of the bicuspid valve.
• The chordae tendineae act in same way as the right ventricle. • The aortic vestibule leads to the aortic semilunar valve and ascending
aorta.
Interventricular septum
Aortic semilunar valve
Tricuspid AV valve
Bicuspid AV valve (mitral valve)
Valve leaflet
Valve leaflet
Chordae tendineae
Chordae tendineae Papillary muscle
Papillary muscle
Trabeculae carneae
Septomarginal trabecula (moderator band) Figure II-2-37. Right and Left Ventricles
Figure II-2-37. Right and Left Ventricles
HEART HISTOLOGY Cardiac muscle is striated in the same manner as skeletal muscle, but it differs in being composed of smaller cells (fibers) with only 1 or 2 nuclei. The nuclei are located centrally, instead of peripherally.
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Layers of the Heart Wall The heart wall is composed of 3 distinct layers: an outer epicardium, a middle myocardium and an inner endocardium. The epicardium, or visceral layer of serous pericardium, consists of a simple squamous epithelium (mesothelium) and its underlying connective tissue. The connective tissue contains a large number of fat cells and the coronary vessels. The muscular wall of the heart is the myocardium and is composed mainly of cardiac muscle cells. The endocardium, which lines the chambers of the heart, is composed of a simple squamous epithelium, the endothelium, and a thin layer of connective tissue. Cardiac muscle is striated like skeletal muscle, but these cells are smaller, with centrally placed nuclei. Cardiac muscle has a similar but somewhat less well developed T-tubule system compared to skeletal muscle that is located at the Z-line.
Intercalated Discs Microbiology
Intercalated discs are special junctional complexes that join myocardial cells. The intercalated discs appear as dark, transverse lines in the light microscope. These disks contain gap junctions and adhering junctions. These junctions permit the spread of electrical (gap) and mechanical (adhering) effects through the walls of the heart, synchronizing activity for the pumping action of the heart chambers. While intercalated discs allow coordinated action of the myocardial cells, the squeezing and twisting movements of the heart chambers (particularly the left ventricle) during systole are due to the disposition of cardiac myocytes. Purkinje cells are modified cardiac muscle cells with fewer contractile filaments. They are specialized for electrical impulse conduction rather than contraction. Purkinje cells are found in the conduction system of the heart.
AUSCULTATION OF HEART VALVES Points of Auscultation Points of auscultation of the semilunar valves (aortic and pulmonary) and the atrioventricular valves (tricuspid and mitral or bicuspid) are shown below. The first heart sound occurs at the closure of the atrioventricular valves at the beginning of systole and the second heart sound occurs at the closure of the aortic and pulmonary semilunar valves at the end of systole.
Heart Murmurs Murmurs in valvular heart disease result when there is valvular insufficiency or regurgitation (the valves fail to close completely) or stenosis (narrowing of the valves). The aortic and mitral valves are more commonly involved in valvular heart disease. For most of ventricular systole, the mitral valve should be closed and the aortic valve should be open, so that “common systolic valvular defects” include mitral insufficiency and aortic stenosis. For most of ventricular diastole, the mitral valve should be open and the aortic valve should be closed, so that “common diastolic valvular defects” include mitral stenosis and aortic insufficiency. A heart murmur is heard downstream from the valve. Thus, stenosis is orthograde direction from valve and insufficiency is retrograde direction from valve.
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Valves of the Heart • A trioventricular Right heart: tricuspid Left heart: bicuspid
Aortic valve Tricuspid valve
Pulmonary valve
• S emilunar Aortic (3 cusps) Pulmonary (3 cusps)
Mitral valve
Figure II-2-40. SurfaceProjections Projections Heart Figure II-2-38. Surface of of thethe Heart
Right upper sternum – Systolic • Aortic stenosis Rib 3
Rib 2 Upper lateral chest – Systolic • Mitral insufficiency Rib 5
Rib 6
Apex – Diastolic • Mitral stenosis • Aortic insufficiency
Right lower sternum – Systolic • Tricuspid insufficiency Figure II-2-41. Auscultation of of Heart Murmurs Figure II-2-39. Auscultation Heart Murmurs
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Table II-2-4. Heart Murmurs
A-V Valves Pharmacology
Biochemistry
Stenosis
Insufficiency
Diastolic murmur
Systolic murmur
Systolic murmur
Diastolic murmur
Tricuspid (right) Mitral (left) Outflow Valves
Physiology
Medical Genetics
Pulmonic (right) Aortic (left)
Pathology
Behavioral Science/Social Sciences
Arterial Supply of the Heart Microbiology
The blood supply to the myocardium is provided by branches of the right and left coronary arteries. These 2 arteries are the only branches of the ascending aorta and arise from the right and left aortic sinuses of the ascending aorta, respectively. Blood flow enters the coronary arteries during diastole.
Left coronary artery Circumflex artery
SA nodal artery
Clinical Correlate In myocardial infarction, the left anterior descending artery is obstructed in 50% of cases, the right coronary in 30%, and the circumflex artery in 20% of cases.
Left anterior descending (LAD) artery
Right coronary artery
Diagonal artery
AV nodal artery
Posterior interventricular artery
Marginal artery
Figure II-2-40. Arterial Figure II-2-42. ArterialSupply Supplytotothe theHeart Heart
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Right coronary artery The right coronary artery courses in the coronary sulcus and supplies major parts of the right atrium and the right ventricle. The branches include the following: • Sinoatrial (SA) nodal artery: One of the first branches of the right
coronary, it encircles the base of the superior vena cava to supply the SA node.
• Atrioventricular (AV) nodal artery: It arises from the distal end of the
right coronary artery as it forms the posterior interventricular artery and penetrates the interatrial septum to supply the AV node.
• Posterior interventricular artery: It is the terminal distribution of
the right coronary artery and courses in the posterior interventricular sulcus to supply parts of the right and left ventricles and, importantly, the posterior third of the interventricular septum.
Left coronary artery The left coronary artery travels a short course between the left auricle and ventricle, and divides into 2 branches: anterior interventricular or left anterior descending (LAD) artery and circumflex artery. • The anterior interventricular artery descends in the anterior interven-
tricular sulcus and provides branches to the (1) anterior left ventricle wall, (2) anterior two-thirds of the interventricular septum, (3) bundle of His, and (4) apex. The LAD is the most common site of coronary occlusion.
• The circumflex artery courses around the left border of the heart in
the coronary sulcus and supplies (1) the left border of the heart via the marginal branch and (2) ends on the posterior aspect of the left ventricle and supplies the posterior-inferior left ventricular wall.
Venous Drainage of the Heart The major cardiac veins draining the heart course in the sulci and accompany the arteries but do not carry the same names. The major veins are the following: • Coronary sinus is the main vein of the coronary circulation; it lies in
the posterior coronary sulcus and drains to an opening in the right atrium. It develops from the left sinus venosus.
• Great cardiac vein lies in the anterior interventricular sulcus with the
LAD artery; it is the main tributary of the coronary sinus.
• Middle cardiac vein lies in the posterior interventricular sulcus with
the posterior interventricular artery; it joins the coronary sinus.
• Venae cordis minimae (thebesian veins) and anterior cardiac
veins open directly to the chambers of the heart.
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Coronary sinus Pharmacology
Biochemistry
Great cardiac vein
RA Physiology
RV
Pathology
Coronary sulcus
Medical Genetics
RA
LV
LV
RV
Behavioral Science/Social Sciences
Anterior interventricular sulcus Microbiology
LA
Posterior interventricular sulcus
Anterior
Middle cardiac vein
Small cardiac vein
Posterior
Figure II-2-43. Venous Drainage of the Heart Figure II-2-41. Venous Drainage of the Heart
Conducting System of the Heart The cardiac conduction system is a specialized group of myocardial cells that initiates the periodic contractions of the heart due to their ability to depolarize at a faster rate than other cardiac myocytes. Electrical activity spreads through the walls of the atria from the SA node and is quickly passed by way of internodal fibers to the atrioventricular node. From the atrioventricular node, activity passes through the bundle of His and then down the right and left bundle branches in the interventricular septum. The bundle branches reach additional specialized cardiac muscle fibers known as Purkinje fibers in the ventricular walls. • The Purkinje fibers run in several bundles along the endocardial sur-
face and initiate ventricle activity starting at the apex of the ventricles.
• Purkinje fibers have a large cross section, a cytoplasm with few con-
tractile fibrils and a large content of glycogen.
The SA node initiates the impulse for contraction of heart muscle (and is therefore termed the “pacemaker” of the heart). It is located at the superior end of the crista terminalis, where the superior vena cava enters the right atrium. • The SA node is supplied by the SA nodal branch of the right coronary
artery.
• Impulse production is speeded up by sympathetic nervous stimulation;
it is slowed by parasympathetic (vagal) stimulation.
The AV node receives impulses from the SA node; it is located in the interatrial septum near the opening of the coronary sinus. The AV node slows the impulse so that it reaches the ventricles after it has reached the atria. • The AV node is supplied by the right coronary artery.
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The bundle of His originates in the AV node. It conducts impulses to the right and left ventricles. It is supplied by the LAD artery. • In the right ventricle, the moderator band (septomarginal trabecula)
contains the right bundle branch.
• Impulses pass from the right and left bundle branches to the papillary
muscles and ventricular myocardium.
Innervation The cardiac plexus is a combination of sympathetic and parasympathetic (vagal) fibers. • Sympathetic stimulation increases the heart rate. Nerves that sense
pain associated with coronary artery ischemia (angina) follow the sympathetic pathways back into spinal cord segments T1–T5.
• Parasympathetic stimulation slows the heart rate. Sensory nerves that
carry the afferent limb of cardiac reflexes travel with the vagus nerve.
Atrioventricular node (AV node)
Superior vena cava
Left atrium
Sinoatrial node (SA node)
Pulmonary veins Common AV bundle Left ventricle
Right atrium
Right and left bundle branches
Right ventricle Inferior vena cava Purkinje fibers
Figure II-2-42. Cardiac Conduction System Figure II-2-44. Cardiac Conduction System
DIAPHRAGM The diaphragm is composed of a muscular portion and a central tendon. It is dome-shaped, and descends upon contraction of its muscular portion. It is innervated by the phrenic nerves that arise from spinal cord segments C3 through C5.
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The diaphragm is formed by the fusion of tissue from 4 sources: • The septum transversum gives rise to the central tendon of the
diaphragm.
Pharmacology
Biochemistry
• The pleuroperitoneal membranes give rise to parts of the tendinous
portion of the diaphragm.
• The dorsal mesentery of the esophagus gives rise to the crura of the Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
diaphragm.
• The body wall contributes muscle to the periphery of the diaphragm.
Apertures in the Diaphragm
Microbiology
Caval hiatus is located to the right of the midline at the level of T8, within the central tendon. It transmits the inferior vena cava and some branches of the right phrenic nerve. Esophageal hiatus is located to the left of the midline at the level of T10, within the muscle of the right crus. It transmits the esophagus and the anterior and posterior vagus trunks. Aortic hiatus is located in the midline at the level of T12, behind the 2 crura. It transmits the aorta and thoracic duct.
Clinical Correlate Pain Referral Because the innervation to the diaphragm (motor and sensory) is primarily from C3 through C5 spinal nerves, pain arising from the diaphragm (e.g., subphrenic access) is referred to these dermatomes in the shoulder region.
T1
T4
Clinical Correlate A congenital diaphragmatic hernia is a herniation of abdominal contents into the pleural cavity due to the failure of the pleuroperitoneal membranes to develop properly. The hernia is most commonly found on the left posterolateral side and causes pulmonary hypoplasia. An esophageal hiatal hernia is a herniation of the stomach into the pleural cavity due to an abnormally large esophageal hiatus to the diaphragm. This condition renders the esophagogastric sphincter incompetent so that contents reflux into the esophagus.
T9 Diaphragm phra agm Inferior riorr vena cava (T8) Esophagus opha agus (T10) Aorta ta (T12) (T T12 2)
Figure II-2-45. The Diaphragm Figure II-2-43. The Diaphragm
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RADIOLOGY
Aortic Arch Left Pulmonary Artery Left Atrium
Superior Vena Cava Right Atrium
Left Ventricle
From Group, Inc. F rom the the IMC, IMC,©©2010 2010DxR DxRDevelopment Development Group, Inc. All rights reserved. All rights reserved.
Figure II-2-46. Anterior Projection of Chest, Male Figure II-2-44. Anterior Projection of Chest, Male
Left Atrium
Right Ventricle Left Ventricle
Right Dome of Diaphragm
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Left Dome of Diaphragm
Figure II-2-45. Lateral Projection of Chest, Male
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Brachiocephalic trunk Right brachiocephalic vein Left brachiocephalic vein From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Anatomy
Microbiology
Trachea
Esophagus
Left subclavian artery
Left common carotid artery
Figure II-2-48. Chest: CT, CT,T2T2 Figure II-2-46. Chest:
Superior Vena Cava
Aortic Arch
Trachea Esophagus
Fromthe theIMC, IMC,©©2010 2010DxR DxRDevelopment Development Group, Group, Inc. From Inc. rightsreserved. reserved. AllAllrights
Ribs
T3 Vertebra
Scapula
Figure II-2-49. Chest: CT, CT,T3 T3 Figure II-2-47. Chest:
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Chapter 2 Superior Vena Cava
Ascending Aorta
Bifurcation of Trachea
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Descending Aorta
From the the IMC, IMC, © From ©2010 2010 DxR DxRDevelopment DevelopmentGroup, Group,Inc. Inc. All rights reserved. All rights reserved.
Ribs
T4 Vertebra
Scapula
Figure II-2-48. Chest: Figure II-2-50. Chest: CT, CT,T4 T4
Right Pulmonary Artery
Superior Body of Vena Cava Sternum
Ascending Pulmonary Aorta Trunk
From the IMC, IMC,©©2010 2010DxR DxRDevelopment DevelopmentGroup, Group, Inc. From the Inc. All rights All rightsreserved. reserved.
Descending Aorta T5 Vertebra
Spinal Cord
Figure II-2-51. Chest: CT, CT,T5 T5 Figure II-2-49. Chest:
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RA = right atrium Pharmacology
Biochemistry
AA = ascending aorta LA = left atrium E = esophagus
Physiology
Medical Genetics
DA = descending aorta
Pathology
Microbiology
Copyright Lippincott Williams & Wilkins. Used with permission.
PA = pulmonary artery
PA RA
PA = pulmonar RA = right atriu AA = ascendin LA = left atrium E = esophagus DA = descendi
AA E
LA DA
Behavioral Science/Social Sciences
Copyright Lippincott Williams & Wilkins. Used with permission.
Figure II-2-52. Chest: CT, T5 Figure II-2-50. Chest: CT, T5
Right Atrium
Right Ventricle
Left Ventricle
From the Inc. From the IMC, IMC,©©2010 2010DxR DxRDevelopment DevelopmentGroup, Group, Inc. All rights All rightsreserved. reserved.
T6 Vertebra Spinal Cord
Descending Left Atrium Aorta Esophagus
Figure II-2-53. Chest: CT, T6 Figure II-2-51. Chest: CT, T6
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ON II
Abdomen, Pelvis, and Perineum
3
Learning Objectives ❏❏ Explain information related to inguinal region and canal ❏❏ Answer questions about embryology of the GI system ❏❏ Solve problems concerning peritoneum ❏❏ Answer questions about GI histology, innervation, and immune functions ❏❏ Solve problems concerning arterial supply and venous drainage to abdominal viscera ❏❏ Explain information related to posterior abdominal body wall ❏❏ Answer questions about urinary histology and function ❏❏ Use knowledge of male and female reproductive histology ❏❏ Demonstrate understanding of radiology of the abdomen and pelvis
ANTERIOR ABDOMINAL WALL Surface Anatomy The linea alba is a shallow groove that runs vertically in the median plane from the xiphoid to the pubis. It separates the right and left rectus abdominis muscles. The components of the rectus sheath intersect at the linea alba. The linea semilunaris is a curved line defining the lateral border of the rectus abdominis, a bilateral feature.
Planes and Regions The anterior abdominal wall is divided into 9 regions separated by several planes and lines. The subcostal plane (horizontal) passes through the inferior margins of the 10th costal cartilages at the level of the third lumbar vertebra. The transpyloric plane passes through the L1 vertebra, being half the distance between the pubis and the jugular notch. The plane passes through several important abdominal landmarks useful for radiology: pylorus of the stomach (variable), fundus of gallbladder, neck and body of the pancreas, hila of kidneys, first part of the duodenum, and origin of the superior mesenteric artery.
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The midclavicular lines (vertical) are the 2 planes that pass from the midpoint of the clavicle to the midpoint of the inguinal ligament on each side.
Biochemistry
RH: right hypochondrium LH: left hypochondrium RL: right lumbar
Physiology
Medical Genetics
LL: left lumbar RI: right inguinal Pathology
LI: left inguinal
Behavioral Science/Social Sciences
Microbiology
Subcostal plane Intertubercular plane
RH
Epigastrium
LH
RL
Umbilical
LL
RI
Inguinal ligament
Hypogastrium
LI
Anterior superior iliac spine Pubic tubercle
Figure II-3-1. Regions and Planes the Abdomen Figure II-3-1. Regions and Planes ofof the Abdomen
Muscles and Fasciae The anterolateral abdominal body wall is a multilayer of fat, fasciae, and muscles (with their aponeuroses) that support and protect the abdominal contents. Three flat abdominal muscles are arranged in layers and the rectus abdominis is oriented vertically adjacent to the midline, extending between the costal margin and the pubis. Abdominal muscles are important in respiration, defecation, micturition, childbirth, etc.
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Chapter 3
Skin Superficial fascia of the anterior abdominal wall below the umbilicus consists of 2 layers: • Camper (fatty) fascia is the outer, subcutaneous layer of superficial
fascia that is variable in thickness owing to the presence of fat.
• Scarpa (membranous) fascia is the deeper layer of superficial fascia
devoid of fat. It is continuous into the perineum with various perineal fascial layers (Colles’ fascia, dartos fascia of the scrotum, superficial fascia of the clitoris or penis).
Muscles The external abdominal oblique muscle and aponeurosis is the most superficial of the 3 flat muscles of the abdominal wall. Its contributions to the abdominal wall and inguinal region are the following:
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Abdomen, Pelvis, and Perineum
Note Anterior Abdominal Wall Layers • Skin • S uperficial fascia: camper (fatty) and scarpa (fibrous) • External oblique • Internal oblique • Transversus abdominis • Transversalis fascia • Extraperitoneal connective tissue • Parietal peritoneum
• Inguinal ligament is the inferior rolled under aponeurotic fibers of
the external oblique that extend between the anterior superior iliac spine and the pubic tubercle. Medially, the fibers of the inguinal ligament form a flattened horizontal shelf called the lacunar ligament that attaches deeply to the pectineal line of the pubis and continues as the pectineal ligament. Lacunar ligament forms the medial border of a femoral hernia.
• Superficial inguinal ring is a vertical triangular cleft in the external
oblique aponeurosis that represents the medial opening of the inguinal canal just superior and lateral to the pubic tubercle. It transmits the structures of the female and male inguinal canals.
• External spermatic fascia is the outer layer of the 3 coverings of the
spermatic cord formed at the superficial inguinal ring in males.
• Rectus sheath: The external aponeuroses contribute to the anterior
layer of the rectus sheath.
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Lumbar vertebrae Pharmacology
Physiology
Biochemistry
Medical Genetics
Anterior superior iliac spine
Sacrum
Ischial spine Pathology
Coccyx
Behavioral Science/Social Sciences
Inguinal ligament
Pubic tubercle Microbiology
Pubic symphysis
Figure II-3-2. Osteology of the Abdominopelvic Cavity
Figure II-3-2. Osteology of the Abdominopelvic Cavity
Internal abdominal oblique muscle and aponeurosis: This middle layer of the 3 flat muscles originates, in part, from the lateral two-thirds of the inguinal ligament. The internal oblique fibers course medially and arch over the inguinal canal in parallel with the arching fibers of the transversus abdominis muscle. The contributions of the internal abdominal oblique to the abdominal wall and inguinal region are the following: • Conjoint tendon (falx inguinalis) is formed by the combined arching
fibers of the internal oblique and the transversus abdominis muscles that insert on the pubic crest posterior to the superficial inguinal ring.
• Rectus sheath: The internal aponeuroses contribute to the layers of the
rectus sheath.
• Cremasteric muscle and fascia represent the middle layer of the sper-
matic fascia covering the spermatic cord and testis in the male. It forms in the inguinal canal.
Transversus abdominis muscle and aponeurosis: This is the deepest of the flat muscles. The transversus muscle originates, in part, from the lateral one-third of the inguinal ligament and arches over the inguinal canal with the internal oblique fibers to contribute to the conjoint tendon. The aponeuroses of the transversus muscle also contribute to the layers of the rectus sheath. It does not contribute to any of the layers of the spermatic fasciae.
Abdominopelvic Fasciae and Peritoneum Transversalis fascia: This fascia forms a continuous lining of the entire abdominopelvic cavity. Its contributions to the inguinal region include the following:
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• Deep inguinal ring is formed by an outpouching of the transversalis
fascia immediately above the midpoint of the inguinal ligament and represents the lateral and deep opening of the inguinal canal. The inferior epigastric vessels are medial to the deep ring.
• Internal spermatic fascia is the deepest of the coverings of the sper-
matic cord formed at the deep ring in the male.
• Femoral sheath is an inferior extension of the transversalis fascia deep
to the inguinal ligament into the thigh containing the femoral artery and vein and the femoral canal (site of femoral hernia).
• Rectus sheath: The transversalis fascia contributes to the posterior
layer of the rectus sheath.
Extraperitoneal connective tissue is a thin layer of loose connective tissue and fat surrounding the abdominopelvic cavity, most prominent around the kidneys. The gonads develop from the urogenital ridge within this layer. Parietal peritoneum is the outer serous membrane that lines the abdominopelvic cavity. Parietal peritoneum Extraperitoneal fat
Deep inguinal ring Inferior epigastric artery & vein
Transversalis fascia
Weak area Rectus abdominus
Transversus abdominus
Conjoint tendon (falx inguinalis)
Internal abdominal oblique External abdominal oblique
External oblique fascia External spermatic fascia
Cremasteric muscle Superficial inguinal ring
Internal oblique fascia Cremaster muscle and fascia Transversalis fascia Internal spermatic fascia
Layers of Anterolateral Abdominal FigureFigure II-3-3.II-3-3. Layers of Anterolateral Abdominal Wall and Inguinal Canal Wall and Inguinal Canal
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Nerves, Blood Vessels, and Lymphatics of Abdominal Wall Innervation of the skin and musculature of the anterior abdominal wall is via branches of the ventral primary rami of the lower 6 thoracic spinal nerves (includes the subcostal nerve), plus the iliohypogastric and ilioinguinal branches of the ventral primary rami of L1. The major arterial blood supply to the anterior wall is derived from the superior epigastric branch of the internal thoracic artery, as well as the inferior epigastric and the deep circumflex iliac branches of the external iliac artery. Venous drainage from the anterior wall is to the superficial epigastric, the lateral thoracic veins superiorly and the great saphenous vein inferiorly.
Pathology
Microbiology
Behavioral Science/Social Sciences
Lymph drainage from tissues of the anterior wall is to axillary nodes superiorly and to superficial inguinal nodes inferiorly.
INGUINAL REGION AND CANAL The inguinal canal is the oblique passageway (approximately 4 cm long) in the lower aspect of the anterior abdominal wall running parallel and superior to the medial half of the inguinal ligament. Clinically, the inguinal region is important because it is the area where inguinal hernias occur. The entrance into the canal is the deep inguinal ring, located just lateral to the inferior epigastric vessels and immediately superior to the midpoint of the inguinal ligament. The superficial inguinal ring is the medial opening of the canal superolateral to the pubic tubercle.
Contents of the Inguinal Canal Female Inguinal Canal Round ligament of the uterus extends between the uterus and labia majora, and is a remnant of the caudal genital ligament and the homologue of the gubernaculum testis of the male. Ilioinguinal nerve (L1), a branch of the lumbar plexus, exits the superficial ring to supply the skin of the anterior part of the mons pubis and labia majora.
Male Inguinal Canal Ilioinguinal nerve (L1), a branch of the lumbar plexus, exits the superficial ring to supply the skin of the lateral and anterior scrotum. The spermatic cord is formed during descent of the testis and contains structures that are related to the testis. The cord begins at the deep ring and courses through the inguinal canal and exits the superficial ring to enter the scrotum. The cord contains the following: • Testicular artery, branch of the abdominal aorta that supplies the testis
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• Pampiniform venous plexus, an extensive network of veins draining
the testis located within the scrotum and spermatic cord. The veins of the plexus coalesce to form the testicular vein at the deep ring. The venous plexus assists in the regulation of the temperature of the testis.
• Vas deferens (ductus deferens) and its artery • Autonomic nerves • Lymphatics: Lymphatic drainage of the testis will drain into the lum-
bar (aortic) nodes of the lumbar region and not to the superficial inguinal nodes which drain the rest of the male perineum.
There are 3 fascial components derived from the layers of the abdominal wall that surround the spermatic cord: • External spermatic fascia is formed by the aponeuroses of the exter-
nal abdominal oblique muscle at the superficial ring.
Clinical Correlate A varicocele develops when blood collects in the pampiniform venous plexus and causes dilated and tortuous veins. This may result in swelling and enlargement of the scrotum or enlargement of the spermatic cord above the scrotum. Varicoceles are more prominent when standing because of the blood pooling into the scrotum. A varicocele will reduce in size when the individual is horizontal.
• Middle or cremasteric muscle and fascia are formed by fibers of the
internal abdominal oblique within the inguinal canal. The cremasteric muscle elevates the testis and helps regulate the thermal environment of the testis.
• Internal spermatic fascia is formed by the transversalis fascia at the
deep ring.
Boundaries of the Inguinal Canal The roof is formed by fibers of the internal abdominal oblique and the transversus abdominis muscles arching over the spermatic cord. The anterior wall is formed by aponeurosis of the external abdominal oblique throughout the inguinal canal and the internal abdominal oblique muscle laterally. The floor formed by inguinal ligament throughout the entire inguinal canal and the lacunar ligament at the medial end. The posterior wall is divided into lateral and medial areas: • Lateral area is formed by the transversalis fascia and represents the
weak area of the posterior wall.
• Medial area is formed and reinforced by the fused aponeurotic fibers
of the internal abdominal oblique and transversus abdominis muscles (conjoint tendon).
• Inferior epigastric artery and vein ascend the posterior wall just lat-
eral to the weak area and just medial to the deep ring.
Clinical Correlate Cancers of the penis and scrotum will metastasize to the superficial inguinal lymph nodes, and testicular cancer will metastasize to the aortic (lumbar) nodes.
Clinical Correlate In males, a cremasteric reflex can be demonstrated by lightly touching the skin of the upper medial thigh, resulting in a slight elevation of the testis. The sensory fibers of the reflex are carried by the L1 fibers of the ilioinguinal nerve and the motor response is a function of the genital branch of the genitofemoral nerve that innervates the cremasteric muscle.
Descent of the Testes The testis develops from the mesoderm of the urogenital ridge within the extraperitoneal connective tissue layer. During the last trimester, it descends the posterior abdominal wall inferiorly toward the deep inguinal ring guided by the fibrous gubernaculum.
Clinical Correlate Failure of one or both of the testes to descend completely into the scrotum results in cryptorchidism, which may lead to sterility if bilateral.
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• An evagination of the parietal peritoneum and the peritoneal cavity
extends into the inguinal canal called the processus vaginalis. The open connection of the processus vaginalis with the peritoneal cavity closes before birth.
Biochemistry
• A portion of the processus vaginalis remains patent in the scrotum and
surrounds the testis as the tunica vaginalis.
Physiology
Medical Genetics
Peritoneum
Peritoneum
Testes
Testes Pathology
Behavioral Science/Social Sciences
Microbiology
Tunica vaginalis
Pubis
Processus vaginalis Gubernaculum A
B
C
D
Figure II-3-4. Descent of the Testes Figure II-3-4. Descent of the Testes
Clinical Correlate
Inguinal Hernias
A persistent process vaginalis often results in a congenital indirect inguinal hernia.
Herniation of abdominal viscera can occur in one of several weak aspects of the abdominal wall (e.g. inguinal, femoral, umbilical, or diaphragmatic). Inguinal hernias are the most common of the abdominal hernias and occur more frequently in males due to the inherent weakness of the male inguinal canal. Inguinal hernias occur superior to the inguinal ligament.
Clinical Correlate A collection of serous fluid in the tunica vaginalis forms a hydrocele, resulting in an enlarged scrotum. A hydrocele does not reduce in size when the patient is lying down.
Note Direct hernias are found medial to the inferior epigastric vessels, and indirect inguinal hernias occur lateral to the inferior epigastric vessels.
• Indirect inguinal hernias result when abdominal contents protrude
through the deep inguinal ring lateral to the inferior epigastric vessels. After passing through the inguinal canal and superficial ring, the viscera can continue and coil in the scrotum. –– Indirect hernias follow the route taken by the testis and are found within the spermatic cord. –– They are covered by the 3 layers of spermatic fascia.
• Direct inguinal hernias result when the abdominal contents protrude
through the weak area of the posterior wall of the inguinal canal medial to the inferior epigastric vessels (in the inguinal [Hesselbach’s] triangle).
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–– Direct hernias rupture through the posterior wall of the inguinal canal and are usually found on the surface of the spermatic cord and bulge at the superficial ring. –– They may be covered by only the external layer of spermatic fascia.
Clinical Correlate Direct inguinal hernias usually pass through the inguinal (Hesselbach’s) triangle: • Lateral border: inferior epigastric vessels
Note Both direct and indirect hernias exit through the superficial ring, but only indirect hernias pass through the deep ring.
• Medial border: rectus abdominis muscle • Inferior border: inguinal ligament
Inferior epigastric artery & vein Indirect
Inguinal triangle Direct
Superficial inguinal ring
Figure II-3-5. Inguinal Hernia Figure II-3-5. Inguinal Hernia
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Clinical Correlate Inguinal hernias pass above the inguinal ligament, while femoral Pharmacology hernias pass below it. Biochemistry
Femoral Hernias Femoral hernias most often occur in women. Inguinal ligament Femoral vein
Physiology
Pathology
Sartorius
Medical Genetics
Femoral sheath contains femoral artery, vein, and canal Behavioral Science/Social Sciences
Femoral canal
Femoral nerve
Site of femoral canal and hernia
Femoral artery
Adductor longus
Microbiology
Figure II-3-6. Femoral Hernia Figure II-3-6. Femoral Hernia
EMBRYOLOGY OF THE GASTROINTESTINAL TUBE Primitive Gut Tube The primitive gut tube is formed by incorporation of the yolk sac into the embryo during 2 body foldings: head to tail (cranial-caudal) and lateral foldings. While the epithelial lining of the mucosa of the primitive gut tube is derived from endoderm, the lamina propria, muscularis mucosae, submucosa, muscularis externa, and adventitia/serosa are derived from mesoderm. The primitive gut tube is divided into the foregut, midgut, and hindgut, each supplied by a specific artery and autonomic nerves.
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Table II-3-1. Adult Structures Derived from the 3 Divisions of the Primitive Gut Tube Foregut
Midgut
Hindgut
Artery: celiac
Artery: superior mesenteric
Artery: inferior mesenteric
Parasympathetic innervation: vagus nerves
Parasympathetic innervation: vagus nerves
Parasympathetic innervation: pelvic splanchnic nerves
Sympathetic innervation:
Sympathetic innervation:
Sympathetic innervation:
• Preganglionics: thoracic splanchnic nerves, T5−T9
• Preganglionics: thoracic splanchnic nerves, T9−T12
reganglionics: lumbar • P splanchnic nerves, L1−L2
• Postganglionic cell bodies: celiac ganglion
• Postganglionic cell bodies: superior mesenteric ganglion
• P ostganglionic cell bodies: inferior mesenteric ganglion
Referred Pain: Epigastrium
Referred Pain: Umbilical
Referred Pain: Hypogastrium
Foregut Derivatives
Midgut Derivatives
Hindgut Derivatives
Esophagus
Duodenum (second, third, and fourth parts)
Transverse colon (distal third— splenic flexure)
Duodenum (first and second parts)
Jejunum
Descending colon
Ileum
Sigmoid colon
Liver
Cecum
Rectum
Pancreas
Appendix
Biliary apparatus
Ascending colon
Anal canal (above pectinate line)
Gallbladder
Transverse colon (proximal two-thirds)
Stomach
Development and Rotation of Foregut
Note
After body foldings and the formation of the gut tube, the foregut is s uspended from the dorsal body wall by the dorsal embryonic mesentery and from the ventral body wall by the ventral embryonic mesentery. Note that the liver develops in the ventral embryonic mesentery, and the spleen and dorsal pancreatic bud develop in the dorsal embryonic mesentery.
The lower respiratory tract, liver and biliary system, and pancreas all develop from an endodermal outgrowth of the foregut.
• The abdominal foregut rotates 90° (clockwise) around its longitudinal
axis. The original left side of the stomach before rotation becomes the ventral surface after rotation and its anterior and posterior borders before rotation will become the lesser and greater curvatures, respectively.
• Foregut rotation results in the liver, lesser omentum (ventral embryonic
mesentery), pylorus of the stomach, and duodenum moving to the right; and the spleen, pancreas, and greater omentum (dorsal embryonic mesentery) moving to the left.
• The ventral embryonic mesentery will contribute to the lesser omen-
tum and the falciform ligament, both of which attach to the liver.
• The dorsal embryonic mesentery will contribute to the greater omen-
tum and the gastro-splenic and splenorenal ligaments, all of which attach to the spleen or the greater curvature of the stomach.
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Amniotic cavity (AM) Biochemistry Ectoderm Mesoderm
Pharmacology
Endoderm YolkMedical sacGenetics (YS)
Physiology
AM
Pathology
Hepatic diverticulum Gallbladder
Microbiology
Esophagus Lung bud
2 3 4
Aorta
Vitelline duct
AM Coelom
Gut tube
90° rotation to right along longitudinal axis
Yolk stalk
Foregut
Vitelline duct
270° rotation counterclockwise Midgut and herniation (6–10th week) Hindgut Septation
Behavioral Science/Social Sciences
Lateral body fold YS
Stomach
Pharyngeal pouches 1
Allantois Cloaca Inferior mesenteric artery Superior mesenteric artery
Celiac artery Dorsal pancreatic bud Ventral pancreatic bud
Figure II-3-7A. Development of Gastrointestinal Tract
Figure II-3-7A. Development of Gastrointestinal Tract
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Development of Liver Dorsal embryonic mesentery
Aorta
Lesser Dorsal omentum
Aorta
Kidney
Kidney
Mesentery
GI tract
Foregut Ventral embryonic mesentery
1A
Falciform ligament 1C
1B
Development of Pancreas
Ventral
Peritoneum Peritoneal cavity Liver & biliary system
Development of Spleen Stomach
Dorsal pancreatic bud
Spleen
Splenorenal ligament Spleen
Ventral pancreatic bud 2A
2B
3A
Gastrosplenic ligament
3B
Secondary Retroperitonealization
Fusion fascia
4A
4C
4B Rotation of Foregut Epiploic foramen Lesser sac*
Splenorenal ligament
Greater sac
5A *Lesser sac = omental bursa
Spleen 5B Lesser Gastrosplenic ligament omentum
Figure II-3-7B. Cross-Sectional View of Foregut Development and Rotation Figure II-3-7B. Cross-Sectional View of Foregut Development and Rotation
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Development and Rotation of Midgut The midgut originally develops from the cranial and caudal intestinal loops. During weeks 6–10, the midgut herniates into the umbilical cord. During herniation into and return from the umbilical cord, the midgut undergoes a 270° counterclockwise rotation around the axis of the superior mesenteric artery. • This rotation results in the jejunum being on the left, and the ileum and cecum being on the right. • It also causes the colon to assume the shape of an inverted “U.”
Peritoneum and Peritoneal Cavity The peritoneum is the serous membrane related to the viscera of the abdominal cavity. It is divided into 2 layers: parietal and visceral. Dorsal
Clinical Correlate
Microbiology
Inflammation of the parietal peritoneum (peritonitis) results in sharp pain that is localized over the area.
Aorta
Kidney
Dorsal mesentery
Parietal peritoneum
GI tract
Visceral peritoneum Peritoneal cavity Ventral FigureFigure II-3-7C. Peritoneum II-3-7C. Peritoneum
The parietal layer lines the body wall and covers the retroperitoneal organs on one surface. Parietal peritoneum is very sensitive to somatic pain and is innervated by the lower intercostal nerves and the ilioinguinal and the iliohypogastric nerves of the lumbar plexus. The visceral layer encloses the surfaces of the intraperitoneal organs. The visceral peritoneum usually forms double-layered peritoneal membranes (mesenteries) that suspend parts of the GI tract from the body wall. The mesenteries allow for the passage of vessels, nerves, and lymphatics to reach the GI tract. Different terms describe the postnatal remnants of mesenteries in the abdomen: • Omentum: lesser and greater omenta attach to the lesser or greater curvatures of the stomach, respectively • Mesocolon: transverse and sigmoid mesocolon attach to the transverse
colon or the sigmoid colon, respectively
• Ligaments: reflections of mesenteries between organs or the body wall,
named according to their attachments
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The peritoneal cavity is the potential space located between the parietal and visceral peritoneal layers. The 90° rotation and the shift of the embryonic mesenteries divide the peritoneal cavity into 2 sacs (Figures II-3-7B and II-3-9). • The lesser sac (omental bursa) is a cul-de-sac formed posterior to the
stomach and the lesser omentum
• The greater sac is formed by the larger area of the remaining perito-
neal cavity. The only communication between the lesser sac and the greater sac is the epiploic foramen (of Winslow).
Intraperitoneal versus Retroperitoneal Organs The abdominal viscera are classified according to their relationship to the peritoneum. • Intraperitoneal organs are suspended by a mesentery and are almost
completely enclosed in visceral peritoneum. They are mobile.
• Retroperitoneal organs are partially covered on one side with parietal
peritoneum. They are immobile or fixed. Many retroperitoneal organs are originally suspended by a mesentery and become secondarily retroperitoneal. In secondary retroperitonealization, parts of the gut tube (most of the duodenum, pancreas, ascending colon, descending colon, part of rectum) fuse with the body wall by way of fusion of visceral peritoneum with parietal peritoneum. This causes the organs to become secondarily retroperitoneal (and the visceral peritoneum covering the organ is renamed as the parietal peritoneum). The vessels within the mesentery of these gut structures become secondarily retroperitoneal.
Table II-3-2. Intraperitoneal and Retroperitoneal Organs Major Intraperitoneal Organs (suspended by a mesentery)
Major Secondary Retroperitoneal Organs (lost a mesentery during development)
Major Primary Retroperitoneal Organs (never had a mesentery)
Stomach
Duodenum, 2nd and 3rd parts
Kidneys
Head, neck, and body of pancreas
Ureters
Liver and gallbladder Spleen Duodenum, 1st part Tail of pancreas Jejunum Ileum
Ascending colon Descending colon Upper rectum
Adrenal glands Aorta Inferior vena cava Lower rectum Anal canal
Appendix Transverse colon Sigmoid colon
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The epiploic foramen is the opening between omental bursa and greater peritoneal sac. The boundaries are described as follows: • Anteriorly: hepatoduodenal ligament and the hepatic portal vein • Posteriorly: inferior vena cava • Superiorly: caudate lobe of the liver • Inferiorly: first part of the duodenum
Physiology
Medical Genetics
Falciform ligament (contains ligamentum teres of liver) Pathology
Gallbladder
Behavioral Science/Social Sciences
Spleen Liver
Microbiology
Stomach Epiploic foramen
Duod enu m
Ascending colon
Greater omentum
Lesser curvature Greater curvature
Hepatogastric ligament Lesser Hepatoduodenal omentum ligament 1. Common bile duct 2. Proper hepatic artery 3. Hepatic portal vein Descending colon
FigureFigure II-3-8.II-3-8. Peritoneal Membranes Peritoneal Membranes
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Proper hepatic artery
IVC: inferior vena cava A: aorta Spl: spleen
Common bile duct
Greater peritoneal sac
Liver
Epiploic foramen
Lesser omentum Stomach
Omental bursa (lesser peritoneal sac)
IVC
A Kidney
Spl
Gastrosplenic ligament Splenorenal ligament (contains tail of pancreas and distal splenic vessels)
Figure II-3-9. Greater and Lesser Peritoneal Figure II-3-9. Greater and Lesser Peritoneal Sacs Sacs
DEVELOPMENT OF ABDOMINAL VISCERA Liver The hepatic diverticulum develops as an outgrowth of the endoderm of the foregut in the region of the duodenum near the border between the foregut and the midgut. • This diverticulum enters the ventral embryonic mesentery and distally
becomes the liver and gallbladder and proximately becomes the biliary duct system.
• The part of the ventral embryonic mesentery between the liver and gut
tube becomes the lesser omentum, and the part between the liver and ventral body wall becomes the falciform ligament.
Pancreas The pancreas develops from 2 pancreatic diverticula (buds), which evaginate from the endodermal lining of the foregut in the region of duodenum. • The ventral bud rotates around the gut tube to fuse with the dorsal
bud, together to form a single pancreas.
• The dorsal pancreatic bud forms the neck, body, and tail of the
pancreas.
• The ventral pancreatic bud forms the head and uncinate process.
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Clinical Correlate A defect in the rotation and fusion of the ventral and dorsal buds results Pharmacology Biochemistry in an annular pancreas which can constrict or obstruct the duodenum and result in polyhydramnios. Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Week 5 Gallbladder Ventral pancreas (forms head, uncinate)
Week 6 Common bile duct
Microbiology
Dorsal pancreas (forms neck, body, tail) Duodenum
Accessory pancreatic duct
Main pancreatic duct
Annular pancreas (polyhydramnios) Figure andDuodenum Duodenum FigureII-3-10. II-3-10.Development Development of of the the Pancreas Pancreas and
Spleen The spleen develops from mesoderm within the dorsal embryonic mesentery (Figure II-3-7B). The embryonic mesentery between the spleen and the gut tube becomes the gastrosplenic ligament. The mesentery between the spleen and the dorsal body wall becomes the splenorenal ligament.
CONGENITAL ABNORMALITIES OF THE GUT TUBE Hypertrophic pyloric stenosis occurs when the muscularis externa hypertrophies, causing a narrow pyloric lumen. It is associated with polyhydramnios; projectile, nonbilious vomiting; and a small knot at the right costal margin. Extrahepatic biliary atresia occurs when the lumen of the biliary ducts is occluded owing to incomplete recanalization. It is associated with jaundice, white-colored stool, and dark-colored urine. Annular pancreas occurs when the ventral and dorsal pancreatic buds form a ring around the duodenum, thereby causing an obstruction of the duodenum and polyhydramnios.
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Duodenal atresia occurs when the lumen of the duodenum is occluded owing to failed recanalization. It is associated with polyhydramnios, bile-containing vomitus, and a distended stomach. An omphalocele occurs when the midgut loop fails to return to the abdominal cavity and remains in the umbilical stalk. The viscera herniate through the umbilical ring and are contained in a shiny sac of amnion at the base of the umbilical cord. It is often associated with multiple anomalies of the heart and nervous system, with a high mortality rate (25%). Gastroschisis occurs when the abdominal viscera herniate through the body wall directly into the amniotic cavity, usually to the right of the umbilicus. • This is a defect in the closure of the lateral body folds and a weakness
of the anterior wall.
• Note that the viscera do not protrude through the umbilical ring and
are not enclosed in a sac of amnion.
Ileal (Meckel) diverticulum occurs when a remnant of the vitelline duct persists, thereby forming a blind pouch on the antimesenteric border of the ileum. It is often asymptomatic but can become inflamed if it contains ectopic gastric, pancreatic, or endometrial tissue, which may produce ulceration. It is typically found 2 feet from the ileocecal junction, are 2 inches long, and appears in 2% of the population. Vitelline fistula occurs when the vitelline duct persists, thereby forming a direct connection between the intestinal lumen and the outside of the body at the umbilicus. It is associated with drainage of meconium from the umbilicus. Malrotation of midgut occurs when the midgut undergoes only partial rotation and results in abnormal position of abdominal viscera. It may be associated with volvulus (twisting of intestines). Colonic aganglionosis (Hirschsprung disease) results from the failure of neural crest cells to form the myenteric plexus in the sigmoid colon and rectum. It is associated with loss of peristalsis and immobility of the hindgut, fecal retention and abdominal distention of the transverse colon (megacolon).
ABDOMINAL VISCERA Liver The liver has 2 surfaces: a superior or diaphragmatic surface and an inferior or a visceral surface. It lies mostly in the right aspect of the abdominal cavity and is protected by the rib cage. The liver is invested by visceral peritoneum: • The reflection of visceral peritoneum between the diaphragmatic
surface of the liver and the diaphragm forms the falciform ligament, which continues onto the liver as the coronary ligament and the right and left triangular ligaments.
• The extension of visceral peritoneum between the visceral surface of
the liver and the first part of the duodenum and the lesser curvature of the stomach forms the hepatoduodenal and hepatogastric ligaments of the lesser omentum, respectively.
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The liver is divided into 2 lobes of unequal size: • Fissures for the ligamentum teres and the ligamentum venosum, the
Pharmacology
Biochemistry
porta hepatis, and the fossa for the gallbladder further subdivide the right lobe into the right lobe proper, the quadrate lobe, and the caudate lobe.
• The quadrate and caudate lobes are anatomically part of the right lobe
Physiology
Medical Genetics
but functionally part of the left. They receive their blood supply from the left branches of the portal vein and hepatic artery and secrete bile to the left hepatic duct.
The liver has a central hilus, or porta hepatis, which receives venous blood from the portal vein and arterial blood from the hepatic artery. Pathology
Behavioral Science/Social Sciences
• The central hilus also transmits the common bile duct, which collects
bile produced by the liver.
• These structures, known collectively as the portal triad, are located Microbiology
in the hepatoduodenal ligament, which is the right free border of the lesser omentum.
The hepatic veins drain the liver by collecting blood from the liver sinusoids and returning it to the inferior vena cava. Ligamentum venosum
Proper hepatic artery
Left lobe
Hepatic vein Inferior vena cava
Caudate lobe
Common bile duct Right lobe
Hepatic portal vein Ligamentum teres of liver
Quadrate lobe Gallbladder
Figure II-3-11. Visceral Surface of the Liver Figure II-3-11. Visceral Surface of the Liver
Gallbladder The gallbladder lies in a fossa on the visceral surface of the liver to the right of the quadrate lobe. It stores and concentrates bile, which enters and leaves through the cystic duct. • The cystic duct joins the common hepatic duct to form the common
bile duct.
• The common bile duct descends in the hepatoduodenal ligament, then
passes posterior to the first part of the duodenum. The common bile duct
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penetrates the head of the pancreas where it joins the main pancreatic duct and forms the hepatopancreatic ampulla, which drains into the second part of the duodenum at the major duodenal papilla.
Right and left hepatic ducts Common hepatic duct
Liver
Cystic duct Pyloric antrum Pylorus
Body
Common bile duct
Fundus of gallbladder
Main pancreatic duct of Wirsung Hepatopancreatic ampulla of Vater
Duodenum Major duodenal papilla (Sphincter of Oddi)
Figure II-3-12. Figure II-3-12. BiliaryBiliary Ducts Ducts
Pancreas The pancreas horizontally crosses the posterior abdominal wall at approximately at the level of the transpyloric plane. The gland consists of 4 parts: head, neck, body, and tail. • The head of the pancreas rests within the C-shaped area formed by the
duodenum and is traversed by the common bile duct. It includes the uncinate process which is crossed by the superior mesenteric vessels.
• Posterior to the neck is the site of formation of the hepatic portal vein. • The body passes to the left and passes anterior to the aorta and the left
kidney. The splenic artery undulates along the superior border of the body of the pancreas with the splenic vein coursing posterior to the body.
• The tail of the pancreas enters the splenorenal ligament to reach the
hilum of the spleen. The tail is the only part of the pancreas that is intraperitoneal.
The main pancreatic duct (Figures II-3-12 and II-3-13) courses through the body and tail of the pancreas to reach the head of the pancreas, where it joins with the common bile duct to form the hepatopancreatic ampulla. The head of the pancreas receives its blood supply from the superior and inferior pancreaticoduodenal branches of the gastroduodenal and superior mesenteric arteries, respectively. This region is important for collateral circulation because there are anastomoses between these branches of the celiac trunk and superior mesenteric artery.
Clinical Correlate Carcinoma of the pancreas commonly occurs in the head of the pancreas and may constrict the main pancreatic duct and the common bile duct. Obstruction of the bile duct may cause jaundice.
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The neck, body, and tail of the pancreas receive their blood supply from the splenic artery.
Hepatic portal vein
Main pancreatic duct (of Wirsung)
Common bile duct Right suprarenal gland Right kidney
Spleen
2nd Tail Body Neck Head
3rd
Microbiology
Duodenum
Pancreas
Superior mesenteric artery and vein Figure II-3-13. Adult Pancreas
Figure II-3-13. Adult Pancreas
Clinical Correlate
Spleen
The spleen may be lacerated with a fracture of the 9th, 10th, or 11th rib on the left side.
The spleen is a peritoneal organ in the upper left quadrant that is deep to the left 9th, 10th, and 11th ribs. The visceral surface of the spleen is in contact with the left colic flexure, stomach, and left kidney. Inasmuch as the spleen lies above the costal margin, a normal-sized spleen is not palpable. The splenic artery and vein reach the hilus of the spleen by traversing the splenorenal ligament.
Clinical Correlate A sliding hiatal hernia occurs when the cardia of the stomach herniates through the esophageal hiatus of the diaphragm. This can damage the vagal trunks as they pass through the hiatus.
Stomach The stomach has a right lesser curvature, which is connected to the porta hepatis of the liver by the lesser omentum (hepatogastric ligament), and a left greater curvature from which the greater omentum is suspended (Figure II-3-8). The cardiac region receives the esophagus; and the dome-shaped upper portion of the stomach, which is normally filled with air, is the fundus. The main central part of the stomach is the body. The pyloric portion of the stomach has a thick muscular wall and narrow lumen that empties into the duodenum approximately in the transpyloric plane (L1 vertebra).
Duodenum The duodenum is C-shaped, has 4 parts, and is located retroperitoneal except for the first part.
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• The first part is referred to as the duodenal cap (bulb). The gastroduode-
nal artery and the common bile duct descend posterior to the first part.
• The second part (descending) receives the common bile duct and main
pancreatic duct at the hepatopancreatic ampulla (of Vater). Smooth muscle in the wall of the duodenal papilla is known as the sphincter of Oddi.
Note that the foregut terminates at the point of entry of the common bile duct; the remainder of the duodenum is part of the midgut.
Jejunum and Ileum The jejunum begins at the duodenojejunal junction and comprises 2/5 of the remaining small intestine. The beginning of the ileum is not clearly demarcated; it consists of the distal 3/5 of the small bowel. The jejunoileum is suspended from the posterior body wall by the mesentery proper. Although the root of the mesentery is only 6 inches long, the mobile part of the small intestine is approximately 22 feet in length.
Colon The cecum is the first part of the colon, or large intestine, and begins at the ileocecal junction. It is a blind pouch, which often has a mesentery and gives rise to the vermiform appendix. The appendix has its own mesentery, the mesoappendix. The ascending colon lies retroperitoneally and lacks a mesentery. It is continuous with the transverse colon at the right (hepatic) flexure of colon. The transverse colon has its own mesentery called the transverse mesocolon. It becomes continuous with the descending colon at the left (splenic) flexure of colon. The midgut terminates at the junction of the proximal two-thirds and distal one-third of the transverse colon. The descending colon lacks a mesentery. It joins the sigmoid colon where the large bowel crosses the pelvic brim. The sigmoid colon is suspended by the sigmoid mesocolon. It is the terminal portion of the large intestine and enters the pelvis to continue as the rectum. The superior one-third of the rectum is covered by peritoneum anteriorly and laterally. It is the fixed, terminal, straight portion of the hindgut. The anal canal is about 1.5 inches long and opens distally at the anus. It is continuous with the rectum at the pelvic diaphragm, where it makes a 90-degree posterior bend (anorectal flexure) below the rectum. • The puborectalis component of the pelvic diaphragm pulls the flexure
forward, helping to maintain fecal continence.
• The internal anal sphincter is circular smooth muscle that surrounds
the anal canal. The sympathetics (lumbar splanchnics) increase the tone of the muscle and the parasympathetics (pelvic splanchnics) relax the muscle during defecation.
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• The external anal sphincter is circular voluntary skeletal muscle sur-
rounding the canal that is voluntarily controlled by the inferior rectal branch of the pudendal nerve and relaxes during defecation.
Pharmacology
Biochemistry
• The anal canal is divided into upper and lower parts separated by the
pectinate line, an elevation of the mucous membrane at the distal ends of the anal columns.
Physiology
Medical Genetics
Table II-3-3. Comparison of Features Above and Below the Pectinate Line
Pathology
Microbiology
Behavioral Science/Social Sciences
Above
Below
Visceral (ANS) sensory innervation
Somatic sensory innervation
Portal venous drainage
Caval venous drainage
Drain to iliac lymph nodes
Drain to superficial inguinal nodes
Internal hemorrhoids (painless)
External hemorrhoids (painful)
Endoderm
Ectoderm
Abbreviations: ANS, autonomic nervous system
GASTROINTESTINAL HISTOLOGY The alimentary or gastrointestinal (GI) tract is a muscular tube that runs from the oral cavity to the anal canal. The GI tract walls are composed of 4 layers: mucosa, submucosa, muscularis externa, and serosa.
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Figure II-3-14. II-3-14. Organization Organization of Figure ofthe theGI GItract tract Mucosa (M) submucosa (SB), muscularis externa (ME), Mucosa (M) submucosa (SB), muscularis externa (ME), serosa or visceral peritoneum (S), mesentery (arrow) serosa or visceral peritoneum (S), mesentery (arrow)
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Mucosa The mucosa is the innermost layer and has 3 components. • The epithelium lining the lumen varies in different regions, depend-
ing on whether the function is primarily conductive and protective (stratified squamous; in the pharynx and esophagus), or secretory and absorptive (simple columnar; stomach and intestine).
• The lamina propria is a layer of areolar connective tissue that supports
the epithelium and attaches it to the underlying muscularis mucosae. Numerous capillaries form extensive networks in the lamina propria (particularly in the small intestine).
Within the lamina propria are blind-ended lymphatic vessels (lacteals)
that carry out absorbed nutrients and white blood cells (particularly lymphocytes). The GALT (gut-associated lymphoid tissue), responsible for IgA production, is located within the lamina propria.
• The muscularis mucosa is a thin smooth-muscle layer that marks the
innermost edge of the mucosa. The muscle confers some motility to the mucosa and facilitates discharge of secretions from glands. In the small intestine, a few strands of smooth muscle may run into the lamina propria and up to the tips of villi.
Submucosa The submucosa is a layer of loose areolar connective tissue that attaches the mucosa to the muscularis externa and houses the larger blood vessels and mucous-secreting glands.
Muscularis Externa The muscularis externa is usually comprised of 2 layers of muscle: an inner circular and an outer longitudinal. The muscularis externa controls the lumen size and is responsible for peristalsis. The muscle is striated in the upper third of the esophagus and smooth elsewhere.
Serosa The serosa (or peritoneum of anatomy) is composed of a mesothelium (a thin epithelium lining the thoracic and abdominal cavities) and loose connective tissue. In the abdominal cavity, the serosa surrounds each intestinal loop and then doubles to form the mesentery within which run blood and lymphatic vessels.
INNERVATION The GI tract has both intrinsic and extrinsic innervation. The intrinsic innervation is entirely located within the walls of the GI tract. The intrinsic system is capable of autonomous generation of peristalsis and glandular secretions. An interconnected network of ganglia and nerves located in the submucosa forms the Meissner’s plexus and controls much of the intrinsic motility of the lining of the alimentary tract. Auerbach’s plexus contains a second network of neuronal ganglia, and is located between the 2 muscle layers of the muscularis externa. All GI-tract smooth muscle is interconnected by gap junctions.
Clinical Correlate Hirschsprung disease or aganglionic megacolon is a genetic disease seen in ~1 per 5,000 live births. It may result from mutations that affect the migration of neural crest cells into the gut. This results in a deficiency of terminal ganglion cells in Auerbach’s plexus and affects digestive tract motility, particularly in the rectum (peristalsis is not as effective and constipation results).
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The extrinsic autonomic innervation to the GI tract is from the parasympathetic (stimulatory) and sympathetic (inhibitory) axons that modulate the activity of the intrinsic innervation. Sensory fibers accompany the parasympathetic nerves and mediate visceral reflexes and sensations, such as hunger and rectal fullness. Visceral pain fibers course back to the CNS with the sympathetic innervation. Pain results from excessive contraction and/or distention of the smooth muscle. Visceral pain is referred to the body wall dermatomes that match the sympathetic innervation to that GI tract structure.
IMMUNE FUNCTIONS Pathology
Microbiology
Behavioral Science/Social Sciences
The lumen of the GI tract is normally colonized by abundant bacterial flora. The majority of the bacteria in the body—comprising about 500 different species— are in our gut, where they enjoy a rich growth medium within a long, warm tube. Most of these bacteria are beneficial (vitamins B12 and K production, additional digestion, protection against pathogenic bacteria) but a few species of pathogenic microbes appear at times. The gut has defense mechanisms to fight these pathogens (GALT and Paneth cells).
REGIONAL DIFFERENCES Major differences lie in the general organization of the mucosa (glands, folds, villi, etc.) and in the types of cells comprising the epithelia and associated glands in the GI tract.
Figure II-3-15. Histologic Organization of the Digestive Tube
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Table II-3-4. Histology of Specific Regions Region
Major Characteristics
Mucosal Cell Types at Surface
Function of Surface Mucosal Cells
Esophagus
• Nonkeratinized stratified squamous epithelium
—
—
Mucous cells
Secrete mucous; form protective layer against acid; tight junctions between these cells probably contribute to the acid barrier of the epithelium.
Chief cells
Secrete pepsinogen and lipase precursor
Parietal cells
Secrete HCl and intrinsic factor
Enteroendocrine (EE) cells
Secrete a variety of peptide hormones
Mucous cells
Same as above
Parietal cells
Same as above
EE cells
High concentration of gastrin
• Skeletal muscle in muscularis externa (upper 1/3) • Smooth muscle (lower 1/3) Stomach (body and fundus)
Pylorus
Rugae: shallow pits; deep glands
Deep pits; shallow, branched glands
Small intestine
Villi, plicae, and crypts
Columnar absorptive cells
Contain numerous microvilli that greatly increase the luminal surface area, facilitating absorption
Duodenum
Brunner glands, which discharge alkaline secretion
Goblet cells
Secrete acid glycoproteins that protect mucosal linings
Paneth cells
Contains granules that contain lysozyme. May play a role in regulating intestinal flora
EE cells
High concentration of cells that secrete cholecystokinin and secretin
Jejunum
Villi, well developed plica, crypts
Same cell types as found in the duodenal epithelium
Same as above
Ileum
Aggregations of lymph nodules called Peyer’s patches
M cells found over lymphatic nodules and Peyer’s patches
Endocytose and transport antigen from the lumen to lymphoid cells
Large intestine
Lacks villi, crypts
Mainly mucous-secreting and absorptive cells
Transports Na+ (actively) and water (passively) out of lumen
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Oral Cavity The epithelium of the oral cavity is a stratified squamous epithelium. Mucous and serous secretions of the salivary glands lubricate food, rinse the oral cavity, moisten the food for swallowing and provide partial antibacterial protection. Secretions of IgA from plasma cells within the connective tissue are transported through the gland epithelia to help protect against microbial attachment and invasion.
Esophagus Pathology
Behavioral Science/Social Sciences
The esophagus is also lined by a stratified squamous epithelium. In the lower part of the esophagus there is an abrupt transition to the simple columnar epithelium of the stomach. Langerhans cells—macrophage-like antigen-presenting cells—are present in the epithelial lining. The muscularis externa of the esophagus consists of striated muscle in the upper third, smooth muscle in the distal third, and a combination of both in the middle third.
Microbiology
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Figure II-3-15. Esophagus with non-keratinizing stratified squamous Figure II-3-16. Esophagus stratified squamous epitheepithelium (arrow) and awith thin non-keratinizing lamina propria with vessels (arrowheads) lium (arrow) and a thin lamina propria with vessels (arrowheads) The underlying muscularis externa (ME) is skeletal muscle from The underlying muscularis externa (ME) is skeletal muscle the upper half of the esophagus from the upper half of the esophagus
Stomach The stomach has 3 distinct histological areas: the cardia, body, and pyloric antrum. The mucosa of the stomach is thrown into folds (rugae) when empty, but disappears when the stomach is full. The surface is lined by a simple columnar epithelium. The stomach begins digestion by initiating the chemical and enzymatic breakdown of ingested food. Proteins are initially denatured by the acidic gastric juice before being hydrolyzed to polypeptide fragments by the enzyme pepsin. The chyme consists of denatured and partially broken-up food particles suspended in a semi-fluid, highly acidic medium.
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Gastric pits form numerous deep tubular invaginations that line the inner surface of the stomach. The gastric pits are closely spaced; they penetrate into the thickness of the mucosa and extend into gastric glands. The transition between pits and glands is marked by the isthmus, where there is a narrowing of the lumen, and by a change in cellular composition of the epithelium. The glands are coiled in the cardiac and pyloric regions of the stomach and straight in the fundus and body regions. Glands in the body of the stomach deliver gastric juice (containing HCl and enzymes, rennin and lipase) to each pit, and from there to the stomach lumen. There are about 5 million glands in the stomach, secreting some 2 liters of fluid per day. Mucous-secreting cells are located on the inner surface of the stomach, in the pit and in the neck, the transitional region between pits and glands. These cells produce a thick layer of mucous which covers and protects the stomach, falling into 2 categories: the surface mucous is composed of neutral glycoproteins, while the mucous secreted by the neck mucous cells is composed of acidic glycoproteins. In cardiac and pyloric regions, mucous cells are also the major cell type in the glands.
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Figure II-3-16. Cardia part of the stomach with gastric pits and Figure II-3-17. Cardiac part of theglands. stomach with gastric pits coiled gastric
and coiled gastric glands.
Stem cells that regenerate all stomach cells are located Stem cells that at regenerate all (arrowhead) stomach cells are located the isthmus
at the isthmus (arrowhead)
Oxyntic or parietal cells secrete 0.1N HCl into the stomach lumen and bicarbonate ions into the lamina propria (a byproduct of the acid production) in response to histamine, gastrin, and acetylcholine. These cells also secrete intrinsic factor (a glycoprotein necessary for absorption of vitamin B12). Vitamin B12 is required for production of erythrocytes; deficiencies result in pernicious anemia and a disruption of peripheral and central nervous system myelin (see subacute combined degeneration in Neuroscience section).
Clinical Correlate Acetylcholine and gastrin increase HCL secretion by parietal cells. Histamine potentiates both by binding to the histamine H2 receptor. Cimetidine and H2 antagonists inhibit histamine.
Parietal cells, located in the upper regions of the gastric glands, have a broader base and narrower apex. Their structure varies greatly depending on their functional state.
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Clinical Correlate Infection by Helicobacter pylori affects the gastric mucosal lining and allows Pharmacology Biochemistry pepsin, HCl, and proteases to erode the mucosa.
Chief or peptic cells secrete pepsinogen, an enzyme precursor that is stored in secretory (zymogen) granules before its induced secretion. Pepsinogen is inactive and protects the peptic cells from autodigestion. Low pH, in the stomach lumen, converts pepsinogen to pepsin.
Hematemesis and melena are common clinical findings. Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
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Figure near the thebase baseofofgastric gastricglands glands FigureII-3-17. II-3-18.Stomach Stomach near Pale-staining and chief chief cells cells(B) (B)are areshown. shown. Pale-stainingparietal parietalcells cells (A) (A) and
The enteroendocrine cells or APUD cells (amine precursor uptake and decarboxylation) are present throughout the GI tract and are also found in the respiratory tract. They constitute a diffuse neuroendocrine system that collectively accounts for more cells than all other endocrine organs in the body. Enteroendocrine cells are dispersed throughout the GI tract so that they can receive and transmit local signals. The stem cells responsible for the regeneration of all types of cells in the stomach epithelium are located in the isthmus. Their mitotic rate can be influenced by the presence of gastrin and by damage (aspirin, alcohol, bile salt reflux). Renewal of many gastric epithelial cells occurs every 4–7 days. • Although the stem cells are capable of differentiating into any of the
stomach cell types, there is evidence that the position of the cell along the gland influences its fate.
• In contrast to the short life span (4–5 days) of the cells near the acidic
environment, the chief cells—deep within the glands—may have a life span >190 days.
Small Intestine The small intestine is tubular in shape and has a total length of about 21 feet. The effective internal surface area of the small intestine is greatly increased by the plicae circulares, villi and microvilli.
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Plicae circulares (circular folds or valves of Kerckring) are foldings of the inner surface that involve both mucosa and sub-mucosa. Plicae circulares increase the surface area by a factor of 3. Villi arise above the muscularis mucosae and they include the lamina propria and epithelium of the mucosa. Villi increase the surface area by a factor of 10. Microvilli of the absorptive epithelial cells increase the surface area by a factor of 20–30. The surface area of microvilli is increased even further by the presence of surface membrane glycoproteins, constituting the glycocalyx to which enzymes are bound. The luminal surface of the small intestine is perforated by the openings of numerous tubular invaginations (the crypts of Lieberkühn) analogous to the glands of the stomach. The crypts penetrate through the lamina propria and reach the muscularis mucosae. The small intestine completes digestion, absorbs the digested food constituents (amino acids, monosaccharides, fatty acids), and transports them into blood and lymphatic vessels. The duodenum is the proximal pyloric end of the small intestine. Distal to the duodenum is the jejunum, and then the ileum. In the small intestine, the chyme from the stomach is mixed with mucosal cell secretions, exocrine pancreatic juice, and bile. Striated border Capillary (shown with red blood cell) Villus
Lymphatic lacteal Goblet cells
Enterocytes
Crypt
Myofibroblast Stem cells Paneth cells Lamina propria
Smooth muscle Muscularis mucosae
Figure II-3-19. Small Intestine Mucosal Histology Figure II-3-18. Small Intestine Mucosal Histology
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Clinical Correlate Any compromise of the mucous protection can lead to significant Pharmacology Biochemistry damage and irritation of the gastrointestinal tract, leading to gastritis, duodenitis, or even peptic ulcer disease. Physiology
Pathology
Medical Genetics
Behavioral Science/Social Sciences
Mucous production occurs in surface epithelial cells throughout the GI tract, by Brunner glands in the duodenum and goblet cells in the mucosa throughout the intestine. Mucous functions include lubrication of the GI tract, binding bacteria, and trapping immunoglobulins where they have access to pathogens. The rate of mucous secretion is increased by cholinergic stimulation, chemical irritation, and physical irritation. In the duodenum, the acidic chyme from the stomach is neutralized by the neutral or alkaline mucous secretions of glands located in the submucosal or Brunner’s glands. The duodenum also receives digestive enzymes and bicarbonate from the pancreas and bile from the liver (via gallbladder) through the bile duct, continuing the digestive process.
Clinical Correlate Microbiology
Peristalsis is activated by the parasympathetic system. For those suffering from decreased intestinal motility manifesting as constipation (paralytic ileus, diabetic gastroparesis), dopaminergic and cholinergic agents are often used (e.g., metoclopramide).
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Figure II-3-19. Duodenum with villi (curved arrow) and submucosal Figure II-3-20. Brunner Duodenum with villi (curved arrow) and glands (arrow) submucosal Brunner glands (arrow) Patches of lymphatic tissue are in the lamina propria (arrowheads). Patches of lymphatic tissue are in the lamina propria (arrowheads).
In the jejunum, the digestion process continues via enterocyte-produced enzymes and absorbs food products. The plicae circulares are best developed here. In the ileum, a major site of immune reactivity, the mucosa is more heavily infiltrated with lymphocytes and the accompanying antigen-presenting cells than the duodenum and jejunum. Numerous primary and secondary lymphatic nodules (Peyer’s patches) are always present in the ileum’s mucosa, though their location is not fixed in time. In the infant, maternal IgGs that are ingested are recognized by the Fc receptors in microvilli and endocytosed to provide passive immunity. In the adult, only trace amounts of intact proteins are transferred from lumen to lamina propria, but IgAs produced in GALT in the ileum are transported in the opposite direction into the lumen.
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Throughout the small intestine, the simple columnar intestinal epithelium has 5 types of differentiated cells, all derived from a common pool of stem cells. • Goblet cells secrete mucous that protects the surface of the intestine
with a viscous fluid consisting of glycoproteins (20% peptides, 80% carbohydrates).
• Enterocytes have 2 major functions. Enterocytes participate in the
final digestion steps and they absorb the digested food (in the form of amino acids, monosaccharides, and emulsified fats) by transporting it from the lumen of the intestine to the lamina propria, where it is carried away by blood vessels and lymphatics.
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Note Histologically, the duodenum contains submucosal Brunner’s glands, and the ileum contains Peyer’s patches in the lamina propria. The jejunum can be easily recognized because it has neither Brunner’s glands nor Peyer’s patches.
• Paneth cells are cells located at the base of the crypts, especially in the
jejunum and ileum; they contain visible acidophilic secretory granules located in the apical region of the cells. These cells protect the body against pathogenic microorganisms by secreting lysozyme and defensins (or cryptins) that destroy bacteria. Their life span is about 20 days.
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Figure II-3-20. Cells at the base of crypts of Lieberkühn include Figure II-3-21. Cells at the base of crypts of Lieberkühn include Paneth cells (A) with large apical granules of lysozyme, and Paneth (A) with large granules of lysozyme, an cells adjacent stem cellapical (circle) undergoing mitosis.and an adjacent stem cell (circle) undergoing mitosis. • Enteroendocrine cells of the small and large intestine, like those of the
stomach, secrete hormones that control the function of the GI tracts and associated organs. They are located in the lower half of the crypts and are detectable by silver-based stains.
• Stem cells are located in the crypts, about one-third of the way up
from the bottom. Their progeny differentiates into all the other cell types. The epithelial lining of the small intestine, particularly that covering the villi, completely renews itself every 5 days (or longer, during starvation). The newly created cells (goblet, enterocytes, and enteroendocrine cells) migrate up from the crypts, while the cells at the tips of microvilli undergo apoptosis and slough off. There is also a
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group of fibroblasts that accompany these epithelial cells as they move toward the tips of the villi. Other cells move to the base of the crypts, replenishing the population of Paneth and enteroendocrine cells. Gut-associated lymphatic tissue (GALT): Throughout the intestine, the lamina propria is heavily infiltrated with macrophages and lymphocytes. Peyer’s patches are patches of GALT that are prominent in the ileum. M cells in the epithelium transport luminal antigens to their base, where they are detected by B lymphocytes and taken up by antigen-presenting macrophages.
Microbiology
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Figure II-3-21. Ileum with Payer’s patches (arrow) and Figure II-3-22. Ileum with Peyer’s patchesin(arrow) and central (arrowcentral lacteals (arrowheads) the lamina proprialacteals of the villi heads) in the lamina propria of the villi
Large Intestine The large intestine includes the cecum (with appendix), ascending, transverse, and descending colon, sigmoid colon, rectum, and anus. The large intestine has a wide lumen, strong musculature, and longitudinal muscle that is separated into 3 strands, the teniae coli. The inner surface has no plicae and no villi but consists of short crypts of Lieberkühn.
General features • The colon is larger in diameter and shorter in length than is the small
intestine. Fecal material moves from the cecum, through the colon (ascending, transverse, descending, and sigmoid colons), rectum, and anal canal.
• Three longitudinal bands of muscle, the teniae coli, constitute the
outer layer. Because the colon is longer than these bands, pouching occurs, creating haustra between the teniae and giving the colon its characteristic “caterpillar” appearance.
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• The mucosa has no villi, and mucous is secreted by short, inward-
projecting colonic glands.
• Abundant lymphoid follicles are found in the cecum and appendix,
and more sparsely elsewhere.
• The major functions of the colon are reabsorption of fluid and elec-
trolytes and temporary storage of feces.
Defecation Rectal distention with feces activates intrinsic and cord reflexes that cause relaxation of the internal anal sphincter (smooth muscle) and produce the urge to defecate. If the external anal sphincter (skeletal muscle innervated by the pudendal nerve) is then voluntarily relaxed, and intra-abdominal pressure is increased via the Valsalva maneuver, defecation occurs. If the external sphincter is held contracted, the urge to defecate temporarily diminishes. Throughout the large intestine, the epithelium contains goblet, absorptive, and enteroendocrine cells. Unlike the small intestine, about half of the epithelial cells are mucous-secreting goblet cells, providing lubrication. The major function of the large intestine is fluid retrieval. Some digestion is still occurring, mainly the breakdown of cellulose by the permanent bacterial flora. Stem cells are in the lower part of the crypts.
Copyright McGraw-Hill permission. Copyright McGraw-HillCompanies. Companies.Used Usedwith with permission.
Figure II-3-22. Large intestine with crypts but no villi and many Figure II-3-23. Large intestine with interspersed crypts but no among villi andenterocytes many light-staining light-staining goblet cells goblet cells interspersed among enterocytes
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GASTROINTESTINAL GLANDS Salivary Glands The major salivary glands are all branched tubuloalveolar glands, with secretory acini that drain into ducts, which drain into the oral cavity. Acini contain serous, mucous, or both types of secretory cells, as well as myoepithelial cells, both surrounded by a basal lamina. Serous cells secrete various proteins and enzymes. Mucous cells secrete predominantly glycosylated mucins.
Table II-3-5. Gastrointestinal Glands Salivary glands Submandibular Parotid Microbiology
Sublingual Functions
• Produce approximately 1.5 L/day of saliva • P resence of food in the mouth; the taste, smell, sight, or thought of food; or the stimulation of vagal afferents at the distal end of the esophagus increase production of saliva • Initial triglyceride digestion (lingual lipase) • Initial starch digestion (α-amylase) • Lubrication
Regulation
Parasympathetic
↑ synthesis and secretion of watery saliva via muscarinic receptor stimulation; (anticholinergics → dry mouth)
Sympathetic
↑ synthesis and secretion of viscous saliva via β-adrenergic receptor stimulation
The ducts that drain the glands increase in size and are lined by an epithelium that transitions from cuboidal to columnar to pseudostratified to stratified columnar cells. The smallest ducts, intercalated ducts, have myoepithelial cells; the next larger ducts, striated ducts, have columnar cells with basal striations, caused by basal infolding of cell membranes between prominent mitochondria. These columnar cells make the saliva hypotonic by transporting Na and Cl ions out of saliva back into the blood.
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Figure II-3-23. Submandibular with a mix of light-staining mucus Figure II-3-24. Submandibular a mix of light-staining mucous acini acini (arrow) adjacentwith to dark-staining serous acini (arrow) adjacent to dark-staining serous acini Small vessels (arrowheads) Small vessels (arrowheads) • The parotid glands lie on the surface of the masseter muscles in the
lateral face, in front of each external auditory meatus. The parotids are entirely serous salivary glands that drain inside each cheek through Stensen’s ducts which open above the second upper molar tooth. The parotid glands contribute 25% of the volume of saliva.
• The submandibular glands lie inside the lower edge of the mandible,
and are mixed serous/mucous glands with a predominance of serous cells. They drain in the floor of the mouth near the base of the tongue through Wharton’s ducts. The submandibular glands contribute 70% of the volume of saliva.
Clinical Correlate The parotid gland is the major site of the mumps and rabies viruses that are transmitted in saliva. Benign tumors most frequently appear at the parotid gland; their removal is complicated by the facial nerve traversing the gland.
• The sublingual glands lie at the base of the tongue, and are also mixed
serous/mucous glands with a predominance of mucous cells. They drain into the mouth through multiple small ducts. The sublingual glands contribute 5% of the volume of saliva.
Exocrine Pancreas The pancreas is a branched tubuloacinar exocrine gland with acini. The acini are composed of secretory cells that produce multiple digestive enzymes including proteases, lipases, and amylases. Acinar cells are functionally polarized, with basophilic RER at their basal ends below the nucleus, and membrane-bound, enzyme-containing eosinophilic zymogen granules toward their apex. The endocrine-producing cells of the islets of Langerhans are embedded within the exocrine pancreas.
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Figure II-3-24. Pancreas with light-staining islets of Langerhans Figure II-3-25. Pancreas with light-staining Langerhans (arrows) surrounded by exocrine acini withislets ductsof(arrowheads) (arrows)and surrounded by exocrine acini with ducts adjacent blood vessels (V) (arrowheads) and adjacent blood vessels (V)
Unlike salivary glands, the pancreas lacks myoepithelial cells in acini and lacks striated ducts. Also, unlike salivary glands, the cells of the intercalated ducts extend partially into the lumen of pancreatic acini as centroacinar cells. The pancreas does not usually have mucinous cells in acini, but may have mucinous cells in its ducts. Pancreatic acini drain via progressively larger ducts into the duodenum. The main pancreatic duct (of Wirsung) is the distal portion of the dorsal pancreatic duct that joined the ventral pancreatic duct in the head of the pancreas. The main duct typically joins with the common bile duct and enters the duodenum through the ampulla of Vater (controlled by the sphincter of Oddi). Sometimes the pancreas has a persistent accessory duct with separate drainage into the duodenum, the accessory duct of Santorini, and a persisting remnant of the proximal part of the dorsal pancreatic duct.
Liver The liver is the largest visceral organ and gland (both exocrine and endocrine) in the body. Hepatocytes, of endodermal epithelial origin, carry out both exocrine and endocrine functions. The liver has unusual capillaries, the hepatic sinusoids, that facilitate exchange (uptake and secretion) between hepatocytes and blood. The liver has Kupffer cells, specialized cells of the mononuclear phagocyte system (blood monocyte derived) which patrol the space of Disse between hepatocytes and blood. The liver has epithelial lined exocrine (excretory) ducts, the bile ducts, lined by biliary epithelium, which drain hepatocyte products (bile) into the duodenum, ultimately through the common bile duct. Blood flow into the liver is dual (75% from portal vein, 25% from hepatic artery), while blood flow out is via hepatic veins into the inferior vena cava.
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Hepatocyte
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Central vein Bile canaliculi Sinusoid ethmoidal cell Sinusoid
Bile flow
Inlet venule Bile duct Portal vein Hepatic artery
Space of Disse Kupffer cell Sinusoid Hepatocyte Bile canaliculi
Figure II-3-25. Organization of a Liver Lobule
Figure II-3-26. Organization of a Liver Lobule
Hepatocytes are functionally polarized, like many other epithelial cells, but rather than being polarized along a single axis, each hepatocyte has multiple “basal” and “apical” surfaces. • Where 2 hepatocytes abut, their “apical” surfaces form bile canaliculi,
extracellular grooved bile channels joined by tight and occluding junctions between adjacent hepatocytes. Bile is secreted into bile canaliculi, which drains into progressively larger bile ducts and empties into the duodenum.
• Where a hepatocyte abuts a sinusoid, its membrane has microvilli,
representing a “basal” or basolateral surface. Exchange between blood and hepatocytes is facilitated by the surface microvilli. This exchange occurs in the space of Disse, which is between the fenestrated endothelial cells of the sinusoid and the basal surface of hepatocytes.
The hepatic artery and portal vein enter and the common hepatic duct exits the liver in the hepatic hilum. Within the liver, branches of the hepatic artery, portal vein, and bile duct tend to run together in thin connective tissue bands. When seen in cross section, these 3 structures and their connective tissue are called a portal triad or portal tract. Blood from both the portal vein and hepatic artery branches flows through and mixes in hepatic sinusoids that run between cords or plates of hepatocytes. After passing by hepatocytes, the sinusoidal blood flows into hepatic venules, which form progressively larger branches draining into the right and left hepatic veins which drain into the inferior vena cava. A classic hepatic lobule is a hexagonal structure with a portal tract at each corner of the hexagon and a central vein in the center of the hexagon. Blood flow is from the triads into the central vein and bile flow is opposite, from the central vein to the triads.
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Copyright McGraw-Hill Companies. Used with permission. Copyright McGraw-Hill Companies. Used with permission.
Figure II-3-26. Liver lobules with central veins (A) in the center of each Figure Livertissue lobules with central veins (A) in the center of and lobule and II-3-27. connective (arrowheads) separating each lobule each lobule and connective tissue (arrowheads) separating portal triads at each point of the lobule (B) each lobule and portal triads at each point of the lobule (B)
A portal lobule is a triangular structure with a central vein at each corner and a portal tract in the center. Bile flows from the periphery of the portal lobule into the central triad. A hepatic acinus is based on blood flow from the hepatic artery branches to central veins. As hepatic arterial blood flow enters the sinusoids from side branches extending away from the center of the hepatic triad (rather than directly from the triad), the center of the acinus is conceived of as centered on such a branch extending out from a triad (or between 2 triads) and ending at 2 nearby central veins, resulting in a roughly elliptical structure with portal tracts at the 2 furthest poles and 2 central veins at the 2 closest edges. In the acinus, the hepatocytes receiving the first blood flow (and the most oxygen and nutrients) are designated zone 1, while those receiving the last blood flow (and least oxygen and nutrients) are near the central veins and designated zone 3. Zone 2 hepatocytes are in between zones 1 and 3. This model helps to explain the differential effect on hepatocytes of changes in blood flow, oxygenation, etc. Zone 3 is most susceptible to injury by decreased oxygenation of blood or decreased blood flow into the liver (as well as stagnation of blood drainage out of the liver due to congestive heart failure). The metabolic activity of hepatocytes varies within the zones of the acinus. Zone 1 hepatocytes are most involved in glycogen synthesis and plasma protein synthesis (albumin, coagulation factors and complement components). Zone 3 cells are most concerned with lipid, drug, and alcohol metabolism and detoxification.
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Ito cells (stellate cells) are mesenchymal cells that live in the space of Disse. They contain fat and are involved in storage of fat-soluble vitamins, mainly vitamin A. Bile formation by hepatocytes serves both an exocrine and excretory function. Bile salts secreted into the duodenum aid in fat emulsification and absorption, as well as excretion of endogenous metabolites (bilirubin) and drug metabolites that cannot be excreted by the kidney.
Gallbladder The gallbladder is lined by a simple columnar epithelium with both absorptive and mucin secretory function, with underlying lamina propria. Unlike the gut tube, the gallbladder lacks muscularis mucosae and submucosa, and the muscularis externa is not organized into 2 distinct layers like the gut. The surface of the gallbladder is covered by peritoneal serosa (mesothelium). The gallbladder has a wide end, the fundus, and a narrowing neck, which empties into the cystic duct and which has spiral valves of Heister. The cystic duct joins the common hepatic duct to form the common bile duct, which joins the pancreatic duct at or just before the ampulla of Vater.
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Clinical Correlate When stimulated during liver injury, Ito cells may release type I collagen and other matrix components into the space of Disse, contributing to scarring of the liver in some diseases (cirrhosis due to ethanol). This may lead to the development of portal hypertension, portacaval anastomoses, and esophageal or rectal bleeding.
Clinical Correlate Disturbance of the balance in the components of bile can lead to precipitation of one or more of the bile components, resulting in stone (or calculus) formation or lithiasis in the gallbladder and/or bile ducts.
Note Main Functions of Bile • A bsorption of fats from intestinal lumen • Excretion • Transport of IgA
Copyright McGraw-Hill Companies. Used with permission.
Copyright McGraw-Hill Companies. Used with permission.
Figure II-3-27. Gallbladder with folds lined by a simple Figure II-3-28. Gallbladder folds lined simplecells columnar epithelium columnar with epithelium withby noagoblet with no goblet cells
The gallbladder stores and concentrates bile by absorption of electrolytes and water. After a meal, entrance of lipid into the duodenum stimulates enteroendocrine cells of the duodenum to secrete cholecystokinin, which stimulates contraction and emptying of the gallbladder. At the same time, it relaxes the sphincter of Oddi in the ampulla of Vater. This delivers a bolus of bile into the duodenum.
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ARTERIAL SUPPLY TO ABDOMINAL VISCERA The blood supply to the abdominal viscera and the body wall is provided by branches of the abdominal aorta. The aorta enters the abdomen by passing through the aortic hiatus of the diaphragm at the T12 vertebra (Figure II-3-28). It descends on the lumbar vertebra just to the left of the midline and bifurcates at the L4 vertebral level. During its short course in the abdomen, the aorta gives origin to 3 groups of branches: (a) 3 unpaired visceral branches, (b) 3 paired visceral branches, and (c) several parietal branches to the body wall.
Note
T12
Abdominal Aorta Branches Pathology
Behavioral Science/Social Sciences
Inferior phrenic
Visceral branches Unpaired: celiac (foregut), superior mesenteric (midgut), inferior Microbiology mesenteric (hindgut)
L1
Paired: middle suprarenals, renals, gonadals
L2
Celiac
Middle suprarenal
Superior mesenteric Renal
Parietal branches Unpaired: median sacral Paired: inferior phrenics, lumbars, common iliac
Gonadal
Lumbars
L3 Inferior mesenteric
L4
Median sacral
Common iliac Internal iliac (to pelvis and perineum) External iliac (to lower limb)
Figure II-3-29. Visceral and Parietal Branches of the Abdominal Aorta Figure II-3-28. Visceral and Parietal Branches of the Abdominal Aorta
Clinical Correlate The most common site for an abdominal aneurysm is in the area between the renal arteries and the bifurcation of the abdominal aorta. Signs include decreased circulation to the lower limbs and pain radiating down the back of the lower limbs. The most common site of atherosclerotic plaque is at the bifurcation of the abdominal aorta.
Three Unpaired Visceral Arteries Celiac Artery (Trunk) The celiac artery is the blood supply to the structures derived from the foregut. The artery arises from the anterior surface of the aorta just inferior to the aortic hiatus at the level of T12–L1 vertebra. The celiac artery passes above the superior border of the pancreas and then divides into 3 retroperitoneal branches. The left gastric artery courses superiorly and upward to the left to reach the lesser curvature of the stomach. The artery enters the lesser omentum and
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follows the lesser curvature distally to the pylorus. The distribution of the left gastric includes the following: • Esophageal branch to the distal one inch of the esophagus in the
abdomen
• Most of the lesser curvature
The splenic artery is the longest branch of the celiac trunk and runs a very tortuous course along the superior border of the pancreas. The artery is retroperitoneal until it reaches the tail of the pancreas, where it enters the splenorenal ligament to enter the hilum of the spleen. The distributions of the splenic artery include: • Direct branches to the spleen • Direct branches to the neck, body, and tail of pancreas • Left gastroepiploic artery that supplies the left side of the greater
curvature of the stomach
• Short gastric branches that supply to the fundus of the stomach
The common hepatic artery passes to the right to reach the superior surface of the first part of the duodenum, where it divides into its 2 terminal branches: • Proper hepatic artery ascends within the hepatoduodenal ligament
of the lesser omentum to reach the porta hepatis, where it divides into the right and left hepatic arteries. The right and left arteries enter the 2 lobes of the liver, with the right hepatic artery first giving rise to the cystic artery to the gallbladder.
• Gastroduodenal artery descends posterior to the first part of the
duodenum and divides into the right gastroepiploic artery (supplies the pyloric end of the greater curvature of the stomach) and the superior pancreaticoduodenal arteries (supplies the head of the pancreas, where it anastomoses the inferior pancreaticoduodenal branches of the superior mesenteric artery).
Clinical Correlate • T he splenic artery may be subject to erosion by a penetrating ulcer of the posterior wall of the stomach into the lesser sac. • T he left gastric artery may be subject to erosion by a penetrating ulcer of the lesser curvature of the stomach. • T he gastroduodenal artery may be subject to erosion by a penetrating ulcer of the posterior wall of the first part of the duodenum.
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Gastroduodenal artery
Proper hepatic artery Pharmacology
Esophageal branch
Biochemistry
Cystic artery
Physiology
Pathology
Microbiology
Common hepatic artery
Left gastric artery Celiac trunk
Superior Medical Genetics pancreaticoduodenal artery
Splenic artery
Right Behavioral Science/Social Sciences gastroepiploic artery
Left gastroepiploic artery Gastroepiploic artery
Inferior pancreaticoduodenal artery
Superior mesenteric artery
Figure II-3-29. Celiac Artery Figure II-3-30. Celiac Artery
Superior Mesenteric Artery The superior mesenteric artery (SMA) supplies the viscera of the midgut. The SMA arises from the aorta deep to the neck of the pancreas just below the origin of the celiac artery at the L1 vertebral level. It then descends anterior to the uncinate process of the pancreas and the third part of the duodenum to enter the mesentery proper. The superior mesenteric vein is to the right of the artery. Branches of the SMA include: • Inferior pancreaticoduodenal arteries which anastomose with the
superior pancreaticoduodenal branches of the gastroduodenal artery in the head of the pancreas
• Intestinal arteries arise as 12–15 branches from the left side of the
SMA and segmentally supply the jejunum and ileum. Distally, they form vascular arcades and vasa recta arteries at the wall of the gut.
• Ileocolic artery is the most inferior branch which descends to the
lower right quadrant to supply the distal ileum and cecum.
• Right colic artery passes to the right to supply the ascending colon. • Middle colic artery ascends and enters the transverse mesocolon to
supply the proximal two-thirds of the transverse colon.
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Transverse colon
Marginal artery
Middle colic artery Inferior pancreaticoduodenal artery Right colic artery
Superior mesenteric artery First jejunal artery
Ileocolic artery
Intestinal arteries (jejunal and ileal)
Ascending colon
Figure II-3-30. Distribution of Superior Mesenteric Artery Figure II-3-31. Distribution of Superior Mesenteric Artery
Inferior Mesenteric Artery The inferior mesenteric artery (IMA) is the third unpaired visceral branch of the aorta that supplies the hindgut (distal third of the transverse colon to the pectinate line). It arises from the aorta just above its bifurcation at the level of the L3 vertebra. It descends retroperitoneally and inferiorly to the left and gives rise to 3 branches: • Left colic artery supplies the distal third of the transverse colon and
the descending colon
• Sigmoid arteries to the sigmoid colon • Superior rectal artery descends into the pelvis and supplies the supe-
rior aspect of the rectum and anal canal.
The branches of the SMA and IMA to the ascending, transverse and d escending parts of the large intestines are interconnected by a continual arterial arch called the marginal artery. The marginal artery provides a collateral circulation between the parts of the large intestines if there is a vascular obstruction in some part of the SMA and IMA.
Clinical Correlate Branches of the celiac and superior mesenteric arteries form a collateral circulation within the head of the pancreas.
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Clinical Correlate The splenic flexure is the most common site of bowel ischemia. Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Inferior mesenteric artery Descending colon Left colic artery
Microbiology
Marginal artery Sigmoid arteries Sigmoid colon Rectum
Superior rectal artery
Figure II-3-31. Distribution of Inferior Mesenteric Artery
Figure II-3-32. Distribution of Inferior Mesenteric Artery
Three Paired Visceral Arteries
Clinical Correlate The left renal vein may be compressed by an aneurysm of the superior mesenteric artery as the vein crosses anterior to the aorta. Patients with compression of the left renal vein may have renal and adrenal hypertension on the left, and, in males, a varicocele on the left.
• Middle suprarenal arteries branch from the aorta above the renal
arteries and supply the medial parts of the suprarenal gland.
• Renal arteries are large paired vessels that arise from the aorta at the
upper border of the L2 vertebra. They course horizontally to the hila of the kidneys. The right renal artery is the longer than the left and passes posterior to the inferior vena cava.
• Gonadal arteries arise from the anterior surface of the aorta just infe-
rior to the renal arteries. They descend retroperitoneally on the ventral surface of the psoas major muscle.
VENOUS DRAINAGE OF ABDOMINAL VISCERA Inferior Vena Cava The inferior vena cava forms to the right of the lumbar vertebrae and the abdominal aorta by the union of the 2 common iliac veins at the L5 vertebral level. The inferior vena cava ascends to the right of the midline and p asses through the caval hiatus of the diaphragm at the T8 vertebral level. The inferior vena cava receives blood from the lower limbs, pelvis and perineum,
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paired abdominal viscera, and body wall. Note that the vena cava does not receive blood directly from the GI tract, except the lower rectum and anal canal. The right tributaries (right gonadal, right suprarenal) drain separately into the inferior vena cava. But on the left side, the left gonadal and left suprarenal veins drain into the left renal vein, which then drains into the vena cava. The left renal vein crosses anterior to the aorta, just inferior to the origin of the superior mesenteric artery. Hepatic veins T8
Inferior phrenic vein Aorta
Left suprarenal vein
Right suprarenal vein Right renal vein
Left renal vein Left gonadal vein
Right gonadal vein
L5
Superior mesenteric artery Common iliac vein Median sacral vein
FigureII-3-32. II-3-33. Inferior Inferior Vena Vena Cava Figure Cavaand andTributaries Tributaries
Hepatic Portal System The hepatic portal system is an extensive network of veins that receives the blood flow from the GI tract above the pectinate line. The venous flow is carried to the liver via the hepatic portal vein where it enters the liver sinusoids, which drain to the hepatic veins, which then drain into the inferior vena cava and ultimately into the right atrium. The hepatic portal vein is formed by the union of the superior mesenteric (drains midgut) and splenic (drains foregut) veins posterior to the neck of the pancreas. The inferior mesenteric vein (drains hindgut) usually drains into splenic vein.
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Left gastric vein
Biochemistry
Splenic vein (foregut) Physiology
Medical Genetics
Superior mesenteric vein (midgut) Pathology
Inferior mesenteric vein (hindgut)
Behavioral Science/Social Sciences
Microbiology
Figure II-3-33A. Portal System FigureHepatic II-3-34A. Hepatic Portal System
Hepatic portal system
Sinusoids Liver
Hepatic veins
Heart
Inferior vena cava Figure Cavaland andPortal Portal Blood Flow FigureII-3-33B. II-3-34B.Comparison Comparison of of Normal Normal Caval Blood Flow
If there is an obstruction to flow through the portal system (portal hypertension), blood can flow in a retrograde direction (because of the absence of valves in the portal system) and pass through anastomoses to reach the caval system. Sites for these anastomoses include the esophageal veins, rectal veins, and thoracoepigastric veins. Enlargement of these veins may result in esophageal varices, hemorrhoids, or a caput medusae.
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Azygos vein (caval) Esophageal vein (caval) A Esophageal varices Esophageal vein (portal) Left gastric vein
Hepatic portal vein
Splenic vein
Paraumbilical vein (portal) Superior mesenteric vein
Inferior mesenteric vein
C Caput Medusae
Superior rectal vein (portal)
Superficial abdominal veins (caval)
B
Internal hemorrhoids
Inferior rectal vein (caval)
Figure II-3-35. Chief Portacaval Anastomoses Figure II-3-34. Chief Portacaval Anastomoses
Table II-3-6. Sites of Portacaval Anastomoses Sites of Anastomoses
Portal
Caval
Clinical Signs
Esophagus
Esophageal veins (left gastric veins)
Veins of the thoracic esophagus, which drain into the azygos system
Esophageal varices
Superior rectal veins (inferior mesenteric vein)
Inferior rectal veins (internal iliac vein)
Internal hemorrhoids
Paraumbilical veins
Superficial veins of the anterior abdominal wall
Caput medusa
A Rectum B Umbilicus C
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URINARY SYSTEM Embryology of Kidneys and Ureter Renal development is characterized by 3 successive, slightly overlapping kidney systems: pronephros, mesonephros, and metanephros.
Stomach Midgut Pathology
Behavioral Science/Social Sciences
Cecum
Microbiology
Allantois
Pronephros
Cloaca
Mesonephros
Metanephrogenic mass
Mesonephric duct Hindgut
Mesonephric duct Figure II-3-35. Pronephros, Mesonephros, and Metanephros
Figure II-3-36. Pronephros, Mesonephros, and Metanephros
During week 4, segmented nephrotomes appear in the cervical intermediate mesoderm of the embryo. These structures grow laterally and canalize to form nephric tubules. The first tubules formed regress before the last ones are formed. By the end of week 4, the pronephros disappears and does not function. In week 5, the mesonephros appears as S-shaped tubules in the intermediate mesoderm of the thoracic and lumbar regions of the embryo. • The medial end of each tubule enlarges to form a Bowman’s capsule
into which a tuft of capillaries, or glomerulus, invaginates.
• The lateral end of each tubule opens into the mesonephric (Wolffian)
duct, an intermediate mesoderm derivative. The duct drains into the hindgut.
• Mesonephric tubules function temporarily and degenerate by the
beginning of month 3. The mesonephric duct persists in the male as the ductus epididymidis, ductus deferens, and the ejaculatory duct. It disappears in the female.
During week 5, the metanephros, or permanent kidney, develops from 2 sources: the ureteric bud, a diverticulum of the mesonephric duct, and the metanephric mass (blastema), from intermediate mesoderm of the lumbar and sacral regions. The ureteric bud penetrates the metanephric mass, which condenses around the diverticulum to form the metanephrogenic cap. The bud dilates to form the renal pelvis, which subsequently splits into the cranial and caudal major calyces. Each major calyx buds into the metanephric tissue to form the minor calyces.
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One to 3 million collecting tubules develop from the minor calyces, thus forming the renal pyramids. The ureteric bud forms the drainage components of the urinary system (calyces, pelvis, ureter). Penetration of collecting tubules into the metanephric mass induces cells of the tissue cap to form nephrons, or excretory units. Lengthening of the excretory tubule gives rise to the proximal convoluted tubule, the loop of Henle, and the distal convoluted tubule. The kidneys develop in the pelvis but appear to ascend into the abdomen as a result of fetal growth of the lumbar and sacral regions. With their ascent, the ureters elongate, and the kidneys become vascularized by arteries which arise from the abdominal aorta.
Hindgut
Mesonephric duct
Allantois
Paramesonephric duct
Mesonephric tissue
Allantois
Kidney
Bladder
Mesonephros
Urorectal septum Cloaca Ureteric bud
Rectum Metanephric blastema (mass)
Urogenital Anal membrane membrane
End of Week 5
Mesonephric duct Ureter
Urorectal septum
End of Week 8
Figure II-3-36. Development Figure II-3-37. Developmentof ofthe theUrinary UrinarySystem System
Embryology of Bladder and Urethra The hindgut does not rotate but it is divided into 2 parts by the urorectal septum. The urorectal septum divides the cloaca into the anorectal canal and the urogenital sinus by week 7.
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The urogenital sinus is divided into 3 parts: • The upper (cranial) and largest part of the urogenital sinus (endoderm)
Pharmacology
Physiology
Pathology
Microbiology
Biochemistry
Medical Genetics
Behavioral Science/Social Sciences
becomes the urinary bladder, which is initially continuous with the allantois.
–– The lumen of the allantois becomes obliterated to form a fibrous cord, the urachus. The urachus connects the apex of the bladder to the umbilicus. In the adult, this structure becomes the median umbilical ligament. –– The trigone of the bladder is formed by the incorporation of the caudal mesonephric ducts into the dorsal bladder wall. This mesodermal tissue is eventually covered by endodermal epithelium so that the entire lining of the bladder is of endodermal origin. The smooth muscle of the bladder is derived from splanchnic mesoderm. –– The mesonephric ducts also form the ejaculatory ducts as they enter the prostatic urethra. • The middle part of the urogenital sinus (endoderm) will form all of the
urethra of the female and the prostatic, membranous, and proximal spongy urethra in the male. –– The prostate gland in the male is formed by an endodermal outgrowth of the prostatic urethra.
• The inferior part of the sinus forms the lower vagina and contributes
to the primordia of the penis or the clitoris.
The anorectal canal forms the hindgut distally to the pectinate line.
Urogenital sinus Allantois Mesonephros Mesonephric duct Ureteric bud Urorectal septum Anorectal canal Cloacal membrane Figure II-3-37. Development of Bladder and Urethra Figure II-3-38. Development of Bladder and Urethra
Congenital Abnormalities of the Renal System Renal agenesis results from failure of one or both kidneys to develop because of early degeneration of the ureteric bud. Unilateral agenesis is fairly common; bilateral agenesis is fatal (associated with oligohydramnios, and the fetus may have Potter sequence: clubbed feet, pulmonary hypoplasia, and craniofacial anomalies).
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Pelvic kidney is caused by a failure of one kidney to ascend. Horseshoe kidney (usually normal renal function, predisposition to calculi) is a fusion of both kidneys at their ends and failure of the fused kidney to ascend. The horseshoe kidney hooks under the origin of the inferior mesenteric artery. Double ureter is caused by the early splitting of the ureteric bud or the development of 2 separate buds. Failure of the allantois to be obliterated results in urachal fistulas or sinuses. In male children with congenital valvular obstruction of the prostatic urethra or in older men with enlarged prostates, a patent urachus may cause drainage of urine through the umbilicus.
Postnatal Anatomy The kidneys are a pair of bean-shaped organs approximately 12 cm long. They extend from vertebral level T12 to L3 when the body is in the erect position. The right kidney is positioned slightly lower than the left because of the mass of the liver. Both kidneys are in contact with the diaphragm, psoas major, and quadratus lumborum. • Right kidney: contacts the above structures and the 12th rib • Left kidney: contacts the above structures and the 11th and 12th ribs
Ureters are fibromuscular tubes that connect the kidneys to the urinary bladder in the pelvis. They run posterior to the ductus deferens in males and posterior to the uterine artery in females. They begin as continuations of the renal pelves and run retroperitoneally, crossing the external iliac arteries as they pass over the pelvic brim. The ureter lies on the anterior surface of the psoas major muscle. Aorta Inferior vena cava
Clinical Correlate The most common sites of ureteral constriction susceptible to blockage by renal calculi are: here the renal pelvis joins the • W ureter • W here the ureter crosses the pelvic inlet • W here the ureter enters the wall of the urinary bladder
Renal pelvis
Quadratus lumborum Psoas major Iliacus Ureter Urinary bladder
Figure Muscles II-3-38A.ofMuscles of the Figure II-3-39A. the Posterior Posterior Abdominal Wall Abdominal Wall
T12 L1 L2 L3 L4 L5
Parietal pleural reflection
Iliac crest Ischial spine Course of pudendal nerve and internal pudendal vessels Figure II-3-38B. Bony Landmarks of Figure II-3-39B. Bony Landmarks of the Posterior the Posterior Abdominal Wall Abdominal Wall
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Note Parasympathetic fibers facilitate micturition and sympathetic fibers Pharmacology Biochemistry inhibit micturition.
The urinary bladder is covered superiorly by peritoneum. The body is a hollow muscular cavity. • The neck is continuous with the urethra. • The trigone is a smooth, triangular area of mucosa located internally at
the base of the bladder.
• The base of the triangle is superior and bounded by the 2 openings of Physiology
Medical Genetics
the ureters. The apex of the trigone points inferiorly and is the opening for the urethra.
• Blood Supply Pathology
Behavioral Science/Social Sciences
–– The bladder is supplied by vesicular branches of the internal iliac arteries and umbilical arteries. –– The vesicular venous plexus drains to internal iliac veins. • Lymphatics
Microbiology
Clinical Correlate Spastic bladder results from lesions of the spinal cord above the sacral spinal cord levels. There is a loss of inhibition of the parasympathetic nerve fibers that innervate the detrusor muscle during the filling stage. Thus, the detrusor muscle responds to a minimum amount of stretch, causing urge incontinence. Atonic bladder results from lesions to the sacral spinal cord segments or the sacral spinal nerve roots. Loss of pelvic splanchnic motor innervation with loss of contraction of the detrusor muscle results in a full bladder with a continuous dribble of urine from the bladder.
Clinical Correlate Weakness of the puborectalis part of the levator ani muscle may result in rectal incontinence. Weakness of the sphincter urethrae part of the urogenital diaphragm may result in urinary incontinence.
–– Drain to the external and internal iliac nodes • Innervation
–– Parasympathetic innervation is from sacral segments S2, S3, and S4. The preganglionic parasympathetic fibers travel in pelvic splanchnic nerves to reach the detrusor muscle. –– Sympathetic innervation is through fibers derived from L1 through L2 (lumbar splanchnics). These fibers supply the trigone muscle and the internal urethral sphincter. • Muscles
–– The detrusor muscle forms most of the smooth-muscle walls of the bladder and contracts during emptying of the bladder (micturition). The contraction of these muscles is under control of the parasympathetic fibers of the pelvic splanchnics (S2, 3, 4) –– The internal urethral sphincter (sphincter vesicae) is smooth-muscle fibers that enclose the origin of the urethra at the neck of the bladder. These muscles are under control of the sympathetic fibers of the lower thoracic and lumbar splanchnics (T11-L2) and are activated during the filling phase of the bladder to prevent urinary leakage. –– The external urethral sphincter (sphincter urethrae) is the voluntary skeletal muscle component of the urogenital diaphragm that encloses the urethra and is relaxed during micturition (voluntary muscle of micturition). The external sphincter is innervated by perineal branches of the pudendal nerve. The male urethra is a muscular tube approximately 20 cm in length. The urethra in men extends from the neck of the bladder through the prostate gland (prostatic urethra) to the urogenital diaphragm of the perineum (membranous urethra), and then to the external opening of the glans (penile or spongy urethra).
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The male urethra is anatomically divided into 3 portions: prostatic, membranous, and spongy (penile). The distal spongy urethra of the male is derived from the ectodermal cells of the glans penis. The female urethra is approximately 4 cm in length and extends from the neck of the bladder to the external urethral orifice of the vulva.
URINARY HISTOLOGY The urinary system consists of 2 kidneys, 2 ureters, the bladder, and the urethra. Cortex Medulla Renal pyramid Renal column (of Bertin)
Minor calyx Major calyx Hilum Renal pelvis Ureter
Figure II-3-39. Organization of the Kidney Figure II-3-40. Organization of the Kidney
The urinary system functions in the removal of waste products from blood. The kidney also functions in fluid balance, salt balance, and acid-base balance. The kidney functions as an endocrine gland; it produces and releases renin, which leads to an increase in extracellular fluid volume; erythropoietin, which stimulates erythropoiesis; and prostaglandins, which act as vasodilators. A sagittal section through the center of a kidney shows a capsule (connective tissue) surrounding and protecting the organ, a wide band of cortex showing radial striations and the presence of glomeruli, and a medulla in the shape of an inverted pyramid. The medulla in turn shows an outer and inner zone. The blunted tip of the pyramid, called the papilla, borders a space that is surrounded by calices of the ureter. The collecting ducts are invaginations of the papilla’s epithelium and the urine drains from their open ends into the calices.
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Table II-3-7. Basic Functions of the Kidneys Fluid balance
Maintain normal extracellular fluid (ECF) and intracellular fluid (ICF) volumes
Electrolytes
Balance excretion with intake to maintain normal plasma concentrations
Wastes
Excrete metabolic wastes (nitrogenous products, acids, toxins, etc.)
Fuels
Reabsorb metabolic fuels (glucose, lactate, amino acids, etc.)
Blood pressure
Regulate ECF volume for the long-term control of blood pressure
Acid−base
Regulate absorption and excretion of H+ and HCO3− to control acid−base balance
Medical Genetics
Behavioral Science/Social Sciences
Organization of the Kidney The cortex is divided into lobules, and contains nephron elements mixed with vascular elements and stroma (a small amount of connective tissue). At the center of each lobule is a medullary ray, containing tubules that are parallel to each other and oriented radially in the cortex. The tubules in the medullary rays are continuous with those in the medulla. Along the 2 edges of each lobule are glomeruli, located along 1 or 2 rows. Radially oriented arterioles and venules with a large lumen are located at the edges of the lobules. The medulla is comprised of radially arranged straight tubules which run from cortex to papilla, vascular elements, and stroma (a small amount of connective tissue). The medulla is divided into 2 zones. A wide strip in proximity to the cortex, the outer medulla contains profiles of tubules with different appearances. The inner medulla has fewer profiles of similar tubes.
Blood Circulation The renal artery enters the kidney at the hilum, near the ureter. The artery branches into interlobar arteries, which travel to the medulla–cortex border remaining outside the medullary pyramids. The vessels branch into arcuate arteries (and veins) that follow the edge of the cortex. The arcuate arteries branch into interlobular arterioles that travel tangentially in the cortex at the edges of the lobules. Intralobular arterioles, feeding the glomeruli, branch off the interlobular arterioles at each renal corpuscle. The kidneys receive 25% of total cardiac output, 1,700 liters in 24 hours. Each intralobular arteriole enters a renal corpuscle at the vascular pole as afferent arteriole and forms a convoluted tuft of capillaries (the glomerulus). A second arteriole (the efferent arteriole) exits the corpuscle. This is a unique situation due to the fact that the pressure remains high in the glomerulus in order to allow filtration. The efferent arterioles carrying blood out of the glomeruli make a second capillary bed. This second capillary bed has lower blood pressure than the glomerulus and it connects to venules at its distal end. The arteriole-capillary-arteriole-capillaryvein sequence in the kidney is unique in the body. The efferent arterioles from glomeruli in the upper cortex divide into a complex capillary system in the cortex.
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NEPHRON The functional unit within the kidney is the nephron. Each kidney contains 1–1.3 million nephrons. Nephrons connect to collecting ducts, and collecting ducts receive urine from several nephrons and converge with each other before opening to and letting the urine flow out of the kidney. The nephron and the collecting duct form the uriniferous tubule. The nephron is a tube about 55 mm in length in the human kidney. It starts at one end with Bowman’s capsule, which is the enlarged end of the nephron. Bowman’s capsule has been invaginated by a tuft of capillaries of the glomerulus so that it has 2 layers: the visceral layer is in direct contact with the capillary endothelium, and the parietal layer surrounds an approximately spherical urinary space. Bowman’s capsule and glomerulus of capillaries form a renal corpuscle.
Cortex
Proximal Bowman's tubule capsule
Distal tubule
Collecting duct
Medulla
Outer zone
Inner zone
Loop of Henle
Figure II-3-40. Nephron Figure II-3-41. Nephron
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Renal Corpuscle The parietal layer of Bowman’s capsule is continuous with the walls of the proximal convoluted tubule (PCT). The visceral layer cells are called podocytes and have a complex shape; the cell body has extensive primary and secondary foot processes which surround the blood vessels. The foot processes of the podocytes lie a basal lamina that is shared by capillary endothelial cells. The podocyte foot processes almost completely cover the capillary surfaces, leaving small slits in between.
Afferent arteriole
Microbiology
Efferent arteriole
Area of detail
Visceral layer (podocytes) Parietal layer Urinary space Fenestrated capillary
Basal lamina
Urinary space Podocyte Foot processes
FigureII-3-41. II-3-42.Renal RenalCorpuscle Corpuscle and Figure and Bowman’s Bowman’sCapsule Capsule
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Copyright McGraw-Hill Companies. Used with permission. Copyright McGraw-Hill Companies. Used with permission.
Figure II-3-42. Renal corpuscle proximal tubule (A), vascular pole (B), Figure II-3-43.glomerulus Renal corpuscle proximal tubule (A),(D) vascular pole (B), (C), and urinary space glomerulus (C), and urinary space (D) Simple cuboidal epithelium of the distal tubule (arrowhead) Simple cuboidal epithelium of the distal tubule (arrowhead)
From ©2010 2010 DxR DxRDevelopment DevelopmentGroup, Group,Inc. Inc. rights reserved. From the the IMC, IMC, © AllAll rights reserved.
Figure II-3-43. Scanning electron micrograph demonstrating podocytes Figure II-3-44. with Scanning electron micrograph their processes (arrows) demonstrating podocytes with their processes (arrows)
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Urinary (Bowman’s) space Physiology
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Podocyte foot processes Pathology
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Podocyte
Microbiology
Capillary endothelial
RBC From the IMC,Group, © 2010Inc. DxRAll Development Group, Inc. All rights reserved. From the IMC, © 2010 DxR Development rights reserved.
Figure II-3-44. Transmission electron micrograph demonstrating podocytes Figure II-3-45. Transmission electron micrograph demonstrating podocytes
Blood plasma is filtered from the lumen of the capillary to the urinary space across the combined capillary endothelium-podocyte complex. Fenestrations in the endothelium are large (50–100 nm) and occupy 20% of the capillary surface. Fenestrations block the exit of cells, but allow free flow of plasma. The shared basal lamina of podocytes and endothelium constitutes the first, coarser filtration barrier; it blocks the passage of molecules larger than 70 kD. The thin diaphragms covering the slit openings between the podocyte foot processes constitute a more selective filter. The slits are composed of elongated proteins which arise from the surface of the adjacent foot process cell membranes and join in the center of the slit, in a zipper-like configuration. The width of the junction between 2 adjacent podocytes varies between 20 and 50 nm, possibly as a function of perfusion pressures of the glomerulus. Podocyte foot processes are motile (they contain actin and myosin). They are connected to each other by the slit diaphragm and to the basal lamina. The slit diaphragm molecular complex is associated with the actin cytoskeleton. Alterations in composition and/or arrangement of these complexes are found in many forms of human and experimental diseases.
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Proximal Convoluted Tubule The proximal convoluted tubule (PCT) opens at the urinary pole of Bowman’s capsule. The PCT follows a circuitous path and ends with a straight segment that connects to the loop of Henle. PCT cells are tall, and they have a pink cytoplasm, long apical microvilli, and extensive basal invaginations. Numerous large mitochondria are located between the basal invaginations. The lateral borders of adjacent cells are extensively interdigitated. These characteristics are typical of cells involved in active transport. The lumen of the PCT is frequently clouded by microvilli which do not preserve well during the histologic preparation process.
Loop of Henle The loop of Henle has a smaller diameter than the PCT and has descending and ascending limbs which go in opposite directions. Some loops of Henle have a wider segment before the distal tubule. The straight and convoluted segments of the distal convoluted tubule (DCT) follow. The straight portions of the PCT and DCT have traditionally been assigned to the loop of Henle (constituting the thick ascending and descending limbs) but they are now thought to be part of the PCT and DCT to which they are more similar. The special disposition of the loops of Henle descending and ascending branches, coupled with their specific transport and permeability properties, allow them to operate as “countercurrent multipliers,” creating a gradient of extracellular fluid tonicity in the medulla. This is used to modulate urine tonicity and final volume.
Distal Convoluted Tubule
Note
The DCT comes back to make contact with its own glomerulus, and then connects to the collecting tubule, which receives urine from several nephrons and is open at its far end. The epithelium of DCT, loops of Henle, and collecting ducts have variable thicknesses and more or less well-defined cell borders. Some have limited surface microvilli. In general, these tubes either do much less active transport than the PCT or are involved only in passive water movements.
Renal cortex and medullary fibroblasts (interstitial cells) produce erythropoietin.
Collecting Ducts Collecting ducts are lined by principal cells and intercalated cells. The cell outline of these cells is more distinct than that of the PCT or the DCT. Principal cells respond to aldosterone.
Note Diuretics act by inhibiting Na+ resorption, leading to an increase in Na+ and water excretion.
Mesangial Cells Mesangial cells (also known as Polkissen or Lacis cells) are located between capillaries, under the basal lamina but outside the capillary lumen. There is no basal lamina between mesangial and endothelial cells. Mesangial cells are phagocytic and may be involved in the maintenance of the basal lamina. Abnormalities of mesangial cells are detected in several diseases resulting in clogged and/or distorted glomeruli.
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Proximal tubule
Glomerular basement membrane Physiology
Pathology
Medical Genetics
Basement membrane of Bowman’s capsule
Glomerular epithelium
Epithelium of Bowman’s capsule
Behavioral Science/Social Sciences
Polkissen cell Juxtaglomerular cells
Microbiology
Efferent arteriole Distal tubule
Afferent arteriole Macula densa
Figure II-3-45. Renal Apparatus Figure II-3-46. RenalCorpuscle Corpuscleand and Juxtaglomerular Juxtaglomerular Apparatus
Juxtaglomerular Complex The juxtaglomerular (JG) complex is a complex comprising JG apparatus (in the wall of the afferent arteriole), the macula densa (a special domain of the DCT), and a group of mesangial cells. The JG cells are modified smooth-muscle cells which secrete renin. The macula densa is formed by tall cuboidal cells in the wall of the DCT which detect sodium levels in the tubular fluid.
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PELVIS Embryology of the Reproductive System Table II-3-8. Embryology of Reproductive System Male and Female Development Adult Female and Male Reproductive Structures Derived From Precursors of the Indifferent Embryo Adult Female
Indifferent Embryo
Adult Male
Ovary, follicles, rete ovarii
Gonads
Testes, seminiferous tubules, rete testes
TDF
+
Uterine tubes, uterus, cervix, and upper part of vagina
Paramesonephric ducts – MIF
Appendix of testes
Duct of Gartner
Mesonephric ducts
Epididymis, ductus deferens, seminal vesicle, ejaculatory duct
Testosterone
+
Clitoris
Genital tubercle
Glans and body of penis
Labia minora
Urogenital folds
Ventral aspect of penis
Labia majora
Labioscrotal swellings
Scrotum
Abbreviations: DHT, dihydrotestosterone; MIF, Müllerian-inhibiting factors; TDF, testes-determining factor
Congenital Reproductive Anomalies Female Pseudointersexuality • 46,XX genotype • Have ovarian (but no testicular) tissue and masculinization of the
female external genitalia
• Most common cause is congenital adrenal hyperplasia, a condition in
which the fetus produces excess androgens
Male Pseudointersexuality • 46,XY genotype • Testicular (but no ovarian) tissue and stunted development of male
external genitalia
• Most common cause is inadequate production of dihydrotestosterone
due to a 5α-reductase deficiency
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5α-reductase 2 deficiency • Caused by a mutation in the 5α-reductase 2 gene that renders
Pharmacology
Biochemistry
5α-reductase 2 enzyme underactive in catalyzing the conversion of testosterone to dihydrotestosterone
• Clinical findings: underdevelopment of the penis and emission of sperm
Physiology
Medical Genetics
(microphallus, hypospadias, and bifid scrotum) and prostate. The epididymis, ductus deferens, seminal vesicle, and ejaculatory duct are normal
• At puberty, these patients undergo virilization due to an increased
T: DHT ratio.
Pathology
Behavioral Science/Social Sciences
Complete androgen insensitivity (CAIS, or testicular feminization syndrome) • Occurs when a fetus with a 46,XY genotype develops testes and female
Microbiology
external genitalia with a rudimentary vagina; the uterus and uterine tubes are generally absent
• Testes may be found in the labia majora and are surgically removed to
circumvent malignant tumor formation.
• Individuals present as normal-appearing females, and their psychoso-
cial orientation is female despite their genotype.
• Most common cause is a mutation in the androgen receptor (AR) gene
that renders the AR inactive.
Abnormalities of the Penis and Testis • Hypospadias occurs when the urethral folds fail to fuse completely,
resulting in the external urethral orifice opening onto the ventral surface of the penis. It is generally associated with a poorly developed penis that curves ventrally (known as chordee).
• Epispadias occurs when the external urethral orifice opens onto the
dorsal surface of the penis. It is generally associated with exstrophy of the bladder.
• Undescended testes (cryptorchidism) occurs when the testes fail
to descend into the scrotum (typically occurs within 3 months after birth). The undescended testes may be found in the abdominal cavity or in the inguinal canal. Bilateral cryptorchidism results in sterility.
• Hydrocele of the testes occurs when a small patency of the processus
vaginalis remains, so that peritoneal fluid can flow into the processus vaginalis. The result is a fluid-filled cyst near the testes.
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Pelvic and Urogenital Diaphragms The pelvic and urogenital diaphragms are 2 important skeletal muscle diaphragms that provide support of the pelvic and perineal structures. They are each innervated by branches of the pudendal nerve. • The pelvic diaphragm forms the muscular floor of the pelvis and sepa-
rates the pelvic cavity from the perineum. The pelvic diaphragm is a strong support for the pelvic organs and transmits the distal parts of the genitourinary system and GI tract from the pelvis to the perineum. –– The diaphragm is formed by 2 layers of fascia and the 2 muscles: the levator ani and coccygeus.
–– The puborectalis component of the levator ani muscle forms a muscular sling around the anorectal junction, marks the boundary between the rectum and anal canal, and is important in fecal continence. • The muscular urogenital diaphragm is located in the perineum
inferior to the pelvic diaphragm. It is formed by 2 muscles (sphincter urethrae and deep transverse perineus muscles) which extend horizontally between the 2 ischiopubic rami. –– The diaphragm is penetrated by the urethra in the male and the urethra and vagina in the female. –– The sphincter urethrae muscle serves as an external urethral sphincter (voluntary muscle of micturition) which surrounds the membranous urethra and maintains urinary continence.
Thorax Thoracic diaphragm Abdomen
Iliac crest Pelvis
Urinary bladder
Pelvic brim Pelvic diaphragm • Levator ani muscle
Ischial tuberosity Urethra
Perineum
Urogenital diaphragm • Sphincter urethrae muscle (voluntary muscle of micturition—external urethral sphincter)
Figure II-3-46. Pelvic Diaphragm
Figure II-3-47. Pelvic Diaphragm
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Male Pelvic Viscera The position of organs and peritoneum in the male pelvis is illustrated below.
Pharmacology
Biochemistry
Detrusor muscle (pelvic splanchnics)
Physiology
Medical Genetics
Parietal peritoneum
Ductus deferens
Trigone
Ureter
Fundus of bladder
Urinary bladder Pathology
Rectovesical pouch
Behavioral Science/Social Sciences
Internal urethral sphincter (lumbar splanchnics) Prostatic
Microbiology
Urethra
Membranous
Rectum
A
M
Ductus deferens
P
Seminal vesicle
Penile (spongy) Corpora cavernosa
Ejaculatory duct
Corpus spongiosum (with urethra) Prostate
Bulb of penis Urogenital diaphragm Bulbourethral (sphincter urethrae-external gland urethral sphincter) pudendal nerve
Median lobe (M) {Periurethral zone} Anterior lobe (A) Posterior lobe (P) {Peripheral zone}
Figure II-3-47. Male Pelvis
Figure II-3-48. Male Pelvis
Clinical Correlate Hyperplasia of the Prostate An enlarged prostate gland will compress the urethra. The patient will complain of the urge to urinate often and has difficulty with starting urination. Because the prostate gland is enclosed in a dense connective tissue capsule, hypertrophy will compress the prostatic portion of the urethra.
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Female Pelvic Viscera The position of organs and peritoneum in the female pelvis is illustrated below.
Parietal peritoneum
Ureter
Suspensory ligament of ovary (ovarian vessels)
Fundus of uterus
Ovary
Uterus (body)
Uterine tube
Cervix
Round ligament of uterus
Rectouterine pouch (Pouch of Douglas)
Vesicouterine pouch
Posterior fornix
Urinary bladder
Rectum
Urogenital diaphragm
Vagina
Clitoris Urethra Vestibule
Figure II-3-48. Female Pelvis
Figure II-3-49. Female Pelvis
Clinical Correlate The ureter courses just medial to the suspensory ligament of the ovary and must be protected when ligating the ovarian vessels.
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Clinical Correlate Support for pelvic viscera is provided by the pelvic and urogenital Pharmacology Biochemistry diaphragms, perineal membrane, perineal body, and the transverse (cardinal) cervical and uterosacral ligaments. Weakness of support Physiologystructures may result in prolapse Medical Genetics of the uterus into the vagina or herniation of the bladder or rectum into the vagina.
Uterus and Broad Ligament A posterior view of the female reproductive tract is shown below.
Broad ligament
Mesosalpinx Mesovarium Mesometrium
Round ligaments of uterus
Ovarian artery
Clinical Correlate
Pathology
Behavioral Science/Social Sciences
The ureter passes inferior to the uterine artery 1–2 centimeters from the cervix (“water under the bridge”) Microbiology and must be avoided during surgical procedures.
Suspensory ligament of ovary
Ovarian ligament
Uterine artery (”water under bridge”) Ureter
Transverse (cardinal) cervical ligament Uterosacral ligament
Figure II-3-49. Broad Ligament Figure II-3-50. Broad Ligament
PERINEUM The perineum is the diamond-shaped outlet of the pelvis located below the pelvic diaphragm. It is divided by a transverse line between the ischial tuberosities into the anal and urogenital triangles. • The sensory and motor innervation to the perineum is provided by the
pudendal nerve (S2, 3, 4) of the sacral plexus.
• The blood supply is provided by the internal pudendal artery, a
branch of the internal iliac artery.
• The pudendal nerve and vessels cross the ischial spine posteriorly to
enter the perineum.
Clinical Correlate A pudendal nerve block to anesthetize the perineum is performed as the pudendal nerve crosses posterior to the ischial spine.
Anal Triangle The anal triangle is posterior and contains the anal canal surrounded by the fat-filled ischioanal fossa. The anal canal is guarded by a smooth-muscle internal anal sphincter innervated by the ANS and an external anal sphincter of skeletal muscle innervated by the pudendal nerve. The pudendal canal transmitting the pudendal nerve and internal pudendal vessels is found on the lateral aspect of the ischioanal fossa.
Urogenital Triangle The urogenital triangle forms the anterior aspect of the perineum and contains the superficial and root structures of the external genitalia. The urogenital triangle is divided into superficial and deep perineal spaces (pouches).
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The superficial perineal pouch is located between the perineal membrane of the urogenital diaphragm and the superficial perineal (Colles’) fascia. It contains: • Crura of penis or clitoris: erectile tissue • Bulb of penis (in the male): erectile tissue; contains urethra • Bulbs of vestibule (in the female): erectile tissue in lateral walls of
vestibule
• Ischiocavernosus muscle: skeletal muscle that covers crura of penis or
clitoris
• Bulbospongiosus muscle: skeletal muscle that covers bulb of penis or
bulb of vestibule
• Greater vestibular (Bartholin) gland (in female only): homologous to
Cowper gland
The deep perineal pouch is formed by the fasciae and muscles of the urogenital diaphragm. It contains: • Sphincter urethrae muscle—serves as voluntary external sphincter of
the urethra
• Deep transverse perineal muscle
Note The bulbourethral (Cowper) glands are located in the deep perineal pouch of the male. The greater vestibular (Bartholin) glands are located in the superficial perineal pouch of the female.
• Bulbourethral (Cowper) gland (in the male only)—duct enters bulbar
urethra
Bladder Prostate Levator ani muscle Obturator internus muscle Deep perineal space (urogenital diaphragm)
Sphincter urethrae Crus of penis
Perineal membrane
Buck fascia Ischiocavernosus muscle
Superficial perineal space
Bulb of penis Bulbourethral (Cowper) gland
Urethra
Buck fascia Bulbospongiosus muscle
Superficial perineal (Colles’) fascia Figure II-3-50. Superficial and Deep Perineal Pouches of Male
Figure II-3-51. Superficial and Deep Perineal Pouches of Male
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External Genitalia Male
Pharmacology
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Crura of penis are continuous with the corpora cavernosa of the penis. Bulb of penis is continuous with corpus spongiosus of the penis (contains urethra).
Physiology
Pathology
Microbiology
Medical Genetics
Corpora cavernosa and corpus spongiosus form the shaft of the penis.
Behavioral Science/Social Sciences
In the male, injury to the bulb of the penis (blue arrow) may result in extravasation of urine from the urethra into the superficial perineal space. From this space, urine may pass into the scrotum, into the penis, and onto the anterior abdominal wall in the plane deep to Scarpa fascia (green arrows).
Ductus deferens
M P
A
Prostate gland Median lobe (M) Anterior lobe (A) Posterior lobe (P)
Urethra
Urogenital diaphragm
Penis
Bulbourethral gland
Figure II-3-51. Male Reproductive System Figure II-3-52. Male Urethra
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Female Crura of the clitoris are continuous with the corpora cavernosa of the clitoris. Bulbs of vestibule are separated from the vestibule by the labia minora. Urethra and vagina empty into the vestibule. Duct of greater vestibular glands enters the vestibule. Pubic symphysis
Pudendal canal • Pudendal nerve • Internal pudendal vessels
Urethra Ischiopubic ramus
Urogenital triangle Vagina Ischial tuberosity Anal triangle
Sacrotuberous ligament Anal canal
Coccyx
Figure Perineum II-3-52. Perineum Figure II-3-53. of Femaleof Female
Pelvic and Perineal Innervation The pudendal nerve (S2, S3, S4 ventral rami) and its branches innervate the skeletal muscles in the pelvic and urogenital diaphragms, the external anal sphincter and the sphincter urethrae, skeletal muscles in both perineal pouches, and the skin that overlies the perineum.
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MALE REPRODUCTIVE HISTOLOGY Testis
Pathology
Behavioral Science/Social Sciences
The testis is surrounded by a dense fibrous capsule called the tunica albuginea. The tunica albuginea is continuous with many of the interlobular septa that ISBN: Author, Title, Ed divide the testis into approximately 250 pyramidal compartments (testicular USMLE Step 1 Anatomy Fig. # File name Date lobules). 1st Pass 09-02-10 I-10-1
Anat_I-10-1.eps
2nd Pass 12-07-10
Within each lobule are 1–4 tubes, seminiferous tubules, where spermatozoa are Artist Author’s review produced. Each tubule is a coiled, non-branching closed loop that is 150–200 µm(if needed) in diameter and 30–70 cm in length. Both ends electronic of eachpublishing tubuleservices converge on the inc. 845 Third Ave 6th Floor NY, cells, NY 10022 Sertoli cells, Initials rete testes. The seminiferous tubules contain spermatogenic and a well-defined basal lamina.
3rd Pass 4th Pass
Approved
Microbiology
Ductus deferens
Seminal vesicle Ejactulatory duct
Corpus cavernosum
Prostate Cowper gland
Corpus spongiosum
Epididymis Testicle
Penis Urethra
Figure II-3-53. Male reproductive system Figure II-3-54. Male Reproductive System
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Cross section of seminiferous tubules
Note The blood–testis barrier is formed by tight junctions between Sertoli cells and protects primary spermatocytes and their progeny.
*Area of detail
Secondary spermatocyte*
Spermatids
Primary spermatocyte
Spermatozoa
Tight junction (blood–testis barrier) Sertoli cell
Spermatogonium Basement membrane Connective tissue
Leydig cell
*least likely to be seen
Figure II-3-55. Seminiferous Tubule Diagram Figure II-3-54. Seminiferous tubule diagram
Spermatogenesis The spermatogenic cells (germinal epithelium) are stacked in 4 to 8 layers that occupy the space between the basement membrane and the lumen of the seminiferous tubule. The stem cells (spermatogonia) are adjacent to the basement membrane. As the cells develop, they move from the basal to the luminal side of the tubule.
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At puberty the stem cells resume mitosis, producing more stem cells as well as differentiated spermatogonia (type A and B) that are committed to meiosis. Type B spermatogonia differentiate into primary spermatocytes that enter meiosis. Primary spermatocytes (4n, diploid) pass through a long prophase (10 days to 2 weeks) and after the first meiotic division form 2 secondary spermatocytes (2n, haploid). The secondary spermatocytes rapidly undergo the second meiotic division in a matter of minutes (and are rarely seen in histologic sections) to produce the spermatids (1n, haploid). The progeny of a single maturing spermatogonium remain connected to one another by cytoplasmic bridges throughout their differentiation into mature sperm.
Microbiology
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Figure II-3-56. Seminiferous tubule surrounded by a basement membrane (A) and myoepithelial cells Spermatogonia (B) lie on the basement membrane, primary spermatocytes (C), and spermatozoa (D) are inside the blood testis barrier. Sertoli cells (arrow) have elongated, pale-staining nuclei.
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Spermiogenesis Spermiogenesis transforms haploid spermatids into spermatozoa. This process of differentiation involves formation of the acrosome, condensation, and elongation of the nucleus; development of the flagellum; and loss of much of the cytoplasm. Acrosome Head
Nucleus Mitochondria Microtubules
Midpiece
Flagellum
Principal piece
Tail
End piece Figure II-3-57. Spermatozoan Figure II-3-56. Spermatozoan
The acrosome, which is located over the anterior half of the nucleus, is derived from the Golgi complex of the spermatid and contains several hydrolytic enzymes such as hyaluronidase, neuraminidase, and acid phosphatase; these enzymes dissociate cells of the corona radiata and digest the zona pellucida of the recently produced secondary oocyte. The basic structure of a flagellum is similar to that of a cilium. Movement is a result of the interaction among microtubules, ATP, and dynein.
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Sertoli Cells and the Blood–Testis Barrier Sertoli cells are tall columnar epithelial cells. These multifunctional cells are the predominant cells in the seminiferous tubule prior to puberty and in elderly men but comprise only 10% of the cells during times of maximal spermatogenesis. • Irregular in shape; the base adheres to the basal lamina and the apical
end extends to the lumen. The nucleus tends to be oval with the long axis oriented perpendicular to the basement membrane.
Physiology
Medical Genetics
• The cytoplasmic extensions make contact with neighboring Sertoli cells
via tight junctions, forming the blood–testis barrier by separating the seminiferous tubule into a basal and an adlumenal compartment.
Pathology
Behavioral Science/Social Sciences
• Do not divide during the reproductive period. • Support, protect, and provide nutrition to the developing spermato-
Microbiology
zoa. During spermiogenesis, the excess spermatid cytoplasm is shed as residual bodies that are phagocytized by Sertoli cells. They also phagocytize germ cells that fail to mature.
• Secrete androgen-binding protein that binds testosterone and dihy-
drotestosterone. High concentrations of these hormones are essential for normal germ-cell maturation. The production of androgen-binding protein is stimulated by follicle-stimulating hormone (FSH receptors are on Sertoli cells).
• Secrete inhibin, which suppresses FSH synthesis. • Produce anti-Müllerian hormone during fetal life that suppresses the
development of female internal reproductive structures.
The blood–testis barrier is a network of Sertoli cells which divides the seminiferous tubule into a basal compartment (containing the spermatogonia and the earliest primary spermatocytes) and an adlumenal compartment (containing the remaining spermatocytes and spermatids). The basal compartment has free access to material found in blood, while the more advanced stages of spermatogenesis are protected from blood-borne products by the barrier formed by the tight junctions between the Sertoli cells. The primary spermatocytes traverse this barrier by a mechanism not yet understood.
Interstitial Tissues of the Testis The interstitial tissue lying between the seminiferous tubules is a loose network of connective tissue composed of fibroblasts, collagen, blood and lymphatic vessels, and Leydig cells (also called interstitial cells). The Leydig cells synthesize testosterone.
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Figure II-3-57. Interstitium between seminiferous tubules Figure II-3-58. Interstitium between seminiferous contains contains Leydig cells (arrow) and fibroblasts tubules (arrowhead) Leydig cells (arrow) and fibroblasts (arrowhead)
Genital Ducts The seminiferous tubules empty into the rete testis and then into 10–20 ductuli efferentes. The ductuli are lined by a single layer of epithelial cells, some of which are ciliated. The ciliary action propels the nonmotile spermatozoa. The non-ciliated cells reabsorb some of the fluid produced by the testis. A thin band of smooth muscle surrounds each ductus.
Copyright McGraw-Hill McGraw-Hill Companies. permission. Copyright Companies.Used Usedwith with permission.
Figure II-3-58. Efferent ductules with ciliated cuboidal and Figure II-3-59. Efferent ductules with ciliated columnar cells cuboidal and columnar cells
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The spermatozoa pass from the ducti efferentes to the epididymis. The major function of this highly convoluted duct (approximately 5 m long) is the accumulation, storage, and maturation of spermatozoa. It is in the epididymis that the spermatozoa become motile. The epididymis is lined with a pseudostratified columnar epithelium which contains stereocilia (tall microvilli) on the luminal surface. This epithelium resorbs testicular fluid, phagocytizes residual bodies and poorly formed spermatozoa, and secretes substances thought to play a role in the maturation of spermatozoa.
Microbiology
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Figure II-3-59. Epididymis lined by pseudostratified columnar Figure II-3-60. Epididymis lined by pseudostratified columnar epithelium with stereocilia (arrow) epithelium with stereocilia (arrow)
The ductus (vas) deferens conducts spermatozoa from the epididymis to the ejaculatory duct and then into the prostatic urethra. The ductus (vas) deferens is a thick walled muscular tube consisting of an inner and outer layer of longitudinal smooth muscle and an intermediate circular layer. Vasectomy or the bilateral ligation of the vas deferens prevents movement of spermatozoa from the epididymis to the urethra.
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Figure II-3-60. Ductus deferens with thick layers of smooth muscle
Figure II-3-61. Ductus deferens with thick layers of smooth muscle
Accessory Glands The seminal vesicles are a pair of glands situated on the posterior and inferior surfaces of the bladder. These highly convoluted glands have a folded mucosa lined with pseudostratified columnar epithelium. The columnar epithelium is rich in secretory granules that displace the nuclei to the cell base. The seminal vesicles produce a secretion that constitutes approximately 70% of human ejaculate and is rich in spermatozoa-activating substances such as fructose, citrate, prostaglandins, and several proteins. Fructose, which is a major nutrient for sperm, provides the energy for motility. The duct of each seminal vesicle joins a ductus deferens to form an ejaculatory duct. The ejaculatory duct traverses the prostate to empty into the prostatic urethra.
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Figure II-3-61. Seminal vesicle showing mucosal folds lined with Figure II-3-62. Seminal vesicle showing mucosal folds lined pseudostratified columnar epithelium (arrow)
with pseudostratified columnar epithelium (arrow)
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The prostate is a collection of 30–50 branched tubuloalveolar glands whose ducts empty into the urethra. The prostate is surrounded by a fibroelastic capsule that is rich in smooth muscle. There are 2 types of glands in the prostate, periurethral submucosal glands and the main prostatic glands in the periphery. Glandular epithelium is pseudostratified columnar with pale, foamy cytoplasm and numerous secretory granules. The products of the secretory granules include acid phosphatase, citric acid, fibrinolysin, and other proteins.
Microbiology
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Figure II-3-62. Prostate with tubuloalveolar glands lined by Figure II-3-63. Prostate with tubuloalveolar glands lined pseudostratified columnar epithelium by pseudostratified columnar epithelium Table II-3-9. Male Reproductive Physiology Penile Erection Erection occurs in response to parasympathetic stimulation (pelvic splanchnic nerves). Nitric oxide is released, causing relaxation of the corpus cavernosum and corpus spongiosum, which allows blood to accumulate in the trabeculae of erectile tissue. Ejaculation • S ympathetic nervous system stimulation (lumbar splanchnic nerves) mediates movement of mature spermatozoa from the epididymis and vas deferens into the ejaculatory duct. ccessory glands such as the bulbourethral (Cowper) glands, prostate, and • A seminal vesicles secrete fluids that aid in sperm survival and fertility. • S omatic motor efferents (pudendal nerve) that innervate the bulbospongiosus and ischiocavernous muscles at the base of the penis stimulate the rapid ejection of semen out the urethra during ejaculation. Peristaltic waves in the vas deferens aid in a more complete ejection of semen through the urethra.
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Clinical Correlate • Injury to the bulb of the penis may result in extravasation of urine from the urethra into the superficial perineal space. From this space, urine may pass into the scrotum, into the penis, and onto the anterior abdominal wall. • Accumulation of fluid in the scrotum, penis, and anterolateral abdominal wall is indicative of a laceration of either the membranous or penile urethra (deep to Scarpa fascia). This can be caused by trauma to the perineal region (saddle injury) or laceration of the urethra during catheterization.
FEMALE REPRODUCTIVE HISTOLOGY Ovary The paired ovaries have 2 major functions: to produce the female gametes and to produce the steroid hormones which prepare the endometrium for conception and maintain pregnancy should fertilization occur. The ovaries are 3 cm long, 1.5 cm wide, and 1 cm thick. They consist of a medullary region, which contains a rich vascular bed with a cellular loose connective tissue, and a cortical region where the ovarian follicles reside.
Fallopian tube
Uterus
Ampulla
Isthmus
Infundibulum
Perimetrium
Fimbria
Endometrium Myometrium
Figure II-3-63. Female FemaleReproductive Reproductive System Figure II-3-64. System
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Folliculogenesis and Ovulation 14 days
Primary follicle
Developing follicles
Primordial follicle Pathology
Secondary oocyte Mature (graafian) follicle
Behavioral Science/Social Sciences
Secondary oocyte arrested in metaphase of meiosis II
Microbiology
Corpus albicans
Ruptured follicle
Mature corpus luteum
Early corpus luteum
Figure II-3-64. Follicular Development Figure II-3-65. Follicular Development Theca externa Theca interna Cumulus oophorus Zona pellucida Corona radiata Follicular antrum Granulosa cells
Figure II-3-65. Follicle Follicle FigureGraafian II-3-66. Graafian
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An ovarian follicle consists of an oocyte surrounded by one or more layers of follicular cells, the granulosa cells. In utero, each ovary initially contains 3 million primordial germ cells. Many undergo atresia as the number of follicles in a normal young adult woman is estimated to be 400,000. A typical woman will ovulate only around 450 ova during her reproductive years. All other follicles (with their oocytes) will fail to mature and will undergo atresia. Before birth, primordial germ cells differentiate into oogonia that proliferate by mitotic division until they number in the millions. They all enter prophase of the first meiotic division in utero and become arrested (they are now designated as primordial follicles). The primordial follicles consist of a primary oocyte surrounded by a single layer of squamous follicular cells, which are joined to one another by desmosomes. Around the time of sexual maturity, the primordial follicles undergo further growth to become primary follicles in which the oocyte is surrounded by 2 or more layers of cuboidal cells. In each menstrual cycle after puberty, several primary follicles enter a phase of rapid growth. The oocyte enlarges and the surrounding follicular cells (now called granulosa cells) proliferate. Gap junctions form between the granulosa cells. A thick layer of glycoprotein called the zona pellucida is secreted (probably by both the oocyte and granulosa cells) in the space between the oocyte and granulosa cells. Cellular processes of the granulosa cells and microvilli of the oocyte penetrate the zona pellucida and make contact with one another via gap junctions. Around this time the stroma surrounding the follicle differentiates into a cellular layer called the theca folliculi. These cells are separated from the granulosa cells by a thick basement membrane. As development proceeds, 2 zones are apparent in the theca: the theca interna (richly vascularized) and the theca externa (mostly connective tissue). Cells of the theca interna synthesize androgenic steroids that diffuse into the follicle and are converted to estradiol by the granulosa cells.
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Figure II-3-66. Ovary Figure II-3-67. Ovary Small primordial follicles top3and 3 primary follicles (arrows) Small primordial follicles are atare topatand primary follicles (arrows) with cuboiwith cuboidal granulosa cells and a thin zona pellucida are dal granulosa cells and a thin zona pellucida are below.below.
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As the follicle grows, follicular fluid containing mainly plasma, glycosaminoglycans and steroids accumulates between the cells. The cavities containing the fluid coalesce and form a larger cavity, the antrum. At this point, when the antrum is present, the follicles are called secondary follicles. The oocyte is at its full size and it is situated in a thickened area of the granulosa called the cumulus oophorus. The mature follicle (graafian follicle) completes the first meiotic division (haploid, 2N amount of DNA) just prior to ovulation. The first polar body contains little cytoplasm and remains within the zona pellucida. The Graafian follicle rapidly commences the second meiotic division where it arrests in metaphase awaiting ovulation and fertilization. The second meiotic division is not completed unless fertilization occurs. The fluid filled antrum has greatly enlarged in the Graafian follicle and the cumulus oophorus diminishes leaving the oocyte surrounded by the corona radiata. After ovulation, the corona radiata remains around the ovum where it persists throughout fertilization and for some time during the passage of the ovum through the oviduct.
Microbiology
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Figure II-3-67. Secondary follicle with an antrum Figure II-3-68. Secondary follicle with an antrum Follicle is surrounded by a corona radiata of Follicle is surrounded by a corona radiata of granulosa cells granulosa cells (arrow) and by a zona pellucida. (arrow) and by a zona pellucida.
Ovulation occurs approximately mid-cycle and is stimulated by a surge of luteinizing hormone secreted by the anterior pituitary. Ovulation consists of rupture of the mature follicle and liberation of the secondary oocyte (ovum) that will be caught by the infundibulum, the dilated distal end of the oviduct. The ovum remains viable for a maximum of 24 hours. Fertilization most c ommonly occurs in the ampulla of the oviduct. If not fertilized, the ovum undergoes autolysis in the oviduct. After ovulation, the wall of the follicle collapses and becomes extensively infolded, forming a temporary endocrine gland called the corpus luteum. During this process, the blood vessels and stromal cells invade the previously avascular layer of granulosa cells and the granulosa cells and those of the theca interna
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ypertrophy and form lutein cells (granulosa lutein cells and theca lutein cells). h The granulosa lutein cells now secrete progesterone and estrogen and the theca lutein cells secrete androstenedione and progesterone. Progesterone prevents the development of new follicles, thereby preventing ovulation. In the absence of pregnancy the corpus luteum lasts only 10–14 days. The lutein cells undergo apoptosis and are phagocytized by invading macrophages. The site of the corpus luteum is subsequently occupied by a scar of dense connective tissue, the corpus albicans. When pregnancy does occur, human chorionic gonadotropin produced by the placenta will stimulate the corpus luteum for about 6 months and then decline. It continues to secrete progesterone until the end of pregnancy. The corpus luteum of pregnancy is large, sometimes reaching 5 cm in diameter.
Oviducts The oviduct (Fallopian tube) is a muscular tube of ~12 cm in length. One end extends laterally into the wall of the uterus and the other end opens into the peritoneal cavity next to the ovary. The oviduct receives the ovum from the ovary, provides an appropriate environment for its fertilization, and transports it to the uterus. The infundibulum opens into the peritoneal cavity to receive the ovum. Finger-like projections (fimbriae) extend from the end of the tube and envelop the ovulation site to direct the ovum to the tube. Adjacent to the infundibulum is the ampulla, where fertilization usually takes place. A slender portion of the oviduct called the isthmus is next to the ampulla. The intramural segment penetrates the wall of the uterus.
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Figure II-3-68. Oviduct with simple columnar epithelium and Figure II-3-69. Oviduct with epithelium and underlying layer of simple smoothcolumnar muscle (arrow) underlying layer of smooth muscle (arrow)
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The wall of the oviduct has 3 layers: a mucosa, a muscularis, and a serosa composed of visceral peritoneum. The mucosa has longitudinal folds that are most numerous in the ampulla. The epithelium lining the mucosa is simple columnar. Some cells are ciliated and the others are secretory. The cilia beat toward the uterus, causing movement of the viscous liquid film (derived predominantly from the secretory cells) that covers the surface of the cells. The secretion has nutrient and protective functions for the ovum and promotes activation of spermatozoa. Movement of the liquid together with contraction of the muscle layer transports the ovum or fertilized egg (zygote) to the uterus. Ciliary action is not essential, so women with immotile cilia syndrome (Kartagener’s syndrome) will have a normal tubal transport of the ovum. The muscularis consists of smooth-muscle fibers in an inner circular layer and an outer longitudinal layer. An ectopic pregnancy occurs when the fertilized ovum implants, most commonly in the wall of the ampulla of the oviduct. Partial development proceeds for a time but the tube is too thin and the embryo cannot survive. The vascular placental tissues that have penetrated the thin wall cause brisk bleeding into the lumen of the tube and peritoneal cavity when the tube bursts.
Uterus The uterus is a pear-shaped organ that consists of a fundus which lies above the entrance sites of the oviducts; a body (corpus) which lies below the entry point of the oviducts and the internal os; a narrowing of the uterine cavity; and a lower cylindrical structure, the cervix, which lies below the internal os. The wall of the uterus is relatively thick and has 3 layers. Depending upon the part of the uterus, there is either an outer serosa (connective tissue and mesothelium) or adventitia (connective tissue). The 2 other layers are the myometrium (smooth muscle) and the endometrium (the mucosa of the uterus). The myometrium is composed of bundles of smooth-muscle fibers separated by connective tissue. During pregnancy, the myometrium goes through a period of growth as a result of hyperplasia and hypertrophy. The endometrium consists of epithelium and lamina propria containing simple tubular glands that occasionally branch in their deeper portions. The epithelial cells are a mixture of ciliated and secretory simple columnar cells. The endometrial layer can be divided into 2 zones. The functionalis is the part that is sloughed off at menstruation and replaced during each menstrual cycle, and the basalis is the portion retained after menstruation that subsequently proliferates and provides a new epithelium and lamina propria. The bases of the uterine glands, which lie deep in the basalis, are the source of the stem cells that divide and migrate to form the new epithelial lining.
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Figure II-3-69. Uterine wall with endometrium Figure II-3-70. Uterine wall with endometrium Simple tubular glands to the right of arrow Simple tubular glandsand to the right of arrow andleft myometrium myometrium to the of arrow to the left of arrow
Vagina The wall of the vagina has no glands and consists of 3 layers: the mucosa, a muscular layer, and an adventitia. The mucous found in the vagina comes from the glands of the uterine cervix. The epithelium of the mucosa is stratified squamous. This thick layer of cells contains glycogen granules and may contain some keratohyalin. The muscular layer of the vagina is composed of longitudinal bundles of smooth muscle.
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Figure II-3-70. Vaginal epithelium with vacuolated stratified squamous Figure epithelial II-3-71. Vaginal epithelium vacuolated stratified squamous cells that containwith glycogen, which is removed duringepithelial cells that contain glycogen, which is removed during histological processing histological processing
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Clinical Correlate Breast cancer affects about 9% of Biochemistry women born in the United States. Most of the cancers (carcinomas) arise from epithelial cells of the lactiferous ducts.
Pharmacology
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Mammary Glands The mammary glands enlarge significantly during pregnancy as a result of proliferation of alveoli at the ends of the terminal ducts. Alveoli are spherical collections of epithelial cells that become the active milk-secreting structures during lactation. The milk accumulates in the lumen of the alveoli and in the lactiferous ducts. Lymphocytes and plasma cells are located in the connective tissue surrounding the alveoli. The plasma cell population increases significantly at the end of pregnancy and is responsible for the secretion of IgA that confers passive immunity on the newborn.
Microbiology
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Figure II-3-71. Breast tissue containing modified mammary gland Figure II-3-72. Breast tissue containing modified mammary gland tissue tissue (arrow) surrounded by dense regular connective tissue (arrowhead) (arrow) surrounded by dense regular connective tissue (arrowhead)
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RADIOLOGY OF THE ABDOMEN AND PELVIS Duodenum Pylorus
Stomach Jejunum
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Ileum Figure Small Bowel Bowel FigureII-3-72. II-3-73.Abdomen: Abdomen:Upper Upper GI, GI, Small
Transverse Colon
Splenic Flexure
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Hepatic Flexure
Descending Colon
Sigmoid Colon
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Figure II-3-73. Abdomen: Barium Enema Figure II-3-74. Abdomen: Barium Enema
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Part II Anatomy
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Gross Anatomy Immunology
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
Inferior Vena Cava Aorta Diaphragm Stomach
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Liver
Spleen
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Figure II-3-74. Abdomen: CT, T11
Figure II-3-75. Abdomen: CT, T11
Liver
Portal Vein
Descending Colon
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Inferior Vena Cava Diaphragm Aorta Stomach Spleen Figure II-3-76. Figure II-3-75. Abdomen: Abdomen:CT, CT,T12 T12
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Chapter 3
Liver
Ascending Colon
Aorta Stomach
l
Abdomen, Pelvis, and Perineum
Descending Colon
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Spleen
Inferior Vena Cava
Diaphragm
Left Kidney
Figure II-3-76. Abdomen: CT, Figure II-3-77. Abdomen: CT,T12 T12
Liver
Superior Mesenteric Splenic Pancreas Artery Vein
Spleen
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Right Kidney
Inferior Portal Vena Cava Vein
Aorta
Left Kidney
Left Adrenal Gland
Figure Abdomen: CT, CT,L1 L1 Figure II-3-77. II-3-78. Abdomen:
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Part II
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Gross Anatomy Immunology
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Superior Superior Ascending Mesenteric Mesenteric Colon Duodenum Vein Artery Jejunum From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Anatomy
Microbiology
Right Kidney
Inferior Renal Pelvis Vena Cava
Aorta Descending Colon
Figure II-3-78.Abdomen: Abdomen: Figure II-3-79. CT,CT, L2 L2
Duodenum
Superior Inferior Mesenteric Vena Cava Artery
Aorta
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Right Kidney Right Ureter
Left Psoas Major
Figure II-3-79. Abdomen: CT, L3 Figure II-3-80. Abdomen: CT, L3
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Chapter 3 Inferior Ureter Vena Cava
l
Abdomen, Pelvis, and Perineum
Left Common Iliac Artery
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Psoas Major
Right Common Iliac Artery
Ureter
Figure Abdomen: CT, CT,L4 L4 Figure II-3-80. II-3-81. Abdomen:
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ON II
Upper Limb
4
Learning Objectives ❏❏ Solve problems concerning the brachial plexus ❏❏ Answer questions about muscle innervation ❏❏ Solve problems concerning sensory innervation and nerve injuries ❏❏ Solve problems concerning upper and lower brachial plexus lesions ❏❏ Use knowledge of lesions of branches of the brachial plexus ❏❏ Use knowledge of arterial supply and major anastomoses ❏❏ Solve problems concerning carpal tunnel ❏❏ Interpret scenarios on rotator cuff ❏❏ Use knowledge of radiology
BRACHIAL PLEXUS The brachial plexus provides the motor and sensory innervation to the upper limb and is formed by the ventral rami of C5 through T1 spinal nerves. Five major nerves arise from the brachial plexus: • The musculocutaneous, median, and ulnar nerves contain anterior
division fibers and innervate muscles in the anterior arm, anterior forearm, and palmar compartments that function mainly as flexors.
• The axillary and radial nerves contain posterior division fibers and
innervate muscles in the posterior arm and posterior forearm compartments that function mainly as extensors.
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Part II Anatomy
Pharmacology
Physiology
Pathology
Microbiology
l
Gross Anatomy Immunology
Terminal Branches: (5)
Cords: (3)
Divisions (6)
Mus, Med, Uln Rad, Axil Biochemistry
Lat & Med Post
Ant Post
Medical Genetics
Behavioral Science/Social Sciences
Musculocutaneous nerve
l era at
di Me
Radial nerve Median nerve
or Superi
C6
Middle
C7
Inferior
or eri t s Po
Axillary nerve
Roots (5)
C5
Suprascapular nerve
L
Trunks (3)
C8 T1
al
Long thoracic nerve
Ulnar nerve
Figure II-4-1. Brachial Plexus Figure II-4-1. Brachial Plexus
MUSCLE INNERVATION Terminal Nerves of Upper Limbs The motor innervation by the 5 terminal nerves of the arm muscles is summarized below.
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Upper Limb
Table II-4-1. Major Motor Innervations by the 5 Terminal Nerves Terminal Nerve
Muscles Innervated
Primary Actions
Musculocutaneous nerve C5–6
All the muscles of the anterior compartment of the arm
Flex elbow
Median nerve
A. Forearm
Flex wrist and all digits
C5–T1
• Anterior compartment except 1.5 muscles by ulnar nerve (flexor carpi ulnaris and the ulnar half of the flexor digitorum profundus) B. Hand • Thenar compartment • Central compartment Lumbricals: Digits 2 and 3
Ulnar nerve C8–T1
A. Forearm
Supination (biceps brachii)
Pronation
Opposition of thumb Flex metacarpophalangeal (MP) and xtend interphalangeal (PIP and DIP) e joints of digits 2 and 3 Flex wrist (weak) and digits 4 and 5
Anterior Compartment: 1 [1/2] muscles not innervated by the median nerve B. Hand
Dorsal – Abduct digits 2-5 (DAB)
• Hypothenar compartment
Palmar – Adduct digits 2-5 (PAD)
• Central compartment
Assist Lumbricals in MP flexion and IP extension digits 2–5
–– Interossei muscles: Palmar and Dorsal • Lumbricals: Digits 4 & 5 • Adductor pollicis
Flex MP and extend PIP & DIP joints of digits 4 and 5 Adduct the thumb
Axillary nerve
Deltoid
Abduct shoulder—15°–110°
C5–6
Teres minor
Lateral rotation of shoulder
Radial nerve
Posterior compartment muscles of the arm and forearm
Extend MP, wrist, and elbow
C5–T1
Supination (supinator muscle)
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Gross Anatomy Immunology
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Collateral Nerves In addition to the 5 terminal nerves, there are several collateral nerves that arise from the brachial plexus proximal to the terminal nerves (i.e., from the rami, trunks, or cords). These nerves innervate proximal limb muscles (shoulder girdle muscles). Table II-4-2 summarizes the collateral nerves.
Table II-4-2. The Collateral Nerves of the Brachial Plexus Collateral Nerve
Muscles or Skin Innervated
Dorsal scapular nerve
Rhomboids
Long thoracic nerve
Serratus anterior—protracts and rotates scapula superiorly
Suprascapular nerve C5–6
Supraspinatus—abduct shoulder 0–15°
Lateral pectoral nerve
Pectoralis major
Medial pectoral nerve
Pectoralis major and minor
Upper subscapular nerve
Subscapularis
Middle subscapular (thoracodorsal) nerve
Latissimus dorsi
Lower subscapular nerve
Subscapularis and teres major
Medial brachial cutaneous nerve
Skin of medial arm
Medial antebrachial cutaneous nerve
Skin of medial forearm
Infraspinatus—laterally rotate shoulder
Microbiology
Segmental Innervation The segmental innervation to the muscles of the upper limbs has a proximal– distal gradient, i.e., the more proximal muscles are innervated by the higher segments (C5 and C6) and the more distal muscles are innervated by the lower segments (C8 and T1). Therefore, the intrinsic shoulder muscles are innervated by C5 and C6, the intrinsic hand muscles are innervated by C8 and T1, the distal arm and proximal forearm muscles are innervated by C6 and C7, and the more distal forearm muscles are innervated by C7 and C8.
Sensory Innervation The skin of the palm is supplied by the median and ulnar nerves. The median supplies the lateral 3½ digits and the adjacent area of the lateral palm and the thenar eminence. The ulnar supplies the medial 1½ digits and skin of the hypothenar eminence. The radial nerve supplies skin of the dorsum of the hand in the area of the first dorsal web space, including the skin over the anatomic snuffbox.
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Upper Limb
Palm sensation is not affected by carpal tunnel syndrome; the superficial palmar cutaneous branch of median nerve passes superficial to the carpal tunnel. Anterior (palmar)
Musculocutaneous nerve (C5–C6) lateral forearm
Posterior (dorsal) (C8–T1) medial forearm
Radial nerve C6 dermatome
Ulnar nerve 1½
3½
3½
C8 dermatome Ulnar nerve 1½
Median nerve FigureSensory II-4-2. Sensory Innervation of and the Hand and Forearm Figure II-4-2. Innervation of the Hand Forearm
BRACHIAL PLEXUS INJURIES On the exam, follow clues as to the location of the injury. An injury will manifest in symptoms distal to the site of injury. Without specifically naming uscles, assign a function to the various compartments of the limbs. For all the m example, posterior arm = extension of the forearm and shoulder. List the nerve(s) that innervate those muscles or that area. For example, posterior arm = radial nerve. You have an area of the limb, a function of the muscles within that area, and a nerve responsible for that function. Now you can damage a nerve and note what function(s) is lost or weakened.
Upper (C5 and C6) Brachial Plexus Lesion: Erb-Duchenne Palsy (Waiter’s Tip Syndrome) • Usually occurs when the head and shoulder are forcibly separated (e.g.,
accident or birth injury or herniation of disk)
• Trauma will damage C5 and C6 spinal nerves (roots) of the upper
trunk.
• Primarily affects the axillary, suprascapular, and musculocutaneous
nerves with the loss of intrinsic muscles of the shoulder and muscles of the anterior arm.
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Pharmacology
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Gross Anatomy Immunology
• The arm is medially rotated and adducted at the shoulder: loss of axil-
lary and suprascapular nerves. The unopposed latissimus dorsi and pectoralis major muscles pull the limb into adduction and medial rotation at the shoulder.
Biochemistry
• The forearm is extended and pronated: loss of musculocutaneous
nerve.
• Sign is “waiter’s tip.” Physiology
• Sensory loss on lateral forearm to base of thumb: loss of musculocuta-
Medical Genetics
neous nerve
Pathology
Behavioral Science/Social Sciences
Lower (C8 and T1) Brachial Plexus Lesion: Klumpke’s Paralysis • Usually occurs when the upper limb is forcefully abducted above the
head (e.g., grabbing an object when falling, thoracic outlet syndrome or birth injury)
Microbiology
• Trauma will injure the C8 and T1 spinal nerve roots of inferior trunk. • Primarily affects the ulnar nerve and the intrinsic muscles of the hand
with a weakness of the median innervated muscles of the hand (Figure II-4-1)
• Sign is combination of “claw hand” and “ape hand” (median nerve). • May include a Horner syndrome. • Sensory loss on medial forearm and medial 1½ digits
Table II-4-3. Lesions of Roots of Brachial Plexus Lesioned Root
C5
C6
C8
T1
Dermatome paresthesia
Lateral border of upper arm
Lateral forearm to thumb
Medial forearm to little finger
Medial arm to elbow
Muscles affected
Deltoid
Biceps
Finger flexors
Hand muscles
Rotator cuff
Brachioradialis
Wrist flexors
Serratus anterior
Brachialis
Hand muscles
Biceps
Supinator
Brachioradialis Reflex test
—
Biceps tendon
—
—
Causes of lesions
Upper trunk compression
Upper trunk compression
Lower trunk compression
Lower trunk compression
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Upper Limb
LESIONS OF BRANCHES OF THE BRACHIAL PLEXUS • Sensory deficits precede motor weakness • Proximal lesions: more signs
Radial Nerve Axilla: (Saturday night palsy or using crutches) • Loss of extension at the elbow, wrist and MP joints • Weakened supination • Sensory loss on posterior arm, forearm, and dorsum of thumb • Distal sign is “wrist drop.”
Mid-shaft of humerus at radial groove or lateral elbow (lateral epicondyle or radial head dislocation) • Loss of forearm extensors of the wrist and MP joints • Weakened supination • Sensory loss on the posterior forearm and dorsum of thumb • Distal sign is “wrist drop.”
Note: Lesions of radial nerve distal to axilla, elbow extension are spared.
Wrist: laceration • No motor loss • Sensory loss only on dorsal aspect of thumb (first dorsal web space)
Median Nerve Elbow: (Supracondylar fracture of humerus) • Weakened wrist flexion (with ulnar deviation) • Loss of pronation • Loss of digital flexion of lateral 3 digits resulting in the inability to
make a complete fist; sign is “hand of benediction”
• Loss of thumb opposition (opponens pollicis muscle); sign is ape (sim-
ian) hand
• Loss of first 2 lumbricals • Thenar atrophy (flattening of thenar eminence) • Sensory loss on palmar surface of the lateral hand and the palmar sur-
faces of the lateral 3½ digits
Note: A lesion of median nerve at elbow results in the “hand of benediction” and “ape hand.”
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Gross Anatomy Immunology
Wrist: carpal tunnel or laceration • Loss of thumb opposition (opponens pollicis muscle); sign is ape or
simian hand
Pharmacology
Biochemistry
• Loss of first 2 lumbricals • Thenar atrophy (flattening of thenar eminence) • Sensory loss on the palmar surfaces of lateral 3½ digits. Note sensory
Physiology
Medical Genetics
loss on lateral palm may be spared.
Note: Lesions of median nerve at the wrist present without benediction hand and with normal wrist flexion, digital flexion, and pronation. Pathology
Behavioral Science/Social Sciences
Ulnar Nerve
Microbiology
Elbow (medial epicondyle), wrist (lacerations), or fracture of hook of hamate • Loss of hypothenar muscles, third and fourth lumbricals, all interossei
and adductor pollicis
• With elbow lesion there is minimal weakening of wrist flexion with
radial deviation
• Loss of abduction and adduction of digits 2–5 (interossei muscles) • Weakened interphalangeal (IP) extension of digits 2–5 (more pro-
nounced in digits 4 and 5)
• Loss of thumb adduction • Atrophy of the hypothenar eminence • Sign is “claw hand.” Note that clawing is greater with a wrist lesion. • Sensory loss on medial 1½ digits
Axillary Nerve Fracture of the surgical neck of the humerus or inferior dislocation of the shoulder • Loss of abduction of the arm to the horizon • Sensory lost over the deltoid muscle
Musculocutaneous Nerve • Loss of elbow flexion and weakness in supination • Loss of sensation on lateral aspect of the forearm
Long Thoracic Nerve • Often damaged during a radical mastectomy or a stab wound to the
lateral chest (nerve lies on superficial surface of serratus anterior muscle).
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Upper Limb
• Loss of abduction of the arm above the horizon to above the head • Sign of “winged scapula”; patient unable to hold the scapula against
the posterior thoracic wall
Suprascapular Nerve • Loss of shoulder abduction between 0 and 15 degrees (supraspinatus
muscle)
• Weakness of lateral rotation of shoulder (infraspinatus muscle)
Table II-4-4. Effects of Lesions to Branches of the Brachial Plexus Lesioned Nerve
Axillary (C5, C6)
Musculocutaneous
Radial
Median
Ulnar
(C5, C6, C7, C8)
(C6, C7, C8, T1)
(C8, T1)
(C5, C6, C7) Altered sensation
Lateral arm
Lateral forearm
Dorsum of hand over first dorsal interosseous and anatomic snuffbox
Lateral 3½ digits; lateral palm
Medial 1½ digits; medial palm
Motor weakness
Abduction at shoulder
Flexion of forearm
Wrist extension
Wrist flexion
Wrist flexion
Metacarpo-phalangeal extension
Finger flexion
Finger spreading
Pronation
Thumb adduction
Supination
Thumb opposition
Finger extension
Wrist drop
Ape hand
Claw hand
Hand of benediction
Radial deviation at wrist
Supination
Common sign of lesion
—
—
Ulnar deviation at wrist Causes of lesions
Surgical neck fracture of humerus Dislocated humerus
Rarely lesioned
Saturday night palsy
Carpal tunnel compression
Midshaft fracture of humerus
Supracondylar fracture of humerus
Subluxation of radius Dislocated humerus
Pronator teres syndrome
Fracture of medial epicondyle of humerus Fracture of hook of hamate Fracture of clavicle
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Part II
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Gross Anatomy
Anatomy
Immunology
Pharmacology
Biochemistry
ARTERIAL SUPPLY AND MAJOR ANASTOMOSES Arterial Supply to the Upper Limb Subclavian artery Branch of brachiocephalic trunk on the right and aortic arch on the left.
Physiology
Medical Genetics
Axillary artery • From the first rib to the posterior edge of the teres major muscle • Three major branches:
Pathology
Microbiology
Behavioral Science/Social Sciences
–– Lateral thoracic artery—supplies mammary gland; runs with long thoracic nerve –– Subscapular artery—collateral to shoulder with suprascapular branch of subclavian artery –– Posterior humeral circumflex artery—at surgical neck with axillary nerve
Brachial artery Profunda brachii artery with radial nerve in radial groove—at midshaft of humerus
Radial artery Deep palmar arch
Ulnar artery • Common interosseus artery • Superficial palmar arch
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Chapter 4
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Upper Limb
Suprascapular artery Brachiocephalic trunk
Subclavian artery Clavicle
1st rib (landmark)
Axillary artery
Aortic arch
Anterior humeral circumflex artery
Superior thoracic artery
Posterior humeral circumflex artery (surgical neck with axillary nerve)
Thoracoacromial artery
Teres major
Pectoralis minor
Profunda brachii artery (radial groove with radial nerve)
Lateral thoracic artery (with long thoracic nerve)
Brachial artery
Subscapular artery
Radial collateral artery
Superior ulnar collateral artery Inferior ulnar collateral artery Radial artery (courses in snuffbox)
Common interosseus artery Ulnar artery
Deep palmar arch (radial) Superficial palmar arch (ulnar)
FigureII-4-3. II-4-3. Arterial Arterial Supply Figure Supply to to the theUpper UpperLimb Limb
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Part II
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Gross Anatomy
Anatomy
Immunology
Collateral Circulation Shoulder
Pharmacology
Biochemistry
Subscapular branch of axillary and suprascapular branch of subclavian arteries
Hand Physiology
Medical Genetics
Superficial and deep palmar arches
CARPAL TUNNEL Pathology
Behavioral Science/Social Sciences
The carpal tunnel is the fibro-osseous tunnel located on the ventral aspect of the wrist. The tunnel is bounded anteriorly by the flexor retinaculum and posteriorly by the proximal row of carpal bones (lunate). • The carpal tunnel transmits 9 tendons and the radial and ulnar bursae
Microbiology
(4 tendons of the flexor digitorum superficialis, 4 tendons of the flexor digitorum profundus, and the tendon of the flexor pollicis longus) and the median nerve.
• There are no blood vessels or any branches of the radial or ulnar
nerves in the carpal tunnel.
Carpal Tunnel Syndrome Entrapment of the median nerve and other structures in the carpal tunnel due to any condition that reduces the space results in carpal tunnel syndrome. The median nerve is the only nerve affected and the patient will present with atrophy of the thenar compartment muscles and weakness of the thenar muscles (opposition of the thumb—ape hand). There is also sensory loss and numbness on the palmar surfaces of the lateral 3½ digits. The skin on the lateral side of the palm (thenar eminence) is spared because the palmar cutaneous branch of the median nerve which supplies the lateral palm, enters the hand superficial to the flexor retinaculum and does not course through the carpal tunnel. Ulnar nerve and artery
Clinical Correlate Carpal tunnel syndrome compresses the median nerve.
Pisiform Carpal tunnel
Flexor retinaculum Median nerve
Triquetrum
Tubercle of scaphoid
Lunate
Scaphoid
at Proximal FigureFigure II-4-4.II-4-4. CarpalCarpal TunnelTunnel at Proximal Row of Carpal Bones Row of Carpal Bones
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Chapter 4
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Upper Limb
ROTATOR CUFF
Clinical Correlate
The tendons of rotator cuff muscles strengthen the glenohumeral joint and include the supraspinatus, infraspinatus, teres minor, and subscapularis (SITS) muscles. The tendons of the muscles of the rotator cuff may become torn or inflamed.
Humeral Head Dislocation
The tendon of the supraspinatus is most commonly affected. Patients with rotator cuff tears experience pain anteriorly and superiorly to the glenohumeral joint during abduction Clavicle (cut) Acromion (cut)
Capsular ligament
Supraspinatus tendon
Synovial membrane Glenoid labrum Glenoid cavity
Deltoid muscle
Axillary recess
Radial nerve Clavicle
Superior glenohumeral ligament
I SC T Rotator cuff
Clinical Correlate
Coracoid process
S
Posterior
Dislocation may injure the axillary or radial nerve.
A rupture or tear of the rotator cuff follows chronic use of the shoulder or a fall with an abducted upper limb. The supraspinatus muscle is the most frequently damaged muscle of the rotator cuff.
Axillary nerve
Acromion
Dislocation of the humeral head from the glenohumeral joint typically occurs through the inferior portion of the joint capsule where the capsule is the slackest and is not reinforced by a rotator cuff tendon (Figure II-4-5). After inferior dislocation, the humeral head is pulled superiorly and comes to lie anterior to the glenohumeral joint.
Supraspinatus (S) Infraspinatus (I) Teres minor (T) Subscapularis (SC)
Biceps brachii tendon (cut)
Anterior
Inferior glenohumeral ligament
Inferior and anterior shoulder dislocation
FigureII-4-5. II-4-5.Rotator RotatorCuff Cuff Figure
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Part II
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Gross Anatomy
Anatomy
Immunology
Clinical Correlate
RADIOLOGY
Humeral Surgical Neck Fracture The axillary nerve accompanies the Biochemistry posterior humeral circumflex artery as it passes around the surgical neck of the humerus. A fracture in this area could lacerate both the artery and Physiology Medical Genetics nerve.
Clavicle
Pharmacology
Glenoid Humeral Greater Coracoid fossa Acromion head tubercle
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Mid-Shaft (Radial Groove) Humeral Fracture The radial nerve accompanies theSciences Behavioral Science/Social profunda brachii artery. Both could be damaged as a result of a mid-shaft humeral fracture.
Pathology
Microbiology
Surgical neck of humerus (axillary nerve and posterior circumflex humeral artery)
Mid-shaft of humerus— radial groove (radial nerve and profunda brachii artery)
Figure II-4-6. Anteroposterior View of Shoulder FigureUpper II-4-6.Extremities: Upper Extremities: Anteroposterior (External Rotation) View of Shoulder (External Rotation)
Location of median nerve Lateral epicondyle (location of radial nerve) Capitulum of humerus
Medial epicondyle of humerus (Location of ulnar nerve)
Coronoid process of ulna
Radial head Radial tuberosity
Ulna
From From the theIMC, IMC,©©2010 2010DxR DxRDevelopment Development Group, Inc. Group, Inc.reserved. All rights reserved. All rights
Figure II-4-7. Upper Extremities: Anteroposterior View of Elbow Figure II-4-7. Upper Extremities: Anteroposterior View of Elbow
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Chapter 4 Capitate Trapezoid
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Hamate Course of Ulnar Nerve Triquetrum Pisiform
Course of Median Nerve Ulna
Lunate Scaphoid
Radius
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Figure II-4-8. Upper Extremities: Posteroanterior View of Wrist Figure II-4-8. Upper Extremities: Posteroanterior View of Wrist
Upper Limb
Clinical Correlate
Trapezium
Hook of Hamate
l
The scaphoid is the most frequently fractured of the carpal bones. This fracture may separate the proximal head of the scaphoid from its blood supply (which enters the bone at the distal head) and may result in avascular necrosis of the proximal head. The lunate is the most commonly dislocated carpal bone (it dislocates anteriorly into the carpal tunnel and may compress the median nerve).
Clinical Correlate • C arpal tunnel syndrome results from compression of the median nerve within the tunnel. fall on the outstretched hand may • A fracture the hook of the hamate, which may damage the ulnar nerve as it passes into the hand.
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N II
Lower Limb
5
Learning Objectives ❏❏ Explain information related to lumbosacral plexus ❏❏ Solve problems concerning nerve injuries and abnormalities of gait ❏❏ Demonstrate understanding of arterial supply and major anastomoses ❏❏ Use knowledge of femoral triangle ❏❏ Demonstrate understanding of hip ❏❏ Explain information related to knee joint ❏❏ Use knowledge of ankle joint ❏❏ Solve problems concerning radiology
LUMBOSACRAL PLEXUS The lumbosacral plexus provides the motor and sensory innervation to the lower limb and is formed by ventral rami of the L2 through S3 spinal nerves. The major nerves of the plexus are: • Femoral nerve: posterior divisions of L2 through L4 • Obturator nerve: anterior divisions of L2 through L4 • Tibial nerve: anterior divisions of L4 through S3 • Common fibular nerve: posterior divisions of L4 through S2 • Superior gluteal nerve: posterior divisions of L4 through S1 • Inferior gluteal nerve: posterior divisions of L5 through S2
The tibial nerve and common fibular nerve travel together through the gluteal region and thigh in a common connective tissue sheath; together, they are called the sciatic nerve. The common fibular nerve divides in the proximal leg into the superficial and deep fibular nerve.
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Part II
l
Gross Anatomy
Anatomy
Immunology
Pharmacology
Biochemistry
L2 L3 L4
Physiology
Medical Genetics
Pathology
Femoral nerve
L5
Obturator nerve Superior gluteal nerve
S1
Inferior gluteal nerve
Behavioral Science/Social Sciences
S2
Common fibular nerve Tibial nerve
S3
Sciatic nerve
Microbiology
Figure II-5-1. Lumbosacral Plexus Figure II-5-1. Lumbosacral Plexus
Terminal Nerves of Lumbosacral Plexus The terminal nerves of the lumbosacral plexus are described below. Table II-5-1. Terminal Nerves of Lumbosacral Plexus Terminal Nerve
Origin
Muscles Innervated
Primary Actions
Femoral nerve
L2–L4 posterior divisions
Anterior compartment of thigh (quadriceps femoris, sartorius, pectineus)
Extend knee
Obturator nerve
L2–L4 anterior divisions
Medial compartment of thigh (gracilis, adductor longus, adductor brevis, anterior portion of adductor magnus)
Adduct thigh
Tibial nerve
L4–S3 anterior divisions
Posterior compartment of thigh (semimembranosus, semitendinosus, long head of biceps femoris, posterior portion of adductor magnus)
Flex knee Extend thigh
Posterior compartment of leg (gastrocnemius, soleus, flexor digitorum longus, flexor hallucis longus, tibialis posterior)
Plantar flex foot (S1–2)
Plantar muscles of foot Common fibular nerve
L4–S2 posterior divisions
Flex hip
Medially rotate thigh
Flex digits Inversion
Short head of biceps femoris
Flex knee
Superficial fibular nerve
Lateral compartment of leg (fibularis longus, fibularis brevis)
Eversion
Deep fibular nerve
Anterior compartment of leg (tibialis anterior, extensor hallucis, extensor digitorum, fibularis tertius)
Dorsiflex foot (L4–5) Extend digits Inversion
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Collateral Nerves of Lumbosacral Plexus The collateral nerves of the lumbosacral plexus (to the lower limb) are summarized below.
Table II-5-2. Collateral Nerves of Lumbosacral Plexus Collateral Nerve
Origin
Muscles or Skin Innervated
Primary Actions
Superior gluteal nerve
L4–S1 posterior divisions
Gluteus medius, gluteus minimus, tensor fasciae latae
Stabilize pelvis
Gluteus maximus
Extension of hip
Inferior gluteal nerve
L5–S2 posterior divisions
Abduct hip
Lateral rotation of thigh
Segmental Innervation to Muscles of Lower Limb The segmental innervation to the muscles of the lower limb has a proximal– distal gradient, i.e., the more proximal muscles are innervated by the higher segments and the more distal muscles are innervated by the lower segments. • Muscles that cross the anterior side of the hip are innervated by L2 and
L3
• Muscles that cross the anterior side of the knee are innervated by
L3 and L4
• Muscles that cross the anterior side of the ankle are innervated by L4
and L5 (dorsiflexion)
• Muscles that cross the posterior side of the hip are innervated by L4
and L5
• Muscles that cross the posterior side of the knee are innervated by
L5 and S1
• Muscles that cross the posterior side of the ankle are innervated by
S1 and S2 (plantar flexion)
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Gross Anatomy
Anatomy
Immunology
Pharmacology
Biochemistry
NERVE INJURIES AND ABNORMALITIES OF GAIT Superior Gluteal Nerve • Weakness in abduction of the hip • Impairment of gait; patient cannot keep pelvis level when standing on
one leg.
Physiology
Medical Genetics
• Sign is “Trendelenburg gait.”
Inferior Gluteal Nerve Pathology
Behavioral Science/Social Sciences
• Weakened hip extension • Difficulty rising from a sitting position or climbing stairs
Microbiology
Femoral Nerve • Weakened hip flexion • Weakened extension of the knee • Sensory loss on the anterior thigh, medial leg, and foot
Obturator Nerve • Loss of adduction of the thigh as well as sensory loss on medial thigh
Clinical Correlate The common fibular nerve crosses the lateral aspect of the knee at the neck of the fibula, where it is the most frequently damaged nerve of the lower limb. Patients will present with loss of dorsiflexion at the ankle (foot drop), loss of eversion, and sensory loss on the lateral surface of the leg and the dorsum of the foot. The common fibular nerve may be compressed by the piriformis muscle when the nerve passes through the piriformis instead of inferior to the muscle with the tibial nerve. Piriformis syndrome results in motor and sensory loss to the lateral and anterior compartments of the leg.
Sciatic Nerve • Weakened extension of the thigh • Loss of flexion of the knee • Loss of all functions below the knee • Sensory loss on the posterior thigh, leg (except medial side), and foot
Tibial nerve only • Weakness in flexion of the knee • Weakness in plantar flexion • Weakened inversion • Sensory loss on the leg (except medial) and plantar foot
Common fibular nerve Produces a combination of deficits of lesions of the deep and superficial fibular nerves
Deep fibular nerve • Weakened inversion • Loss of extension of the digits
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• Loss of dorsiflexion (“foot drop”) • Sensory loss limited to skin of the first web space between the great
and second toes
Clinical Correlate
Superficial fibular nerve • Loss of eversion of the foot • Sensory loss on anterolateral leg and dorsum of the foot, except for the
first web space
Sensory Innervation of the Lower Leg and Foot
The sciatic nerve is often damaged following posterior hip dislocation. A complete sciatic nerve lesion results in sensory and motor deficits in the posterior compartment of the thigh and all functions below the knee.
• The lateral leg and the dorsum of the foot are supplied mainly by the
superficial fibular nerve, with the exception of the first dorsal web space, which is supplied by the deep fibular nerve.
• The sole of the foot is supplied by the lateral and medial plantar
branches of the tibial nerve.
• The sural nerve (a combination of both peroneal and tibial branches)
supplies the posterior leg and lateral side of the foot.
• The saphenous nerve (a branch of the femoral nerve) supplies the
medial leg and medial foot.
Sural nerve Superficial fibular nerve
Saphenous nerve
Sural nerve Deep fibular nerve
Sural nerve
Medial plantar nerve Lateral plantar nerve
Tibial nerve
FigureFigure II-5-2.II-5-2. Sensory Innervation of the LegLeg and Foot Sensory Innervation of Lower the Lower and Foot
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ARTERIAL BLOOD SUPPLY The obturator artery supplies the medial compartment of the thigh.
Pharmacology
Biochemistry
• External iliac artery • Femoral artery
–– Profunda femoris artery Physiology
Medical Genetics
ºº Medial circumflex femoral artery—supplies head of femur (avascular necrosis) ºº Lateral circumflex femoral artery ºº Perforating arteries—supplies posterior compartment of thigh
Pathology
Behavioral Science/Social Sciences
• Popliteal artery: supplies knee joint
–– Anterior tibial artery: courses with deep fibular nerve in anterior compartment of leg Microbiology
ºº Dorsalis pedis artery: pulse on dorsum of foot lateral to extensor hallucis longus tendon; used to note quality of blood supply to foot
–– Posterior tibial artery: courses with tibial nerve in posterior compartment of leg and passes posterior to the medial malleolus ºº Fibular artery: supplies lateral compartment of leg ºº Plantar arterial arch ºº Lateral plantar artery ºº Medial plantar artery
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Lower Limb
External iliac artery Inguinal ligament
Femoral artery Lateral circumflex femoral artery
Femoral triangle
Deep femoral artery
Medial circumflex femoral artery
Clinical Correlate Tibial shaft fractures can cause lacerations of the anterior or posterior tibial arteries, producing either anterior or posterior compartment syndromes.
Popliteal artery
Popliteal artery
Anterior tibial artery Posterior tibial artery
Anterior tibial artery
Fibular artery
Medial plantar artery
Dorsalis pedis artery
Lateral plantar artery Plantar arch artery Arterial supply to lower limb Anterior
Posterior
Figure II-5-3. Limb Figure II-5-3.Arterial ArterialSupply SupplytotoLower Lower Limb
FEMORAL TRIANGLE The femoral triangle is bounded by the inguinal ligament, and the sartorius and adductor longus muscles. Within the triangle are the femoral sheath (containing the femoral artery and vein and canal) and the femoral nerve (which is outside of the femoral sheath). Passing under the inguinal ligament (from lateral to medial) are the femoral nerve, femoral artery, femoral vein, an empty space within the femoral sheath called the femoral canal, and inguinal lymph nodes within the femoral canal (NAVEL). The femoral canal is the site of femoral hernias.
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HIP The hip joint is formed by the head of the femur and the acetabulum.
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
The fibrous capsule of the hip joint is reinforced by 3 ligamentous thickenings: iliofemoral ligament, ischiofemoral ligament, and pubofemoral ligament.
Ligamentum capitis femorum (round ligament) (cut) Microbiology
Anterior superior iliac spine
Head of femur
Anterior inferior iliac spine Iliopubic eminence Acetabular labrum
Greater trochanter Neck of femur
Transverse acetabular ligament
Iliofemoral ligament and joint capsule
Figure FigureII-5-4. II-5-4.Hip Hip
Most of the blood supply to the head of the femur (arising mostly from the medial femoral circumflex artery) ascends along the neck of the femur. Fracture of the femoral neck can compromise this blood supply and lead to avascular necrosis of the head of the femur.
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KNEE JOINT The knee joint is a synovial joint formed by the articulations of the medial and lateral femoral condyles, the medial and lateral tibial condyles, and the patella. The primary movement at the knee joint is flexion and extension of the leg. The knee joint is a weight-bearing joint and its stability depends on the muscles (quadriceps and hamstring muscles) that cross the joint. The knee is strengthened by several sets of ligaments.
Posterior cruciate ligament
Anterior cruciate ligament Lateral condyle
Anterior cruciate ligament Lateral condyle
Medial condyle
Lateral meniscus
Lateral meniscus
Medial meniscus
Popliteus ligament
Popliteus ligament
Transverse ligament
Fibular (lateral) collateral ligament
Fibular collateral ligament
Tibial (medial) collateral ligament
Fibula
Tibial tuberosity Anterior
Posterior
Figure II-5-5. Structures of the Knee Figure II-5-5. Structures of the Knee
Tibial (Medial) and Fibular (Lateral) Collateral Ligaments
Clinical Correlate
Tibial collateral ligament extends from the medial epicondyle of the femur inferiorly to attach to the medial aspect of the tibia. It is firmly attached to the capsule and medial meniscus. The tibial ligament prevents lateral displacement (abduction) of the tibia under the femur.
The tibial collateral ligament is the most frequently torn ligament at the knee, commonly seen following lateral trauma to the knee.
Fibular collateral ligament extends from the lateral condyle of the femur inferiorly to attach to the head of the fibula and is not attached to the lateral meniscus. The fibular ligament prevents medial displacement (adduction) of the tibia under the femur. The collateral ligaments are taut with knee extension.
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Anatomy
Immunology
Clinical Correlate The tests for the integrity of the anterior and posterior cruciate Pharmacology ligaments are the anteriorBiochemistry and posterior drawer signs. Tearing of the anterior cruciate ligaments allows the tibia to be easily pulled forward of the Physiology(anterior drawer sign). Tearing Medical Genetics posterior cruciate ligament allows the tibial to be easily pulled posteriorly (posterior drawer sign). Pathology
Behavioral Science/Social Sciences
Anterior and Posterior Cruciate Ligaments These are intracapsular ligaments but are located outside the synovial membrane. • Anterior cruciate ligament (ACL) attaches to the anterior aspect of the
tibia and courses superiorly, posteriorly, and laterally to attach to the lateral condyle of the femur. The anterior ligament prevents anterior displacement of the tibia under the femur. Tension on the ACL is greatest when the knee is extended and resists hyperextension. It is weaker than the posterior cruciate ligament.
• Posterior cruciate ligament (PCL) attaches to the posterior aspect of
the tibia and courses superiorly, anteriorly, and medially to attach to the medial condyle of the femur. The PCL prevents posterior displacement of the tibia under the femur. Tension on the PCL is greatest when the knee is flexed.
Microbiology
Femur
Femur
Posterior cruciate ligament Anterior cruciate ligament (cut)
Posterior Tibia
Anterior cruciate ligament
Anterior Tibia
Posterior cruciate ligament (cut)
Figure II-5-6. Anterior an Posterior igaments Figure II-5-6. Anterior and Posterior Cruciateruciate Ligaments
Medial and Lateral Menisci These are intracapsular wedges of fibrocartilage located between the articulating condyles that help make the articulating surfaces more congruent and also serve as shock absorbers. • Medial meniscus is C-shaped and is firmly attached to the tibial collat-
eral ligament. Therefore, it is less mobile and is more frequently injured than the lateral meniscus.
• Lateral meniscus is circular and more mobile. It is not attached to the
fibular collateral ligament.
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Common Knee Injuries The 3 most commonly injured structures at the knee are the tibial collateral ligament, the medial meniscus, and the ACL (the terrible or unhappy triad)— injury usually results from a blow to the lateral aspect of the knee with the foot on the ground. Patients with a medial meniscus tear have pain when the leg is medially rotated at the knee.
ANKLE JOINT Tibia Lateral (collateral) ligament of ankle
Fibula
Posterior talofibular ligament Calcaneofibular ligament Anterior talofibular ligament
Tibia Medial (deltoid) ligament of ankle Posterior tibiotalar part Tibiocalcaneal part Tibionavicular part Anterior tibiotalar part
Clinical Correlate • Inversion sprains are most common.
Figure II-5-7. of the of Ankle Figure Structures II-5-7. Structures the Ankle
• A nterior talofibular ligament is frequently damaged.
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Gross Anatomy
Anatomy
Immunology
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
RADIOLOGY
Lateral Femoral Condyle Lateral femoral condyle
Patella
Lateral tibial condyle
Microbiology
Fibular head Fibular neck
Medial femoral condyle Medial tibial condyle
Medial Femoral Condyle Fibular Head
Intercondylar eminence
the © IMC, © DxR 2010Development DxR Development Group, Inc. FromFrom the IMC, 2010 Group, All rights reserved. AllInc. rights reserved.
Figure II-5-9. Lower Extremities: Figure II-5-8. Lower Extremities:Anteroposterior AnteroposteriorView View of of Knee Knee
From the IMC, © 2 Group, Inc. All righ
Figure II-5-10. Lowe
Lateral Femoral Condyle Lateral femoral condyle
Patella
Lateral tibial condyle Fibular head Fibular neck
Medial femoral condyle Medial tibial condyle
Medial Femoral Condyle
Patella
Fibular Head
Intercondylar eminence
From the IMC, © 2010 DxR Development Group, Inc. All rights reserved.
Figure II-5-9. Lower Extremities: Anteroposterior View of Knee
From the IMC, IMC, ©©2010 From 2010DxR DxRDevelopment Development Group, Inc. Group, Inc. All rights reserved. All rights reserved.
Figure II-5-10. Lower Extremities: Lateral Knee Figure II-5-9. Lower Extremities: Lateral Knee
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Head and Neck
6
Learning Objectives ❏❏ Explain information related to neck
N II
❏❏ Answer questions about carotid and subclavian arteries ❏❏ Demonstrate understanding of embryology of the head and neck ❏❏ Solve problems concerning cranium ❏❏ Answer questions about cranial meninges and dural venous sinuses ❏❏ Use knowledge of intracranial hemorrhage ❏❏ Interpret scenarios on orbital muscles and their innervation
NECK The thoracic outlet is the space bounded by the manubrium, the first rib, and T1 vertebra. The interval between the anterior and middle scalene muscles and the first rib (scalene triangle) transmits the structures coursing between the thorax, upper limb and lower neck. The triangle contains the trunks of the brachial plexus and the subclavian artery. Thoracic outlet syndrome results from the compression of the trunks of the brachial plexus and the subclavian artery within the scalene triangle. Compression of these structures can result from tumors of the neck (Pancoast on apex of lung), a cervical rib or hypertrophy of the scalene muscles. The lower trunk of the brachial plexus (C8, T1) is usually the first to be affected. Clinical symptoms include the following:
Note The subclavian vein and phrenic nerve (C 3, 4, and 5) are on the anterior surface of the anterior scalene muscle and are not in the scalene triangle.
• Numbness and pain on medial aspect of the forearm and hand • Weakness of the muscles supplied by ulnar nerve in the hand (claw
hand)
• Decreased blood flow into upper limb, indicated by weakened radial
pulse
Compression can also affect the cervical sympathetic trunk (Horner’s syndrome) and the recurrent laryngeal nerves (hoarseness).
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Gross Anatomy Immunology
Sternocleidomastoid Anterior scalene Pharmacology
Biochemistry
Middle scalene Phrenic nerve Brachial plexus Trapezius
Physiology
Medical Genetics
Subclavian vein
Clavicle (cut)
1st rib Subclavian artery
Deltoid Pathology
2nd rib
Behavioral Science/Social Sciences
Figure II-6-1. Scalene Triangle ofof the Neck Figure II-6-1. Scalene Triangle the Neck Microbiology
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CAROTID AND SUBCLAVIAN ARTERIES Common Carotid Artery
4
A. Internal carotid artery— ophthalmic artery and brain B. External carotid artery 1. Superior thyroid 2. Ascending pharyngeal (not shown) 3. Lingual 4. Facial 5. Occipital 6. Posterior auricular 7. Superficial temporal 8. Maxillary—deep face; middle meningeal artery
3
Subclavian Artery
1
9. Internal thoracic— cardiac bypass 10. Vertebral—brain 11. Costocervical 12. Thyrocervical 13. Transverse cervical 14. Suprascapular— collaterals to shoulder 15. Inferior thyroid
7 6 5 A B Common carotid
8
13 14 Subclavian
15 10 12 11 9
FigureII-6-2. II-6-2.Arteries Arteries Head Neck Figure to to thethe Head andand Neck
Clinical Correlate The most significant artery of the external carotid system is the middle meningeal artery. It arises from the maxillary artery in the infratemporal fossa and enters the skull through the foramen spinosum to supply skull and dura. Lacerations of this vessel result in an epidural hematoma.
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Gross Anatomy
Anatomy
Immunology
Pharmacology
Biochemistry
EMBRYOLOGY OF THE HEAD AND NECK Pharyngeal Apparatus The pharyngeal apparatus consists of the following: • Pharyngeal arches (1, 2, 3, 4, and 6) composed of mesoderm and
neural crest
Physiology
Medical Genetics
• Pharyngeal pouches (1, 2, 3, 4) lined with endoderm • Pharyngeal grooves or clefts (1, 2, 3, and 4) lined with ectoderm
Pathology
Behavioral Science/Social Sciences
The anatomic associations relating to these structures in the fetus and adult are summarized below.
Section level in Figure II-6-4 Microbiology
Mandibular swelling and maxillary swelling
2 1
3
4
6
Upper limb bud Somites
Lower limb bud
Figure II-6-3. The Fetal Pharyngeal Apparatus
Figure II-6-3. Fetal Pharyngeal Apparatus
Pharyngeal arch (mesoderm and neural crest)
4
3
3
6
4
4
6
3
4 4
1
2
rm
4
2
2 3
ode
3
2
3
1
1
rm
2
2
Pharyngeal pouch
1
ode
Developing pharynx
1
End
1
Pharyngeal groove
Ect
Pharyngeal groove
Figure II-6-4. Section through the Developing Pharynx Figure II-6-4. Section through the Developing Pharynx
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The components of the pharyngeal arches are summarized below. Table II-6-1. Components of the Pharyngeal Arches Arch
Nerve* (Neural Ectoderm)
1
Trigeminal: mandibular nerve
Artery (Aortic Arch Mesoderm)
Muscle (Mesoderm)
Skeletal/Cartilage (Neural Crest)
Four muscles of mastication:
Maxilla
• Masseter • Temporalis • Lateral pterygoid
Mandible Incus Malleus
• Medial pterygoid Plus: • Digastric (anterior belly) • Mylohyoid • Tensor tympani • Tensor veli palatini 2
VII
Muscles of facial expression:
Stapes
Plus:
Styloid process
• Digastric (posterior belly) • Stylohyoid
Lesser horn and upper body of hyoid bone
• Stapedius 3
IX
Right and left common carotid arteries
Stylopharyngeus muscle
Greater horn and lower body of hyoid bone
Right subclavian artery (right arch)
Cricothyroid muscle
Thyroid cartilage
Arch of aorta (left arch)
Pharynx (5 muscles)
Right and left pulmonary arteries
Intrinsic muscles of larynx (except cricothyroid muscle)
Right and left internal carotid arteries 4
X –– Superior laryngeal nerve
Soft palate
–– P haryngeal branches 6
X Recurrent laryngeal nerve
All other laryngeal cartilages
Ductus arteriosus (left arch)
*Nerves are not derived from pharyngeal arch; they grow into the arch.
Note: The ocular muscles (III, IV, VI) and the tongue muscles (XII) do not derive from pharyngeal arch mesoderm but from mesoderm of the occipital somites (somitomeres).
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Anatomy
Immunology
Pharmacology
Biochemistry
The anatomic structures relating to the pharyngeal pouches are summarized below.
Auditory tube and middle ear cavity (pharyngeal pouch 1) Physiology
Pathology
External auditory meatus (pharyngeal groove 1)
Medical Genetics
Behavioral Science/Social Sciences
Microbiology
Foregut
Tympanic membrane (pharyngeal membrane 1)
IP: inferior parathyroid gland SP: superior parathyroid gland T: thymus C: c-cells of thyroid
Foramen cecum
1 2 3 SP IP
C
4
Thyroid Gland
Site of thyroid gland development Path of thyroglossal duct
T
Figure II-6-5. Fetal Pharyngeal Pouches Figure II-6-5. Fetal Pharyngeal Pouches
The adult structures derived from the fetal pharyngeal pouches are summarized below.
Clinical Correlate Normally, the second, third, and fourth pharyngeal grooves are obliterated by overgrowth of the second pharyngeal arch. Failure of a cleft to be completely obliterated results in a branchial cyst or lateral cervical cyst.
Table II-6-2. Adult Structures Derived From the Fetal Pharyngeal Pouches Pouch
Adult Derivatives
1
Epithelial lining of auditory tube and middle ear cavity
2
Epithelial lining of crypts of palatine tonsil
3
Inferior parathyroid (IP) gland Thymus (T)
Clinical Correlate The DiGeorge sequence presents with immunologic problems and hypocalcemia, and may be combined with cardiovascular defects (persistent truncus arteriosus), abnormal ears, and micrognathia.
4
Superior parathyroid (SP) gland C-cells of thyroid
*Neural crest cells migrate to form parafollicular C-cells of the thyroid.
Pharyngeal groove 1 gives rise to the epithelial lining of external auditory meatus. All other grooves are obliterated.
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Thyroid Gland The thyroid gland does not develop from a pharyngeal pouch. It develops from the thyroid diverticulum, which forms from the midline endoderm in the floor of the pharynx. • The thyroid diverticulum migrates caudally to its adult anatomic posi-
tion in the neck but remains connected to the foregut via the thyroglossal duct, which is later obliterated.
• The former site of the thyroglossal duct is indicated in the adult by the
foramen cecum.
Tongue The anterior two-thirds of the tongue is associated with pharyngeal arches 1 and 2. General sensation is carried by the lingual branch of the mandibular nerve (cranial nerve [CN] V). Taste sensation is carried by chorda tympani of CN VII. The posterior one third of the tongue is associated with pharyngeal arch 3. General sensation and taste are carried by CN IX. Most of the muscles of the tongue are innervated by CN XII.
Circumvallate papillae Posterior 1/3
Anterior 2/3
Foliate papillae Fungiform papillae
Sensory General sensation Taste Post 1/3 IX IX Ant 2/3 V VII Lingual branch Chorda tympani of mandibular branch of Foramen VII nerve cecum Filiform papillae
Somatic Motor CN XII innervates the intrinsic and extrinsic skeletal muscles of the tongue except palatoglossus muscle.
Figure II-6-6. Tongue Figure II-6-6. Tongue
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Anatomy
Immunology
Face and Palate
Clinical Correlate
The face develops from 5 primordia of mesoderm (neural crest) of the first pharyngeal arch: a single frontonasal prominence, the pair of maxillary prominences, and the pair of mandibular prominences.
Cleft lip occurs when the maxillary prominence fails to fuse with the Pharmacology medial nasal prominence.Biochemistry Cleft palate occurs when the palatine shelves fail to fuse with each other or the primary palate. Physiology
Medical Genetics
• The intermaxillary segment forms when the 2 medial nasal promi-
nences of the frontonasal prominences fuse together at the midline and form the philtrum of the lip and the primary palate.
• The secondary palate forms from palatine shelves (maxillary promi-
nence), which fuse in the midline, posterior to the incisive foramen.
• The primary and secondary palates fuse at the incisive foramen to Pathology
Behavioral Science/Social Sciences
form the definitive hard palate.
Frontonasal prominence
Medial nasal prominence
Microbiology
Maxillary prominence
Lateral nasal prominence Maxillary prominence
Philtrum Mandibular prominence
Intermaxillary segment primary palate
Primary palate
Four incisor teeth Philtrum of lip Incisive foramen
Secondary palate (maxillary prominence)
Fused palatine shelves (secondary palate) Figure II-6-7. Face and Palate Figure II-6-7. Face and PalateDevelopment Development
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Clinical Correlate
First arch syndrome results from abnormal formation of pharyngeal arch 1 because of faulty migration of neural crest cells, causing facial anomalies. Two well-described syndromes are Treacher Collins syndrome and Pierre Robin sequence. Both defects involve neural crest cells.
Robin sequence presents with a triad of poor mandibular growth, cleft palate, and a posteriorly placed tongue.
Pharyngeal fistula occurs when pouch 2 and groove 2 persist, thereby forming a fistula generally found along the anterior border of the muscle.
Treacher Collins syndrome also presents with mandibular hypoplasia, zygomatic hypoplasia, down-slanted palpebral fissures, colobomas, and malformed ears.
Pharyngeal cyst occurs when pharyngeal grooves that are normally obliterated persist, forming a cyst usually located at the angle of the mandible. Ectopic thyroid, parathyroid, or thymus results from abnormal migration of these glands from their embryonic position to their adult anatomic position. Ectopic thyroid tissue is found along the midline of the neck. Ectopic parathyroid or thymus tissue is generally found along the lateral aspect of the neck. May be an important issue during neck surgery.
Clinical Correlate Cribriform plate fractures may result in dysosmia and rhinorrhea (CSF).
Thyroglossal duct cyst or fistula occurs when parts of the thyroglossal duct persist, generally in the midline near the hyoid bone. The cyst may also be found at the base of the tongue (lingual cyst). DiGeorge sequence occurs when pharyngeal pouches 3 and 4 fail to differentiate into the parathyroid glands and thymus. Neural crest cells are involved.
CRANIUM Cranial Fossae
Cribriform plate (I) Optic canal (II and ophthalmic artery)
Anterior
Superior orbital fissure (III, IV, VI, V1 and ophthalmic veins) Foramen rotundum (maxillary nerve/V2) Foramen ovale (mandibular nerve/V3)
Middle
Foramen spinosum (middle meningeal artery) Foramen lacerum Internal auditory meatus (VII and VIII)
Posterior
Jugular foramen (IX, X, and XI) Hypoglossal canal (XII) Foramen magnum (XI, spinal cord, vertebral arteries)
Figure II-6-8. Foramina: Cranial Fossae Figure II-6-8. Foramina: Cranial Fossae
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Gross Anatomy
Anatomy
Immunology
Pharmacology
Biochemistry
Physiology
Medical Genetics
Foramen magnum (XI, spinal cord, vertebral arteries) Stylomastoid foramen (VII) Jugular foramen (IX, X, XI)
Pathology
Microbiology
Behavioral Science/Social Sciences
Carotid canal (internal carotid artery, carotid sympathetic nerve) Foramen spinosum (middle meningeal artery) Foramen ovale (mandibular nerve) Foramen lacerum
Figure II-6-9. Foramina: Base of Skull
Figure II-6-9. Foramina: Base of Skull
Supraorbital foramen (supraorbital VAN) Optic canal (II and ophthalmic artery) Superior orbital fissure (III, IV, VI, ophthalmic nerve and veins) Inferior orbital fissure Infraorbital foramen (infraorbital VAN)
Mental foramen (mental VAN)
Figure II-6-10. Foramina: Front of Skull
Figure II-6-10. Foramina: Front of Skull
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Chapter 6
CRANIAL MENINGES AND DURAL VENOUS SINUSES Cranial Meninges The brain is covered by 3 meninges that are continuous through the foramen magnum with the spinal meninges. There are several similarities and differences between spinal and cranial meninges. • Pia mater tightly invests the surfaces of the brain and cannot be dissected
away, having the same relationship with the brain as spinal pia mater.
• Dura mater (thickest) unlike the spinal dura, consists of 2 layers (peri-
osteal and meningeal) that are fused together during most of their course in the cranial cavity.
l
Head and Neck
Clinical Correlate Jugular foramen syndrome may be caused by a tumor pressing on CN IX, X, and XI. Patients present with hoarseness, dysphagia (CN IX and X), loss of sensation over the oropharynx and posterior third of the tongue (CN IX), and trapezius and sternocleidomastoid weakness (CN XI). The nearby CN XII may be involved, producing tongue deviation to the lesioned side.
–– Periosteal layer: outer layer lines the inner surfaces of the flat bones and serves as their periosteum; can easily be peeled away from the bones –– Meningeal (true dura) layer: innermost layer that is mostly fused with the periosteal dura mater throughout the cranial cavity. At certain points in the cranium, the meningeal layer separates from the periosteal layer and forms the dural venous sinuses and connective tissue foldings or duplications: falx cerebri, diaphragma sellae and tentorium cerebelli. These duplications separate and support different parts of the CNS. • Arachnoid is the thin, delicate membrane which lines and follows the
inner surface of the meningeal dura. Projections of arachnoid called arachnoid granulations penetrate through the dura mater and extend into the superior sagittal dural venous sinus. Arachnoid granulations are where CSF returns to the systemic venous circulation.
Arachnoid granulations
Deep vein of scalp
Emissary vein Diploic vein
Skin Galea aponeurotica Pericranium Skull (diploic bone)
Superior sagittal sinus Falx cerebri Subarachnoid space Inferior sagittal sinus
Periosteal dura mater Meningeal dura mater Arachnoid
Cranial meninges
Pia mater Bridging veins Figure II-6-11. Coronal Section of the Dural Sinuses Figure II-6-11. Coronal Section of the Dural Sinuses
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There are several spaces related to the cranial meninges: • Epidural space is a potential space between the periosteal dura and the
bones of the skull: site of epidural hematomas (described later).
Pharmacology
Biochemistry
• Subdural space is the potential space between the meningeal dura and
the arachnoid membrane: site of subdural hematomas (described later).
• Subarachnoid space lies between the arachnoid and pia mater containPhysiology
ing CSF: site of subarachnoid hemorrhage (described later).
Medical Genetics
Dural Venous Sinuses Pathology
Behavioral Science/Social Sciences
Microbiology
Dural venous sinuses are formed at different points in the cranial cavity where the periosteal and meningeal dural layers separate to form endothelial lined venous channels called dural venous sinuses. The sinuses provide the major venous drainage from most structures within the cranial cavity. They drain mostly into the internal jugular vein, which exits the cranial floor at the jugular foramen. Most of the dural venous sinuses are located in the 2 largest duplications of meningeal dura mater (falx cerebri and the tentorium cerebelli). The primary tributaries that flow into the sinuses are the following: • Cerebral and cerebelli veins form bridging veins, which pass across
the subdural space to drain into the sinuses.
• Emissary veins are valveless channels that course through the bones of
the skull and allow dural sinuses to communicate with extracranial veins.
• Diploic veins drain the spongy (diploe) core of the flat bones. • Arachnoid granulations are where CSF returns to the venous circulation. • Meningeal veins drain the meninges.
1
A
Names of the Major Dural Sinuses 1. Superior sagittal* 2. Inferior sagittal 3. Straight* 4. Transverse* (2) 5. Sigmoid (2) 6. Cavernous (2) 7. Superior petrosal (2) * Drain into the confluence of sinuses located at the inion.
2 6 3
B
4
Orbit (ophthalmic veins)
7 6
4 5
5
Deep face veins Confluence of sinuses
Jugular foramen
Folds (Duplications) of Dura Mater
Internal jugular vein
A. Falx cerebri B. Tentorium cerebelli
Dural Venous FigureFigure II-6-12.II-6-12. Dural Venous Sinuses Sinuses
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Head and Neck
Major dural venous sinuses The major dural venous sinuses are the following: • The superior sagittal sinus is located in the midsagittal plane along
the superior aspect of the falx cerebri. It drains primarily into the confluence of the sinuses.
• The inferior sagittal sinus is located in the midsagittal plane near the
inferior margin of the falx cerebri. It terminates by joining with the great cerebral vein (of Galen) to form the straight sinus at the junction of the falx cerebri and tentorium cerebelli.
• The straight sinus is formed by the union of the inferior sagittal sinus
and the great cerebral vein. It usually terminates by draining into the confluence of sinuses (or into the transverse sinus).
• The occipital sinus is a small sinus found in the posterior border of the
tentorium cerebelli. It drains into the confluence of sinuses.
• The confluence of sinuses is formed by the union of the superior sagit-
tal, straight, and occipital sinuses posteriorly at the occipital bone. It drains laterally into the 2 transverse sinuses.
• The transverse sinuses are paired sinuses in the tentorium cerebelli
and attached to the occipital bone that drain venous blood from the confluence of sinuses into the sigmoid sinuses.
• The sigmoid sinuses are paired and form a S-shaped channel in the
floor of the posterior cranial fossa. The sigmoid sinus drains into the internal jugular vein at the jugular foramen.
• The paired cavernous sinuses are located on either side of the body of
the sphenoid bone.
–– Each sinus receives blood primarily from the orbit (ophthalmic veins) and via emissary veins from the deep face (pterygoid venous plexus). Superficial veins of the maxillary face drain into the medial angle of the eye, enter the ophthalmic veins, and drain into the cavernous sinus. –– Each cavernous sinus 1 via the superior and inferior petrosal sinuses into the sigmoid sinus and internal jugular vein, respectively. –– The cavernous sinuses are the most clinically significant dural sinuses because of their relationship to a number of cranial nerves. CN III and IV and the ophthalmic and maxillary divisions of the trigeminal nerve are located in lateral wall of the sinus. CN VI and internal carotid artery are located centrally in the sinus.
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Gross Anatomy Immunology
Cavernous sinus Pharmacology
Optic chiasm
Oculomotor nerve (III)
Internal carotid artery
Biochemistry
Trochlear nerve (IV)
Pituitary gland
Abducent nerve (VI) Physiology
Internal carotid artery
Ophthalmic nerve (V1) Medical Genetics
Sphenoidal sinus
Maxillary nerve (V2) Pathology
Microbiology
Behavioral Science/Social Sciences
Nasopharynx
Figure II-6-13. Coronal Section ThroughPituitary PituitaryGland Gland and and Cavernous Cavernous Sinuses Figure II-6-13. Coronal Section Through Sinuses
Clinical Correlate Cavernous Sinus Thrombosis Infection can spread from the superficial and deep face into the cavernous sinus, producing a thrombosis that may result in swelling of sinus and damage the cranial nerves that are related to the cavernous sinus. CN III and IV and the ophthalmic and maxillary divisions of CN V will be compressed in the lateral wall of the sinus. CN VI and the internal carotid artery with its periarterial plexus of postganglionic sympathetic fibers will be compressed in the central part of the cavernous sinus. CN VI is typically affected first in a cavernous sinus thrombosis with the other nerves being affected later. Initially, patients have an internal strabismus (medially deviated eyeball) (CN VI lesion). Later, all eye movements are affected, along with altered sensation in the skin of the upper face and scalp.
INTRACRANIAL HEMORRHAGE Epidural Hematoma An epidural hematoma results from trauma to the lateral aspect of the skull which lacerates the middle meningeal artery. Arterial hemorrhage occurs rapidly in the epidural space between the periosteal dura and the skull. • Epidural hemorrhage forms a lens-shaped (biconvex) hematoma at the lateral hemisphere. • Epidural hematoma is associated with a momentary loss of conscious-
ness followed by a lucid (asymptomatic) period of up to 48 hours.
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• Patients then develop symptoms of elevated intracranial pressure such
as headache, nausea, and vomiting, combined with neurological signs such as hemiparesis.
• Herniation of the temporal lobe, coma, and death may occur rapidly if
the arterial blood is not evacuated.
Subdural Hematoma A subdural hematoma results from head trauma that tears superficial (“bridging”) cerebral veins at the point where they enter the superior sagittal sinus. A subdural hemorrhage occurs between the meningeal dura and the arachnoid. • Subdural hemorrhage forms a crescent-shaped hematoma at the lateral hemisphere. • Large subdural hematomas result in signs of elevated intracranial pres-
sure such as headache and nausea.
• Small or chronic hematomas are often seen in elderly or chronic alco-
holic patients.
• Over time, herniation of the temporal lobe, coma, and death may result
if the venous blood is not evacuated.
Subarachnoid Hemorrhage A subarachnoid hemorrhage results from a rupture of a berry aneurysm in the circle of Willis. The most common site is in the anterior part of the circle of Willis at the branch point of the anterior cerebral and anterior communicating arteries. Other common sites are in the proximal part of the middle cerebral artery or at the junction of the internal carotid and posterior communicating arteries. Typical presentation is the onset of a severe headache.
ORBITAL MUSCLES AND THEIR INNERVATION In the orbit, there are 6 extraocular muscles that move the eyeball. A seventh muscle, the levator palpebrae superioris, elevates the upper eyelid. • Four of the 6 extraocular muscles (the superior, inferior, and medial
rectus, and the inferior oblique, plus the levator palpebrae superioris) are innervated by the oculomotor nerve (CN III).
• The superior oblique muscle is the only muscle innervated by the
trochlear nerve (CN IV).
• The lateral rectus is the only muscle innervated by the abducens nerve
(CN VI).
• The levator palpebrae superioris is composed of skeletal muscle
innervated by the oculomotor nerve (CN III) and smooth muscle (the superior tarsal muscle) innervated by sympathetic fibers.
• Sympathetic fibers reach the orbit from a plexus on the internal carotid
artery of postganglionic axons that originate from cell bodies in the superior cervical ganglion.
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Gross Anatomy
Anatomy
Immunology
Superior oblique Pharmacology
Levator palpebrae superioris (cut) Biochemistry
Superior rectus Lateral rectus (cut) Physiology
Common annular tendon Medical Genetics
Pathology
Right Eye
Trochlea (pulley)
SR (III)
IO (III) MR (III)
LR (VI) IR (III)
SO (IV)
Arrows show direction of eye movement produced by each muscle.
Behavioral Science/Social Sciences
Microbiology
Medial rectus Optic nerve (II) Inferior rectus Inferior oblique
Figure II-6-15. Muscles of the Eye Figure II-6-14. Muscles of the Eye
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Neuroscience
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Nervous System Organization and Development
1
Learning Objectives ❏❏ Explain information related to autonomic nervous system ❏❏ Use knowledge of general organization
NERVOUS SYSTEM The central nervous system (CNS) contains the brain and spinal cord, which develop from the neural tube. The peripheral nervous system (PNS) contains cranial and spinal nerves which consist of neurons that give rise to axons, which grow out of the neural tube, and neurons derived from neural crest cells. Skeletal motor neurons and axons of preganglionic autonomic neurons are derived from the neural tube. Neural crest cells form sensory neurons and postganglionic autonomic neurons. The neuronal cell bodies of these neurons are found in ganglia. Therefore, all ganglia found in the PNS contain either sensory or postganglionic autonomic neurons and are derived from neural crest cells. Chromaffin cells are neural crest cells, which migrate into the adrenal medulla to form postganglionic sympathetic neurons.
Development of the Nervous System
Note
Neurulation begins in the third week; both CNS and PNS derived from neuroectoderm. The notochord induces the overlying ectoderm to form the neural plate (neuroectoderm). By end of the third week, neural folds grow over midline and fuse to form neural tube.
Alpha-fetoprotein (AFP) levels may also be elevated in gastroschisis and omphalocele. AFP levels are low in pregnancy of Down syndrome fetus.
• During closure, neural crest cells also form from neuroectoderm. • Neural tube 3 primary vesicles → 5 primary vesicles → brain and spinal
cord
• Brain stem and spinal cord have an alar plate (sensory) and a basal
plate (motor); plates are separated by the sulcus limitans.
• Neural crest → sensory and postganglionic autonomic neurons, and
other non-neuronal cell types.
• Peripheral NS (PNS): cranial nerves (12 pairs) and spinal nerves (31
pairs)
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Neuroectoderm
Neural plate
Pharmacology
Ectoderm
Biochemistry
A
Notochord (induces formation of the nervous system)
Endoderm Medical Genetics
Notochordal process Pathology
Neural fold
Mesoderm
A Physiology
Neural groove
Neural groove B
Behavioral Science/Social Sciences
Neural crest Somite
Day 18 Neural fold
Microbiology
Rostral neuropore (closes at day 25)
Neural tube C
Failure to close results in anencephaly, causing polyhydramnios and increased alphafetoprotein and AChE
B C D
Caudal neuropore (closes at 27D)
Day 22
Neural crest Alar plate (sensory)
Basal plate (motor) Neural crest D
Failure to close results in spina bifida and increased alphafetoprotein and AChE Figure III-1-1. NervousSystem System Figure III-1-1.Development Development of of Nervous
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Nervous System Organization and Development
Central Nervous System 5 secondary vesicles
3 primary vesicles Forebrain Midbrain Hindbrain Spinal cord
Adult Derivatives CNS Ventricles
Telencephalon
Cerebral Lateral hemispheres ventricles
Diencephalon
Thalamus
Third ventricle
Mesencephalon
Midbrain
Metencephalon
Pons and cerebellum
Cerebral aqueduct
Myelencephalon
Medulla
Spinal cord
Clinical Correlate Axonal polyneuropathies produce distal “glove-and-stocking” weakness or sensory deficits, and are related to axonal transport failure. Diabetes mellitus patients present with sensory neuropathies.
Fourth ventricle
Central canal
Neural tube
Figure III-1-2.Adult AdultDerivatives Derivatives of Secondary Vesicles Figure III-1-2. of Secondary Brain Brain Vesicles Table III-1-1. Adult Derivatives of Secondary Brain Vesicles Structures
Neural Canal Remnant
Telencephalon
Cerebral hemispheres, most of basal ganglia
Lateral ventricles
Diencephalon
Thalamus, hypothalamus, subthalamus, epithalamus (pineal gland), retina and optic nerve
Third ventricle
Mesencephalon
Midbrain
Cerebral aqueduct
Metencephalon
Pons, cerebellum
Fourth ventricle
Myelencephalon
Medulla
Central canal
Spinal cord
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Table III-1-2. Congenital Malformations of the Nervous System Condition Anencephaly
Pharmacology
Description
—
Failure of anterior neuropore to close Brain does not develop Incompatible with life Increased AFP during pregnancy and AChE
Biochemistry
Spina bifida
Physiology
Types
Pathology
Spina bifida occulta (Figure A)
Medical Genetics
Behavioral Science/Social Sciences
Microbiology
Muscle
Failure to induce bone growth around the spinal cord Mildest form Vertebrae fail to form around spinal cord No increase in AFP Asymptomatic; tuft of hair over defect.
Spina bifida with meningocele (Figure B)
Meninges protrude through vertebral defect Increase in AFP
Spina bifida with meningomyelocele (Figure C)
Meninges and spinal cord protrude through vertebral defect; seen with Arnold-Chiari Type II Increase in AFP
Spina bifida with myeloschisis (Figure D)
Most severe Spinal cord can be seen externally Increase in AFP and AChE A
Skin
B
C
D
Unfused laminae
A. Spina bifida occulta: a defect in the vertebral arches; asymptomatic
Dura and arachnoid Subarachnoid space Spinal cord Vertebral body
Arnold-Chiari malformation
Type I
Most common Mostly asymptomatic in children Downward displacement of cerebellar tonsils through foramen magnum Frequent association with syringomyelia
Type II
More often symptomatic Downward displacement of cerebellar vermis Compression of IV ventricle → obstructive hydrocephaly Frequent lumbar meningomyelocele
Dandy-Walker malformation
Failure of foramina of Luschka and Magendie to open → dilation of IV ventricle Agenesis of cerebellar vermis and splenium of the corpus callosum
Hydrocephalus
Most often caused by stenosis of cerebral aqueduct CSF accumulates in ventricles and subarachnoid space Increased head circumference
Holoprosencephaly
Incomplete separation of cerebral hemispheres One ventricle in telencephalon Seen in trisomy 13 (Patau)
Abbreviation: AFP, alpha-fetoprotein
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Table III-1-3. Germ Layer Derivatives Ectoderm
Mesoderm
Endoderm
Surface ectoderm
Muscle
Forms epithelial parts of:
Epidermis
Smooth
Tonsils
Hair
Cardiac
Thymus
Nails
Skeletal
Pharynx
Inner ear, external ear
Connective tissue
Larynx
Enamel of teeth
All serous membranes
Trachea
Lens of eye
Bone and cartilage
Bronchi
Anterior pituitary (Rathke’s pouch)
Blood, lymph, cardiovascular organs
Lungs
Neuroectoderm
Adrenal cortex
Urethra
Neural tube
Gonads and internal reproductive organs
Tympanic cavity
Parotid gland
Central nervous system Retina and optic nerve Pineal gland Neurohypophysis
Spleen Kidney and ureter
Urinary bladder
Auditory tube GI tract
Dura mater
Astrocytes Oligodendrocytes (CNS myelin)
Ectoderm Neural crest
Mesoderm
Endoderm Forms parenchyma of:
Adrenal medulla
Liver
Ganglia
Pancreas
Sensory (unipolar)
Tonsils
Autonomic (postganglionic)
Thyroid gland
Pigment cells (melanocytes)
Parathyroid glands
Schwann cells (PNS myelin)
Glands of the GI tract
Meninges
Submandibular gland
Pia and arachnoid mater
Sublingual gland
Pharyngeal arch cartilage (first arch syndromes) Odontoblasts Parafollicular (C) cells Aorticopulmonary septum (tetralogy of Fallot) Endocardial cushions (Down syndrome)
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Neuroscience
Anatomy
Immunology
Pharmacology
AUTONOMIC NERVOUS SYSTEM The autonomic nervous system (ANS) is responsible for the motor innervation of smooth muscle, cardiac muscle, and glands of the body. It is divided into the sympathetic and parasympathetic nervous systems. In both systems there are 2 neurons in the peripheral distribution of the motor innervation.
Biochemistry
• Preganglionic neuron with cell body in CNS Physiology
• Postganglionic neuron with cell body in a ganglion in the PNS
Medical Genetics
Central nervous system (CNS) Pathology
Ganglion
Preganglionic nerve fiber
Behavioral Science/Social Sciences
Postganglionic nerve fiber
Target
Microbiology
Figure III-1-3. Autonomic Nervous System Figure III-1-3. Autonomic Nervous System
Peripheral Nervous System
Craniosacral
PANS
Thoracolumbar
SANS
CNS
NN: neuronal nicotinic receptor NM: muscle nicotinic receptor
Postganglionic neuron ACh NN
SOMATIC
various organs heart, smooth muscle, glands
α various organs heart, smooth NE or muscle, glands β
ACh NN
ACh M Neurohumoral transmission
Adrenal medulla
M: muscarinic receptor
ACh M
ACh NN
ACh NN
NE: norepinephrine
ACh: acetylcholine
Preganglionic neuron
Motor neuron
sweat glands piloerector muscles
α Epi or β
various organs transported via blood
ACh NM
skeletal muscle
Neuromuscular junction
Figure III-1-4. Autonomic and Somatic Figure III-1-4. Autonomic andNervous Somatic System Nervous Neurotransmitters/Receptors System
Neurotransmitters/Receptors
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Nervous System Organization and Development
• Somatic nervous system: 1 neuron (from CNS → effector organ) • ANS: 2 neurons (from CNS → effector organ)
–– Preganglionic neuron: cell body in CNS –– Postganglionic neuron: cell body in ganglia in PNS –– Parasympathetic: long preganglionic, short postganglionic –– Sympathetic: short preganglionic, long postganglionic (except adrenal medulla)
Parasympathetic Nervous System Ciliary ganglion
Pupillary sphincter Ciliary m. Submandibular gland Sublingual gland Lacrimal gland Nasal mucosa Oral mucosa Parotid gland
III
Submandibular ganglion
IV
Pterygopalatine VIIa ganglion
Midbrain
V
Pons
VIII
Otic ganglion
Viscera of the thorax and abdomen (foregut and midgut)
VI
IX
X
Medulla XI
C1
Terminal ganglia T1
Clinical Correlate Hirschsprung’s disease results from missing terminal ganglia in the wall of the rectum. Infants cannot pass meconium.
Preganglionic Postganglionic
L1
Hindgut and pelvic viscera (including the bladder, erectile tissue, and rectum)
Terminal ganglia
Pelvic splanchnic nerves
S2 S3 S4
Figure III-1-5. Overview of Parasympathetic Outflow Figure III-1-5. Overview of Parasympathetic Outflow
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Table III-1-4. Parasympathetic = Craniosacral Outflow
Pharmacology
Physiology
Origin
Site of Synapse
Innervation
Cranial nerves III, VII, IX
Four cranial ganglia
Glands and smooth muscle of the head
Cranial nerve X
Terminal ganglia (in or near the walls of viscera)
Viscera of the neck, thorax, foregut, and midgut
Pelvic splanchnic nerves (S2, S3, S4)
Terminal ganglia (in or near the walls of viscera)
Hindgut and pelvic viscera (including bladder and erectile tissue)
Biochemistry
Medical Genetics
Note
Sympathetic Nervous System
Horner’s syndrome results in ipsilateral Pathologyptosis, miosis, anhydrosis. Behavioral Science/Social Sciences
Horner’s Syndrome Lesion Sites
Hypothalamus Microbiology
III IV V VI VII VIII IX XI Descending hypothalamic fibers (drive all preganglionic sympathetic neurons)
Head (sweat glands, dilator pupillae m., superior tarsal m.)
X
Internal carotid a. External carotid a. Superior cervical ganglion Middle cervical ganglion Vertebral ganglion
T1
Cervicothoracic ganglion Heart, trachea, bronchi, lungs (Thorax) Smooth muscle and glands of the foregut and midgut
Gray rami *Rejoin branches of spinal nerve
* * *
Prevertebral ganglia Thoracic splanchnic nerves Prevertebral ganglia Smooth muscle and glands of the hindgut and pelvic viscera
L1 L2
Lumbar splanchnic nerves Sympathetic chain
Figure III-1-6. Overview of Sympathetic Outflow Figure III-1-6. Overview of Sympathetic System
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Nervous System Organization and Development
Table III-1-5. Sympathetic = Thoracolumbar Outflow
Note
Origin
Site of Synapse
Innervation
Spinal cord levels T1–L2
Sympathetic chain ganglia (paravertebral ganglia)
Smooth muscle and glands of body wall and limbs; head and thoracic viscera
Thoracic splanchnic nerves T5–T12
Prevertebral ganglia (collateral; e.g., celiac, aorticorenal superior mesenteric ganglia)
Smooth muscle and glands of the foregut and midgut
Lumbar splanchnic nerves L1, L2
Prevertebral ganglia (collateral; e.g., inferior mesenteric and pelvic ganglia)
Smooth muscle and glands of the pelvic viscera and hindgut
Gray rami are postganglionics that rejoin spinal nerves to go to the body wall.
Lateral horn (T1–L2)
Dorsal ramus
Ventral ramus Spinal nerve Gray ramus communicans (postganglionic)
White ramus communicans (preganglionic)
To smooth muscle and glands of body wall and in limbs
Sympathetic ganglion
Figure III-1-7. III-1-7.Cross Cross Section Section of of Spinal Spinal Cord Cord Showing Figure Showing Sympathetic Sympathetic Outflow Outflow
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III
Histology of the Nervous System
2
Learning Objectives ❏❏ Explain information related to neurons ❏❏ Solve problems concerning disorders of myelination
NEURONS Neurons are cells which are morphologically and functionally polarized so that information may pass from one end of the cell to the other. Neurons may be classified by the form and number of their processes as bipolar, unipolar, or multipolar. The cell body of the neuron contains the nucleus and membrane-bound cytoplasmic organelles typical of a eukaryotic cell, including endoplasmic reticulum (ER), Golgi apparatus, mitochondria, and lysosomes. The nucleus and nucleolus are prominent in neurons. The cytoplasm contains Nissl substance, clumps of rough ER with bound polysomes. The cytoplasm also contains free polysomes; free and bound polysomes in the Nissl substance are sites of protein synthesis.
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Neuroscience Immunology
Multipolar Neuron
Pharmacology
Biochemistry
Physiology
Medical Genetics
Dendrites
Mitochondria
Pathology
Behavioral Science/Social Sciences
Cytoskeleton
Nucleolus Perikaryon (SOMA) Pe Nissl Nissl body
Microbiology
Inital segment ent nt of axon Golgi apparatus Node of Ranvier R Schwann Schwa cell
Axon
Myelin sheath M
Figure FigureIII-2-1. III-2-1.Neuron NeuronStructure Structure
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Histology of the Nervous System
Copyright McGraw-Hill Companies. Used with permission. Copyright McGraw-Hill Companies. Used with permission.
Figure III-2-2. Neural Tissue with Nissl stain that stains rough Figure III-2-2. Neural Tissue with Nissl stain that stains rough ER in ER in cell body (arrowhead) and proximal parts of dendrites (B) cell body (arrowhead) and proximal parts of dendrites (B) The axon (A) lacks Nissl substance. The nucleus of an The axon (A) lacks Nissl substance. The nucleus of an adjacent adjacent neuron has a prominent nucleolus (arrow). neuron has a prominent nucleolus (arrow).
Cytoskeleton The cytoskeleton of the neuron consists of neurofilaments, microfilaments, and microtubules. • Neurofilaments provide structural support for the neuron, and are
most numerous in the axon and the proximal parts of dendrites.
• Microfilaments form a matrix near the periphery of the neuron.
A microfilament matrix is prominent in growth cones of neuronal processes and functions to aid in the motility of growth cones during development. A microfilament matrix is also prominent in dendrites and forms structural specializations at synaptic membranes.
Clinical Correlate CNS Disease and Cytoplasmic Inclusions in Neurons Lewy bodies are cytoplasmic inclusions of degenerating neurons of the substantia nigra, pars compacta, evident in Parkinson’s disease and in cortical and brain-stem neurons seen in certain forms of dementia. Negri bodies are eosinophilic cytoplasmic inclusions seen in degenerating neurons in the hippocampus and cerebellar cortex in patients with rabies.
• Microtubules are found in all parts of the neuron, and are the cyto-
plasmic organelles used in axonal transport.
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Copyright McGraw-Hill Companies. Used with Copyright McGraw-Hill Companies. Usedpermission. with permission.
Figure III-2-3. EM of Neuropil including the Cell Body of a
Figure III-2-3. EM of Neuropil Cell Body a Neuron with Rough ER Neuron with Rough including ER (arrowheads) andofGolgi (arrows) (arrowheads) and Golgi (arrows) Surrounding neuropil has myelinated axons(M) Surrounding neuropil has myelinated axons(M) and unmyelinated bare axons (box). and unmyelinated bare axons (box).
Clinical Correlate In degenerative neuronal diseases of the CNS, a tau protein becomes excessively phosphorylated, which prevents crosslinking of microtubules. The affected microtubules form helical filaments and neurofibrillary tangles and senile plaques in the cell body and dendrites of neurons. Neurofibrillary tangles are prominent features of degenerating neurons in Alzheimer’s disease, amyotrophic lateral sclerosis, and Down syndrome.
Dendrites taper from the cell body and provide the major surface for synaptic contacts with axons of other neurons. Dendrites may contain spines, which are small cytoplasmic extensions that dramatically increase the surface area of dendrites. Dendrites may be highly branched; the branching pattern of dendrites may be used to define a particular neuronal cell type. The axon has a uniform diameter and may branch at right angles into collaterals along the length of the axon, in particular near its distal end. The proximal part of the axon is usually marked by an axon hillock, a tapered extension of the cell body that lacks Nissl substance. The initial segment is adjacent to the axon hillock. The membrane of the initial segment contains numerous voltage-sensitive sodium ion channels. The initial segment is the “trigger zone” of an axon where conduction of electrical activity as an action potential is initiated. If the axon is myelinated, the myelin sheath begins at the initial segment. The cytoplasm of the entire axon lacks free polysomes, Nissl substance, and Golgi apparatus but contains mitochondria and smooth ER. Anterograde axonal transport moves proteins and membranes that are synthesized in the cell body through the axon to the synaptic terminal. In fast anterograde transport, there is a rapid (100–400 mm/day) movement of materials from the cell body to the axon terminal. • Fast anterograde transport is dependent on kinesin, which acts as the
motor molecule. Fast anterograde transport delivers precursors of peptide neurotransmitters to synaptic terminals.
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• In slow anterograde transport, there is a slow (1–2 mm/day) antero-
grade movement of soluble cytoplasmic components. Cytoskeletal proteins, enzymes, and precursors of small molecule neurotransmitters are transported to synaptic terminals by slow anterograde transport. Slow transport is not dependent on microtubules or ATPase motor molecules.
Clinical Correlate Neuropathies and Axonal Transport • D isruption of fast anterograde transport may result in an axonal polyneuropathy. The cause may be anoxia (which affects mitochondrial oxidative phosphorylation) or anticancer agents e.g., colchicine and vinblastine (which depolymerize microtubules). • In patients with diabetes, hyperglycemia results in an alteration of proteins that form microtubules, which may disrupt axonal transport. Patients may develop axonal polyneuropathies in long axons in nerves, producing a “glove-and-stocking” pattern of altered sensation and pain in the feet and then in the hands.
Clinical Correlate Retrograde axonal transport returns intracellular material from the synaptic terminal to the cell body to be recycled or digested by lysosomes. Retrograde transport uses microtubules and is slower than anterograde transport (60–100 mm/day). It is dependent on dynein, an ATPase, which acts as the retrograde motor molecule. Retrograde transport also permits communication between the synaptic terminal and the cell body by transporting trophic factors emanating from the postsynaptic target or in the extracellular space.
Glial and Supporting Cells in the CNS and PNS
Retrograde Axonal Transport and Neurological Disorders The polio, herpes, and rabies viruses and tetanus toxins are taken up and retrogradely transported by axons that innervate skeletal muscle. Herpes is taken up and retrogradely transported in sensory fibers and remains dormant in sensory ganglia.
The supporting (or glial) cells of the CNS are small cells that differ from neurons. Supporting cells have only one kind of process and do not form chemical synapses. Unlike neurons, they readily divide and proliferate; glioma is the most common type of primary tumor of the CNS. Astrocytes are the most numerous glial cells in the CNS, and they have large numbers of radiating processes. • They provide the structural support or scaffolding for the CNS and
contain large bundles of intermediate filaments that consist of glial fibrillary acidic protein (GFAP).
• They have uptake systems which remove the neurotransmitter gluta-
mate and K+ ions from the extracellular space.
• They have foot processes which contribute to the blood–brain barrier
by forming a glial-limiting membrane.
• They hypertrophy and proliferate after an injury to the CNS, filling up
the extracellular space left by degenerating neurons by forming an astroglial scar. Also contributing to the blood-brain barrier are the pericytes that surround the capillaries in the brain.
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Radial glia are precursors of astrocytes that guide neuroblast migration during CNS development. Microglia cells are the smallest glial cells in the CNS. Unlike the rest of the CNS neurons and glia, which are derived from neuroectoderm, microglia are derived from bone marrow monocytes and enter the CNS after birth. • They provide a link between cells of the CNS and the immune system.
Physiology
Medical Genetics
• They proliferate and migrate to the site of a CNS injury and phagocy-
tose neuronal debris after injury.
• They determine the chances of survival of a CNS tissue graft, and are Pathology
Microbiology
Behavioral Science/Social Sciences
the cells in the CNS that are targeted by the HIV-1 virus in those with AIDS. The affected microglia may produce cytokines that are toxic to neurons.
CNS microglia that become phagocytic in response to neuronal tissue damage may secrete toxic free radicals. Accumulation of free radicals, such as superoxide, may lead to disruption of the calcium homeostasis of neurons. Oligodendrocytes form myelin for axons in the CNS. Each of the processes of the oligodendrocyte can myelinate individual segments of many axons. Unmyelinated axons in the CNS are not ensheathed by oligodendrocyte cytoplasm. Schwann cells are the supporting cells of the peripheral nervous system (PNS), and are derived from neural crest cells. Schwann cells form the myelin for axons and processes in the PNS. Each Schwann cell forms myelin for only a single internodal segment of a single axon. Unmyelinated axons in the PNS are enveloped by the cytoplasmic processes of a Schwann cell. Schwann cells act as phagocytes and remove neuronal debris in the PNS after injury. A node of Ranvier is the region between adjacent myelinated segments of axons in the CNS and the PNS. In all myelinated axons, nodes of Ranvier are sites that permit action potentials to jump from node to node (saltatory conduction). Saltatory conduction dramatically increases the conduction velocity of impulses in myelinated axons.
DISORDERS OF MYELINATION Demyelinating diseases are acquired conditions involving selective damage to myelin. Other diseases (e.g., infectious, metabolic, inherited) can also affect myelin and are generally called leukodystrophies.
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Table III-2-1. Conditions of Impaired Myelination Disease
Symptoms
Notes
Multiple sclerosis (MS)
Symptoms separated in space and time
Occurs 2x more often in women
Vision loss (optic neuritis)
Higher prevalence in temperate zones
Internuclear ophthalmoplegia (MLF)
Relapsing–remitting course is most common
Motor and sensory deficits Vertigo
Well-circumscribed demyelinated plaques often in periventricular areas
Neuropsychiatric
Chronic inflammation; axons initially preserved
Onset often in decades 3 or 4
Increased IgG (oligoclonal bands) in CSF Treatment: high-dose steroids, interferon-beta, glatiramer (Copaxone®) Guillain-Barré syndrome
Acute symmetric ascending inflammatory neuropathy of PNS myelin Weakness begins in lower limbs and ascends; respiratory failure can occur in severe cases
Two-thirds of patients have history of respiratory or GI illness 1–3 weeks prior to onset Elevated CSF protein with normal cell count (albuminocytologic dissociation)
Autonomic dysfunction may be prominent Cranial nerve involvement is common Sensory loss, pain, and paresthesias rarely occur Reflexes invariably decreased or absent Abbreviations: JC, John Cunningham; MLF, medial longitudinal fasciculus
Copyright McGraw-Hill Companies. Used with permission. Copyright McGraw-Hill Companies. Used with permission.
Figure III-2-4. Figure III-2-4. Section of a Peripheral Nerve Note endoneurial border of an individual axon (arrowhead) and 2 Schwann cell nuclei (arrows)
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Myelin
Schwann cell nuclei
Microbiology
From thethe IMC, © 2010 DxR Development Group, Inc. All reserved. From IMC, ® 2010 DxR Development Group, Inc.rights All rights reserved.
Figure III-2-5. n u Sec i n Figure III-2-5. Axons Cut in in Cross-Section
Ependymal cells line the ventricles in the adult brain. Some ependymal cells differentiate into choroid epithelial cells, forming part of the choroid plexus, which produces cerebrospinal fluid (CSF). Ependymal cells are ciliated; ciliary action helps circulate CSF. Tanycytes are specialized ependymal cells that have basal cytoplasmic processes in contact with blood vessels; these processes may transport substances between a blood vessel and a ventricle.
Blood–Brain Barrier
Clinical Correlate Drugs of addiction—heroin, ethanol, and nicotine—are lipid-soluble compounds that readily diffuse across the blood–brain barrier.
The blood–brain barrier restricts access of micro-organisms, proteins, cells, and drugs to the nervous system. It consists of capillary endothelial cells, an underlying basal lamina, astrocytes, and pericytes. • The most important elements of the blood-brain barrier are the cerebral capillary endothelial cells and their intercellular tight junctions. • Astrocytes and pericytes are found at the blood–brain barrier outside
the basal lamina. Astrocytes have processes with “end feet” that cover >95% of the basal lamina adjacent to the capillary endothelial cells.
Substances cross the blood–brain barrier into the CNS by diffusion, by selective transport, and via ion channels. Oxygen and carbon dioxide are lipid-soluble gases that readily diffuse across the blood–brain barrier. Glucose, amino acids, and vitamins K and D are selectively transported across the blood–brain barrier. Sodium and potassium ions move across the blood–brain barrier through ion channels.
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Chromatolysis (dispersion of Nissl substance and swelling of the neuron cell body)
Retrograde degeneration
Schwann cell
Site of injury
Proximal stump
A
Aberrant axonal sprouts degenerate
Node of Ranvier B
Anterograde (Wallerian) degeneration
Distal stump
Degenerating nerve terminal
Schwann cells guide the growth of the regenerating axon; regeneration rate 1–3 mm per day
Axonal sprout Distal axon and terminals completely degenerate
Undergoing Axotomy, Chromatolysis, Regeneration in the PNS Figure Figure III-2-6.III-2-6. NeuronNeuron Undergoing Axotomy, Chromatolysis, andand Regeneration in the PNS
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Clinical Correlate Schwannomas typically affect VIII Behavioral Science/Social Sciences nerve fibers seen in neurofibromatosis type 2.
Pathology
Response of Axons to Destructive Lesions (Severing an Axon or Axotomy) or Irritative Lesions (Compression of an Axon) Anterograde or Wallerian degeneration distal to the cut occurs when an axon is severed in either the CNS or PNS. The closer the destructive lesion is to the neuronal cell body, the more likely the neuron is to die. In the PNS, anterograde degeneration of axons is rapid and complete after several weeks. In the PNS, the endoneurial Schwann cell sheath that envelops a degenerating axon does not degenerate and provides a scaffold for regeneration and remyelination of the axon. Neurons with severed axons in the PNS are capable of complete axonal regeneration. Successful sprouts from the cut axon grow into and through endoneurial sheaths and are guided by Schwann cells back to their targets. Regeneration proceeds at the rate of 1–2 mm/day, which corresponds to the rate of slow anterograde transport. Half of brain and spinal cord tumors are metastatic.
Microbiology
Table III-2-2. Primary Tumors Tumor
Features
Pathology
Schwannoma
• Third most common primary brain tumor
ntoni A (hypercellular) and B (hypocellular) • A areas
• Most frequent location: CN VIII at cerebellopontine angle
• B ilateral acoustic schwannomas— pathognomonic for neurofibromatosis type 2
• H earing loss, tinnitus, CN V + VII signs • G ood prognosis after surgical resection Craniopharyngioma
erived from oral epithelium • D (remnants of Rathke pouch)
• Histology resembles ameloblastoma (most common tumor of tooth)
• Usually children and young adults • Often calcified • S ymptoms due to encroachment on pituitary stalk or optic chiasm • Benign but may recur
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N III
Ventricular System
3
Learning Objectives ❏❏ Demonstrate understanding of ventricular system and venous drainage ❏❏ Explain information related to CSF distribution, secretion, and circulation
The brain and spinal cord float within a protective bath of cerebrospinal fluid (CSF), which is produced continuously by the choroid plexus within the ventricles of the brain. Each part of the CNS contains a component of the ventricular system. There are 4 interconnected ventricles in the brain: 2 lateral ventricles, a third ventricle, and a fourth ventricle. • A lateral ventricle is located deep within each cerebral hemisphere.
Note Choroid plexus secretes CSF into all ventricles. Arachnoid granulations are sites of CSF resorption.
Each lateral ventricle communicates with the third ventricle via an interventricular foramen (foramen of Monro).
• The third ventricle is found in the midline within the diencephalon
and communicates with the fourth ventricle via the cerebral aqueduct (of Sylvius), which passes through the midbrain.
• The fourth ventricle is located between the dorsal surfaces of the
pons and upper medulla and the ventral surface of the cerebellum. The fourth ventricle is continuous with the central canal of the lower medulla and spinal cord.
VENTRICULAR SYSTEM AND VENOUS DRAINAGE The brain and spinal cord float within a protective bath of CSF, which is produced by the lining of the ventricles, the choroid plexus. CSF circulation begins in the ventricles and then enters the subarachnoid space to surround the brain and spinal cord.
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Neuroscience Immunology
Third ventricle Pharmacology
Biochemistry
Foramen of Monro
Body of lateral ventricle
Anterior horn of the lateral ventricle Physiology
Posterior horn of lateral ventricle (occipital)
Medical Genetics
Inferior horn of lateral ventricle (temporal) Pathology
Cerebral aqueduct (of Sylvius)
Behavioral Science/Social Sciences
Fourth ventricle Central canal
Microbiology
Figure III-3-1. Ventricles andand CSFCSF Circulation Figure III-3-1. Ventricles Circulation
Note A total of 400–500 cc of CSF is produced per day; ventricles and subarachnoid space contain 90–150 cc, so all of CSF is turned over 2–3 times per day.
Superior sagittal sinus
Arachnoid granulation (CSF return)
Lateral ventricle
Choroid plexus
Interventricular foramen of Monro Third ventricle Cerebral aqueduct
Foramen of Magendie (median aperture)
Foramen of Luschka (lateral aperture) Fourth ventricle Subarachnoid space
Figure III-3-2. Section of of the the Brain Brain Figure III-3-2. Sagittal Sagittal Section interventricular foramen of Monro cerebral aqueduct ∨
∨ Lateral ventricles → third ventricle → fourth ventricle → subarachnoid space (via foramina of Luschka and foramen of Magendie)
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CSF Production and Barriers Choroid plexus—contains choroid epithelial cells and is in the lateral, third, and fourth ventricles. Secretes CSF. Tight junctions form blood-CSF barrier. Blood-brain barrier—formed by capillary endothelium with tight junctions; astrocyte foot processes contribute. Once CSF is in the subarachnoid space, it goes up over convexity of the brain and enters the venous circulation by passing through arachnoid granulations into dural venous sinuses.
Arachnoid granulations
Deep vein of scalp
Emissary vein Diploic vein
Skin Galea aponeurotica Pericranium Skull (diploic bone) Dura mater Arachnoid mater
Cranial meninges
Pia mater Superior sagittal sinus Falx cerebri Subarachnoid space Inferior sagittal sinus Figure III-3-3. Coronal Section the Dural Sinuses Figure III-3-3. Coronal Section of theofDural Sinuses
Sinuses Superior sagittal sinus (in superior margin of falx cerebri)—drains into 2 transverse sinuses. Each of these drains blood from the confluence of sinuses into sigmoid sinuses. Each sigmoid sinus exits the skull (via jugular foramen) as the internal jugular veins. Inferior sagittal sinus (in inferior margin of falx cerebri)— terminates by joining with the great cerebral vein of Galen to form the straight sinus at the falx cerebri and tentorium cerebelli junction. This drains into the confluence of sinuses. Cavernous sinus—a plexus of veins on either side of the sella turcica. Surrounds internal carotid artery and cranial nerves III, IV, V, and VI. It drains into the transverse sinus (via the superior petrosal sinus) and the internal jugular vein (via the inferior petrosal sinus).
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Superior sagittal sinus
Falx cerebrii Pharmacology
Biochemistry
Inferior sagittal sinus Cavernous sinus
Tentorium cerebelli Sigmoid sinus Physiology
Medical Genetics
Superior petrosal sinus Straight sinus
Pathology
Behavioral Science/Social Sciences
Transverse sinus Microbiology
Tentorium cerebelli Occipital sinus
Dural Venous FigureFigure III-3-4. III-3-4. Dural Venous Sinuses Sinuses
Hydrocephalus Excess volume or pressure of CSF, leading to dilated ventricles
Table III-3-1. Types and Features of Hydrocephalus Type of Hydrocephalus
Description
Noncommunicating
Obstruction of flow within ventricles; most commonly occurs at narrow points, e.g., foramen of Monro, cerebral aqueduct and/or openings of fourth ventricle
Communicating
Impaired CSF reabsorption in arachnoid granulations or obstruction of flow in subarachnoid space
Normal pressure (chronic)
CSF is not absorbed by arachnoid villi (a form of communicating hydrocephalus). CSF pressure is usually normal. Ventricles chronically dilated. Produces triad of dementia, apraxic (magnetic) gait, and urinary incontinence. Peritoneal shunt.
Ex vacuo
Descriptive term referring to excess CSF in regions where brain tissue is lost due to atrophy, stroke, surgery, trauma, etc. Results in dilated ventricles but normal CSF pressure.
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CSF DISTRIBUTION, SECRETION, AND CIRCULATION CSF fills the subarachnoid space and the ventricles of the brain. The average adult has 90–150 mL of total CSF, although 400–500 mL is produced daily. Only 25 mL of CSF is found in the ventricles themselves. Approximately 70% of the CSF is secreted by the choroid plexus, which consists of glomerular tufts of capillaries covered by ependymal cells that project into the ventricles (the remaining 30% represents metabolic water production). The choroid plexus is located in parts of each lateral ventricle, the third ventricle, and the fourth ventricle. CSF from the lateral ventricles passes through the interventricular foramina of Monro into the third ventricle. From there, CSF flows through the aqueduct of Sylvius into the fourth ventricle. The only sites where CSF can leave the ventricles and enter the subarachnoid space outside the CNS are through 3 openings in the fourth ventricle, 2 lateral foramina of Luschka and the median foramen of Magendie. Within the subarachnoid space, CSF also flows up over the convexity of the brain and around the spinal cord. Almost all CSF returns to the venous system by draining through arachnoid granulations into the superior sagittal dural venous sinus. • Normal CSF is a clear fluid, isotonic with serum (290–295 mOsm/L). • The pH of CSF is 7.33 (arterial blood pH, 7.40; venous blood pH, 7.36). • Sodium ion (Na+) concentration is equal in serum and CSF
(≈138 mEq/L).
• CSF has a higher concentration of chloride (Cl–) and magnesium
(Mg2+) ions than does serum.
Clinical Correlate The concentration of protein (including all immunoglobulins) is much lower in the CSF as compared with serum. Normal CSF contains 0–4 lymphocytes or mononuclear cells per cubic millimeter. Although the presence of a few monocytes or lymphocytes is normal, the presence of polymorphonuclear leukocytes is always abnormal, as in bacterial meningitis. • R ed blood cells are not normally found in the CSF but may be present after traumatic spinal tap or subarachnoid hemorrhage. • Increased protein levels may indicate a CNS tumor. • T umor cells may be present in the CSF in cases with meningeal involvement.
• CSF has a lower concentration of potassium (K+), calcium (Ca2+), and
bicarbonate (HCO3–) ions, as well as glucose, than does serum.
The blood–CSF barrier is a mechanism which protects the chemical integrity of the brain. Tight junctions located along the epithelial cells of the choroid plexus form the blood–CSF barrier. Transport systems are similar but not identical to the those of blood–brain barrier. The ability of a substance (drug) to enter the CSF does not guarantee it will gain access to the brain.
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The Spinal Cord
4
Learning Objectives ❏❏ Solve problems concerning general features ❏❏ Interpret scenarios on neural systems
GENERAL FEATURES The spinal cord is housed in the vertebral canal. It is continuous with the medulla below the pyramidal decussation and terminates as the conus medullaris at the second lumbar vertebra of the adult. The roots of 31 pairs of spinal nerves arise segmentally from the spinal cord. There are 8 cervical pairs of spinal nerves (C1 through C8). The cervical enlargement (C5 through T1) gives rise to the rootlets that form the brachial plexus, which innervates the upper limbs. There are 12 thoracic pairs of spinal nerves (T1 through T12). Spinal nerves emanating from thoracic levels innervate most of the trunk. There are 5 lumbar pairs of spinal nerves (L1 through L5). The lumbar enlargement (L2 through S3) gives rise to rootlets that form the lumbar and sacral plexuses, which innervate the lower limbs. There are 5 sacral pairs of spinal nerves (S1 through S5). Spinal nerves at the sacral level innervate part of the lower limbs and the pelvis. There is 1 coccygeal pair of spinal nerves. The cauda equina consists of the dorsal and ventral roots of the lumbar, sacral, and coccygeal spinal nerves. Inside the spinal cord, gray matter is centrally located and shaped like a butterfly. It contains neuronal cell bodies, their dendrites, and the proximal parts of axons. White matter surrounds the gray matter on all sides. White matter contains bundles of functionally similar axons called tracts or fasciculi, which ascend or descend in the spinal cord.
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White matter: tracts and fasciculi Behavioral Science/Social Sciences
Arachnoid Microbiology
White matter Gray matter
Gray matter
Dorsal ramus (mixed)
Dura mater Pia mater Dorsal root (sensory)
Supplies: • Skin of back and dorsal neck • Deep intrinsic back muscles (Erector spinae)
Dorsal root ganglion
Ventral root (motor)
Gray matter: Dorsal horn (sensory) Ventral horn (motor) Intermediate zone (autonomic neurons T1-L2 S2-S4) Clarke’s nucleus (T1-L2)
Spinal nerve
Ventral ramus (mixed) Sympathetic ganglion
Supplies: • Skin of anterolateral trunk and limbs • Skeletal muscles of anterolateral trunk and limbs
Figure III-4-1. CrossSection SectionofofSpinal SpinalCord Cord and Figure III-4-1. Cross and Parts PartsofofSpinal SpinalNerve Nerve
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Table III-4-1. General Spinal Cord Features Conus medullaris
Caudal end of the spinal cord (S3–S5). In adult, ends at the L2 vertebra
Cauda equina
Nerve roots of the lumbar, sacral, and coccygeal spinal nerves
Filum terminale
Slender pial extension that tethers the spinal cord to the bottom of the vertebral column
Doral root ganglia
Cell bodies of primary sensory neurons
Dorsal and ventral roots
Each segment has a pair
Dorsal horn
Sensory neurons
Ventral horn
Motor neurons
Spinal nerve
Formed from dorsal and ventral roots (mixed nerve)
Cervical enlargement
(C5–T1) → branchial plexus → upper limbs
Lumbar enlargement
(L2–S3) → lumbar and sacral plexuses → lower limbs
Posterior (dorsal) gray horn Lateral funiculus Anterior (ventral) gray horn Anterior funiculus
Posterior funiculus Posterior median sulcus Posterior intermediate sulcus Dorsal root entry zone Intermediate (lateral) gray horn Dorsal Root filaments Ventral Dorsal root ganglion
Anterior median fissure Anterolateral sulcus
Spinal nerve
FigureGeneral III-4-2. Spinal General Spinal Cord Features Figure III-4-2. Cord Features
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Dorsal Horn The dorsal horn is dominated by neurons that respond to sensory stimulation. All incoming sensory fibers in spinal nerves enter the dorsolateral part of the cord adjacent to the dorsal horn in a dorsal root. Neurons in the dorsal horn project to higher levels of the CNS to carry sensations to the brain stem, cerebral cortex, or cerebellum. Other dorsal horn neurons participate in reflexes. Dorsal root ganglion cell
Medical Genetics
Dorsal horn: rexed laminae I–VI Ventral horn: rexed laminae VIII–IX Intermediate zone: lamina VII
Pathology
Behavioral Science/Social Sciences
Medial division Proprioception (Ia, Ib fibers)
Collaterals enter dorsal columns
Touch (II, A-beta fibers) Lateral division Sharp pain, cold (III, A-delta fibers)
Microbiology
I II
III
Dull pain, warmth (IV, C fiber)
IV Contribute to reflexes
V VII
IX VIII
IX IX
VIII
X
IX
Figure III-4-3. Dorsal Roots Sites of Termination Figure III-4-3. Dorsal Roots andand Sites of Termination in the in the Spinal Cord Gray Matter Spinal Cord Gray Matter
Ventral Horn The ventral horn contains alpha and gamma motoneurons. The alpha motoneurons innervate skeletal muscle (extrafusal fibers) by way of a specialized synapse at a neuromuscular junction, and the gamma motoneurons innervate the contractile intrafusal muscle fibers of the muscle spindle. Within the ventral horn, alpha and gamma motoneurons that innervate flexors are dorsal to those that innervate extensors. Alpha and gamma motoneurons that innervate the proximal musculature are medial to those that innervate the distal musculature. Axons of alpha and gamma motoneurons and axons of preganglionic autonomic neurons leave the cord by way of a ventral root.
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Corticospinal and rubrospinal tracts
Note EXORS
HAND FOREARM ARM SHOULDER TRUNK
FL
C5–T1 and L2–S3 have large ventral horn.
EXT
Note Alpha motor neurons make skeletal muscles contract. Gamma motor neurons make muscle spindles more sensitive to stretch.
E N S O RS
Topgraphic organization of alpha and gamma motor neurons in lamina IX of cervical cord
Reticulospinal and vestibulospinal tracts
Alpha and gamma motor axons from lamina IX in ventral root Renshaw cells
Figure III-4-4.Figure Topographic Organization of Organization Alpha and Gamma III-4-4. Topographic of Alpha Motoneurons in Lamina IX and Gamma(LMNs) Motoneurons (LMNs) in Lamina IX
Intermediate Zone The intermediate zone of the spinal cord from T1 to L2 contains preganglionic sympathetic neuron cell bodies and Clarke nucleus, which sends unconscious proprioception to the cerebellum.
NEURAL SYSTEMS There are 3 major neural systems in the spinal cord that use neurons in the gray matter and tracts or fasciculi of axons in the white matter. These neural systems have components which can be found at all levels of the CNS, from the cerebral cortex to the tip of the spinal cord. A knowledge of these 3 neural systems is essential to understanding the effects of lesions in the spinal cord and brain stem, and at higher levels of the CNS.
Motor System
Note Upper motoneuron
Voluntary innervation of skeletal muscle Upper and Lower Motoneurons Two motoneurons, an upper motoneuron and a lower motoneuron, together form the basic neural circuit involved in the voluntary contraction of skeletal muscle everywhere in the body. The lower motoneurons are found in the ventral horn of the spinal cord and in cranial nerve nuclei in the brain stem.
Lower motoneuron Motor end plate of skeletal muscles
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Physiology
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Pathology
Behavioral Science/Social Sciences
Axons of lower motoneurons of spinal nerves exit in a ventral root, then join the spinal nerve to course in one of its branches to reach and synapse directly at a neuromuscular junction in skeletal muscle. Axons of lower motoneurons in the brain stem exit in a cranial nerve. To initiate a voluntary contraction of skeletal muscle, a lower motoneuron must be innervated by an upper motoneuron. The cell bodies of upper motoneurons are found in the brain stem and cerebral cortex, and their axons descend into the spinal cord in a tract to reach and synapse on lower motoneurons, or on interneurons, which then synapse on lower motoneurons. At a minimum, therefore, to initiate a voluntary contraction of skeletal muscle, 2 motoneurons, an upper and a lower, must be involved. The upper motoneuron innervates the lower motoneuron, and the lower motoneuron innervates the skeletal muscle. The cell bodies of upper motoneurons are found in the red nucleus, reticular formation, and lateral vestibular nuclei of the brain stem, but the most important location of upper motoneurons is in the cerebral cortex. Axons of these cortical neurons course in the corticospinal tract.
Microbiology
Note UMNs have net inhibitory effect on muscle stretch reflexes.
Right
Left
Precentral gyrus (primary motor cortex)
Note Voluntary contraction: UMN → LMN Reflect contraction: muscle sensory neuron → LMN
Frontal lobe Brodmann Areas 4&6
Cerebral cortex
Upper motor neuron (UMN)
Caudal medulla-spinal cord junction
Lateral corticospinal tract Function: voluntary refined movements of the distal extremities
Brain stem
Pyramidal decussation
Spinal cord Muscle spindle (Ia) afferent from muscle spindle Muscle stretch reflex
Lower motor neuron (LMN) (Alpha)
Muscle spindle Skeletal muscle
Figure III-4-5. III-4-5. Voluntary Voluntary Contraction Contraction of of Skeletal Skeletal Muscle: Figure Muscle: UMN UMN and and LMNs LMNs
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Corticospinal Tract
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Clinical Correlate
The primary motor cortex, located in the precentral gyrus of the frontal lobe, and the premotor area, located immediately anterior to the primary motor cortex, give rise to about 60% of the fibers of the corticospinal tract (Figure III-4-4). Primary and secondary somatosensory cortical areas located in the parietal lobe give rise to about 40% of the fibers of the corticospinal tract.
Lesions of the Corticospinal Tract The crossing or decussation of axons of the corticospinal tract at the medulla/spinal cord junction has significant clinical implications.
Fibers in the corticospinal tract leave the cerebral cortex in the internal capsule, which carries all axons in and out of the cortex. Corticospinal fibers then descend through the length of the brain stem in the ventral portion of the midbrain, pons, and medulla.
• If lesions of the corticospinal tract occur above the pyramidal decussation, a weakness is seen in muscles on the contralateral side of the body.
In the lower medulla, 80–90% of corticospinal fibers cross at the decussation of the pyramids and continue in the contralateral spinal cord as the lateral corticospinal tract. The lateral corticospinal tract descends the full length of the cord in the lateral part of the white matter. As it descends, axons leave the tract and enter the gray matter of the ventral horn to synapse on lower motoneurons.
• If lesions occur below this level, an ipsilateral muscle weakness is seen. In contrast to upper motoneurons, the cell bodies of lower motoneurons are ipsilateral to the skeletal muscles that their axons innervate. A lesion to any part of a lower motoneuron will result in an ipsilateral muscle weakness at the level of the lesion.
UMN cell bodies in cerebral cortex and brainstem medulla pper U Corticospinal tract in medulla Pyramidal decussation Extensor biased UMN tracts
Lowe
la ul
rm ed
Medullary pyramids
Lower motor neurons to muscles of upper limb
rv Ce
Lower motor neurons to muscles of lower limb
rd co
A lesion here results in a flaccid weakness that is ipsilateral and at the level of the lesion
al pi n ls ica
A lesion here results in a spastic weakness that is ipsilateral and below the lesion
Pyramidal decussation
LMN
Corticospinal tracts (flexor biased UMN tracts)
Lumbar spin al cord
Figure III-4-6. Course of Axons of Upper Motor Neurons in the Medulla and Spinal Cord Figure III-4-6. Course of Axons of Upper Motor Neurons in the Medulla with Representative C ross-Sections and Spinal Cord with Representative Cross-Sections
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Reflex innervation of skeletal muscle A reflex is initiated by a stimulus of a sensory neuron, which in turn innervates a motoneuron and produces a motor response. In reflexes involving skeletal muscles, the sensory stimulus arises from receptors in the muscle, and the motor response is a contraction or relaxation of one or more skeletal muscles. In the spinal cord, lower motoneurons form the specific motor component of skeletal muscle reflexes. Upper motoneurons provide descending control over the reflexes. Both alpha and gamma motoneurons are lower motoneurons that participate in reflexes.
Pathology
Microbiology
Behavioral Science/Social Sciences
• Alpha motoneurons are large cells in the ventral horn that innervate
extrafusal muscle fibers. A single alpha motoneuron innervates a group of muscle fibers, which constitutes a motor unit, the basic unit for voluntary, postural, and reflex activity.
• Gamma motoneurons supply intrafusal muscle fibers, which are
modified skeletal muscle fibers. The intrafusal muscle fibers form the muscle spindle, which acts as a sensory receptor in skeletal muscle stretch reflexes.
Both ends of the muscle spindle are connected in parallel with the extrafusal fibers, so these receptors monitor the length and rate of change in length of extrafusal fibers. Muscles involved with fine movements contain a greater density of spindles than those used in coarse movements.
Commonly tested muscle stretch reflexes The deep tendon (stretch, myotatic) reflex is monosynaptic and ipsilateral. The afferent limb consists of a muscle spindle, Ia sensory neuron, and efferent limb (lower motor neuron). These reflexes are useful in the clinical exam. Reflex
Cord Segment Involved
Muscle Tested
Knee (patellar)
L2–L4 (femoral n.)
Quadriceps
Ankle
S1 (tibial n.)
Gastrocnemius
Elbow
C5–C6 (musculocutaneous n.)
Biceps
Elbow
C7–C8 (radial n.)
Triceps
Forearm
C5–C6 (radial n.)
Brachioradialis
Muscle stretch (myotatic) reflex The muscle stretch (myotatic) reflex is the stereotyped contraction of a muscle in response to stretch of that muscle. The stretch reflex is a basic reflex that occurs in all muscles and is the primary mechanism for regulating muscle tone. Muscle tone is the tension present in all resting muscle. Tension is controlled by the stretch reflexes. The best example of a muscle stretch or deep tendon reflex is the knee-jerk reflex. Tapping the patellar ligament stretches the quadriceps muscle and its muscle spindles. Stretch of the spindles activates sensory endings (Ia afferents),
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and afferent impulses are transmitted to the cord. Some impulses from stretch receptors carried by Ia fibers monosynaptically stimulate the alpha motoneurons that supply the quadriceps. This causes contraction of the muscle and a sudden extension of the leg at the knee. Afferent impulses simultaneously inhibit antagonist muscles through interneurons (in this case, hamstrings).
Inverse muscle stretch reflex The inverse muscle stretch reflex monitors muscle tension. This reflex uses Golgi tendon organs (GTOs). These are encapsulated groups of nerve endings that terminate between collagenous tendon fibers at the junction of muscle and tendon. GTOs are oriented in series with the extrafusal fibers and respond to increases in force or tension generated in that muscle. Increases in force in a muscle increase the firing rate of Ib afferent neurons that innervate the GTOs, which, in turn, polysynaptically facilitate antagonists and inhibit agonist muscles. Muscle tone and reflex activity can be influenced by gamma motoneurons and by upper motoneurons. Gamma motoneurons directly innervate the muscle spindles and regulate their sensitivity to stretch. Upper motoneurons innervate gamma motoneurons and also influence the sensitivity of muscle spindles to stretch. Stimulation of gamma motoneurons causes intrafusal muscle fibers located at the pole of each muscle spindle to contract, which activates alpha motoneurons, causing an increase in muscle tone. Collaterals to dorsal columns
Dorsal root
Note UMN lesions result in:
Dorsal root ganglion + LMNs in ventral root Muscle spindle (activated by ↑ in muscle stretch)
Inhibitory interneuron
–
–
• H yperactive muscle stretch reflexes • C lasp knife reflex due to oversensitive Golgi tendon organs
LMN
Leg extensor muscles (quadriceps)
Motor end plates Leg flexor muscles (hamstrings) Patellar tendon
Muscle stretch reflex (causes stretched muscle to contract)
Golgi tendon organ (activated by ↑ in muscle force)
Inverse muscle stretch reflex (causes activated muscle to relax)
Figure III-4-7. Muscle Stretch and Golgi Tendon ReflexReflex Components Figure III-4-7. Muscle Stretch and Golgi Tendon Components
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Flexor withdrawal reflex The flexion withdrawal reflex is a protective reflex in which a stimulus (usually painful) causes withdrawal of the stimulated limb. This reflex may be accompanied by a crossed extension reflex in which the contralateral limb is extended to help support the body.
Clinical Correlate Upper Motoneuron Versus Lower Motoneuron Muscle Lesions
Pathology
Microbiology
Behavioral Science/Social Sciences
A fundamental requirement of interpreting the cause of motor weakness in neuroscience cases is the ability to distinguish between a lesion of an upper versus a lower motoneuron. Because a lesion to either one produces a weakness in the ability to voluntarily contract skeletal muscles, the key to distinguishing them will be the condition of reflexes of the affected muscles. A lesion of any part of a lower motoneuron will result in hypoactive muscle stretch reflexes and a reduction in muscle tone (hypotonicity) because lower motoneurons form the motor component of the reflex. Therefore, lower motoneuron lesions result in a paresis combined with suppressed or absent muscle stretch reflexes. An early sign is muscle fasciculations, which are twitches or contractions of groups of muscle fibers, that may produce a twitch visible on the skin. Later, lower motoneuron lesions produce fibrillations, which are invisible 1- to 5-ms potentials, detected with electromyography. Muscles denervated by a lower motoneuron lesion undergo pronounced wasting or atrophy. The constellation of signs combining paresis with suppressed or absent reflexes, fasciculations, and atrophy is known as a flaccid paralysis. With few exceptions, lower motoneuron lesions produce a flaccid paralysis ipsilateral and at the level of the lesion. Neurologically, upper motoneurons including the corticospinal tract have a net overall inhibitory effect on muscle stretch reflexes. As a result, they combine paresis of skeletal muscles with muscle stretch or deep tendon reflexes that are hyperactive or hypertonic. The hypertonia may be seen as decorticate rigidity (i.e., postural flexion of the arm and extension of the leg) or decerebrate rigidity (i.e., postural extension of the arm and leg) depending on the location of the lesion. Lesions above the midbrain produce decorticate rigidity; lesions below the midbrain produce decerebrate rigidity. Upper motoneuron lesions result in atrophy of weakened muscles only as a result of disuse, because these muscles can still be contracted by stimulating muscle stretch reflexes. Upper motoneuron lesions are also accompanied by reversal of cutaneous reflexes, which normally yield a flexor motor response. The best known of the altered flexor reflexes is the Babinski sign. The test for the Babinski reflex is performed by stroking the lateral surface of the sole of the foot with a slightly painful stimulus. Normally, there is plantar flexion of the big toe. With a lesion of the corticospinal tract, the Babinski reflex is present, which is characterized by extension of the great toe and fanning of the other toes. Two other flexor reflexes, the abdominal and cremasteric, are also lost in upper motoneuron lesions. The constellation of signs combining paresis with increases or hyperactive reflexes, disuse atrophy of skeletal muscles, and altered cutaneous reflexes is known as a spastic paresis. In contrast to lower motoneuron lesions, lesions of upper motoneurons result in a spastic paresis that is ipsilateral or contralateral and below the site of the lesion. Upper motoneuron lesions anywhere in the spinal cord will result in an ipsilateral spastic paresis below the level of the lesion. Upper motoneuron lesions between the cerebral cortex and the medulla above the decussation of the pyramids will result in a contralateral spastic paresis below the level of the lesion.
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Right
The Spinal Cord
Left Cerebral cortex
Upper motor neuron (UMN) A & B: Spastic paresis contralateral and below lesion
l
Precentral gyrus
A
B
Caudal medulla (decussation)
Lateral corticospinal tract Function: Voluntary refined movements of the distal extremities
C
Brain stem C: Spastic weakness ipsilateral and below lesion
Spinal cord
D & E: Flaccid paralysis ipsilateral and at level of lesion
D
E
Lower motor neuron (LMN)
Skeletal muscle
FigureIII-4-8. III-4-8.Upper UpperVersus Versus Lower Motor Neuron Lesions Figure Lesions Table III-4-2. Upper Versus Lower Motoneuron Lesions Upper Motor Neuron Lesion*
Lower Motor Neuron Lesion†
Spastic paresis
Flaccid paralysis
Hyperreflexia
Areflexia
Babinski sign present
No Babinski
Increased muscle tone
Fasciculations
Clasp knife reflex
Decreased muscle tone or atonia
Disuse atrophy of muscles
Atrophy of muscle(s)
Decreased speed of voluntary movements
Loss of voluntary movements
Large area of the body involved
Small area of the body affected
*Deficits contralateral or ipsilateral and below the lesion †Deficits ipsilateral and at the level of lesion
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Sensory Pathways Two sensory systems, the dorsal column–medial lemniscal system and the anterolateral (spinothalamic) system, use 3 neurons to convey sensory information from peripheral sensory receptors to conscious levels of cerebral cortex. In both systems, the first sensory neuron that innervates a sensory receptor has a cell body in the dorsal root ganglion and carries the information into the spinal cord in the dorsal root of a spinal nerve. The first neuron synapses with a second neuron in the brain stem or the spinal cord, and the axon of the second neuron crosses the midline and is carried in a tract in the CNS. The axon of the second neuron then synapses on a third neuron that is in the thalamus. The axon of the third neuron projects to primary somatosensory cortex. Midline
Microbiology
3: third-order neuron in thalamus
Left
Postcentral gyrus
Somatosensory cortex
Cerebral cortex
Parietal lobe Brodmann areas 3, 1, 2
Thalamus
3 Third order neuron
1: first-order neuron in sensory ganglion 2: second-order neuron in CNS (axon always crosses midline)
Right
Brain stem or spinal cord
Courses in a tract or lemniscus 2 Second order neuron (always crosses midline near cell body)
Neuron #2 cell body is ipsilateral to neuron #1
1
Dorsal root ganglion cell (DRG) (pseudounipolar neuron)
First order neuron
Receptor
Figure III-4-9. III-4-9. General General Sensory Pathways Figure Pathways
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Ascending Pathways The 2 most important ascending pathways use a 3-neuron system to convey sensory information to the cortex. Key general features are listed below.
Pathway
Function
Overview
Dorsal column–medial lemniscal system
Discriminative touch, conscious proprioception, vibration, pressure
3-neuron system:
Anterolateral system (spinothalamic)
Pain and temperature
1˚ neuron: cell body in DRG 2˚ neuron: decussates 3˚ neuron: thalamus (VPL) → cortex
Abbreviations: DRG, dorsal root ganglia; VPL, ventral posterolateral nucleus.
Dorsal column–medial lemniscal system The dorsal column–medial lemniscal system carries sensory information for discriminative touch, joint position (kinesthetic or conscious proprioceptive) sense, vibratory, and pressure sensations from the trunk and limbs. The primary afferent neurons in this system have their cell bodies in the dorsal root ganglia, enter the cord via class II or A-beta dorsal root fibers, and then coalesce in the fasciculus gracilis or fasciculus cuneatus in the dorsal funiculus of the spinal cordfasciculus cuneatus in the dorsal funiculus of the spinal cord. The fasciculus gracilis, found at all spinal cord levels, is situated closest to the midline and carries input from the lower extremities and lower trunk. The fasciculus cuneatus, found only at upper thoracic and cervical spinal cord levels, is lateral to the fasciculus gracilis and carries input from the upper extremities and upper trunk. These 2 fasciculi form the dorsal columns of the spinal cord that carry the central processes of dorsal root ganglion cells and ascend the length of the spinal cord to reach their second neurons in the lower part of the medulla. In the lower part of the medulla, fibers in the fasciculus gracilis and fasciculus cuneatus synapse with the second neurons found in the nucleus gracilis and nucleus cuneatus, respectively. Cells in these medullary nuclei give rise to fibers that cross the midline as internal arcuate fibers and ascend through the brain stem in the medial lemniscus ascend through the brain stem in the medial lemniscus. Fibers of the medial lemniscus terminate on cells of the ventral posterolateral (VPL) nucleus of the thalamus. From the VPL nucleus, thalamocortical fibers project to the primary somesthetic (somatosensory) area of the postcentral gyrus, located in the most anterior portion of the parietal lobe.
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Left Cerebral cortex
Postcentral gyrus Pharmacology
Biochemistry
A B
Thalamus
3 Physiology
Medical Genetics
C
Pathology
Microbiology
Behavioral Science/Social Sciences
Medial lemniscus
Medulla
N. Cuneatus N. Gracilis
2
Function: Conscious proprioception, fine touch, vibration, pressure, 2-point discrimination Lesion: Loss of above senses
Ventropostero-lateral nucleus (VPL)
Dorsal columns
Spinal cord
D
Site of lesion: Affected side of body
1
A, B, and C: Contralateral and below
Fasciculus cuneatus– upper limb T5↑ (lateral column) Fasciculus gracilis– lower limb T6↓ (medial column) Dorsal root ganglion cell (DRG) Receptor Pacinian corpuscle –vibration Meissner corpuscle –touch muscle spindle –proprioception
D: Ipsilateral and below
Figure III-4-10. Dorsal Column Pathway–Medial Pathway–Medial Lemniscal Lemniscal System System Figure III-4-10. Dorsal Column
Clinical Correlate Lesions of the dorsal columns result in a loss of joint position sensation, vibratory and pressure sensations, and 2-point discrimination. There is loss of the ability to identify the characteristics of an object, called astereognosis (e.g., size, consistency, form, shape), using only the sense of touch. Typically, dorsal column–medial lemniscal lesions are evaluated by testing vibratory sense using a 128-Hz tuning fork. Romberg sign is also used to distinguish between lesions of the dorsal columns and the midline (vermal area) of the cerebellum. Romberg sign is tested by asking the patients to place their feet together. If there is a marked deterioration of posture (if the patient sways) with the eyes closed, this is a positive Romberg sign, suggesting that the lesion is in the dorsal columns (or dorsal roots of spinal nerves). With the eyes open, interruption of proprioceptive input carried by the dorsal columns can be compensated for by visual input to the cerebellum. Therefore, if the patient has balance problems and tends to sway with the eyes open, this is indicative of cerebellar damage.
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Primary somatosensory cortex Neuron #3
Lemniscal fibers ascending to thalamus (VPL)
Thalamus (VPL)
Medial lemniscus Crossing axons in lower medulla Neuron #2 in dorsal column nuclei Fasciculus cuneatus
Medial lemniscus
Lowe rm ed
Cuneate nucleus
la
Gracile nucleus
Ce rv ic
Dorsal column nuclei
Crossing axons of neurons #2 (internal arcuate fibers)
al l ina sp
rd co
A lesion here results in deficits that are ipsilateral and below the lesion
Medullary pyramids
ul
From T5 up including upper limb
ulla er med Upp
Fasciculus cuneatus Fasciculus gracilis Neuron #1 From T6 down including lower limb
Fasciculus gracilis Lower motor neuron Fasciculus gracilis Lumbar spin al cord
Lower motor neuron
Reflex synapse
Figure III-4-11. Dorsal Column/Medial Lemniscal System in the Spinal Cord and Medulla
Figure III-4-11. Dorsal Column/Medial Lemniscal System in the Spinal Cord and Medulla
Anterolateral (spinothalamic tract) system
Clinical Correlate
The anterolateral system carries pain, temperature, and crude touch sensations from the extremities and trunk.
Because the pain and temperature information crosses almost as soon as it enters the spinal cord, any unilateral lesion of the spinothalamic tract in the spinal cord or brain stem will result in a contralateral loss of pain and temperature. This is an extremely useful clinical sign because it means that if a patient presents with analgesia on one side of the trunk or limbs, the location of the lesion must be on the contralateral side of the spinal cord or brain stem. The analgesia begins 1 to 2 segments below the lesion and includes everything below that level.
Pain and temperature fibers have cell bodies in the dorsal root ganglia and enter the spinal cord via A-delta and C or class III and class IV dorsal root fibers. Their fibers ascend or descend a couple of segments in the dorsolateral tract of Lissauer before entering and synapsing in the dorsal horn. The second neuron cell bodies are located in the dorsal horn gray matter. Axons from these cells cross in the ventral white commissure just below the central canal of the spinal cord and coalesce to form the spinothalamic tract in the ventral part of the lateral funiculus. The spinothalamic tract courses through the entire length of the spinal cord and the brain stem to terminate in the VPL nucleus of the thalamus. Cells in the VPL nucleus send pain and temperature information to the primary somatosensory cortex in the postcentral gyrus.
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Left Cerebral cortex
Postcentral gyrus Pharmacology
Biochemistry
A B Physiology
Thalamus
Medical Genetics
3
Pathology
Ventroposterolateral nucleus (VPL)
Spinothalamic tract
Behavioral Science/Social Sciences
Medulla
Brain stem
C Microbiology
Lesion: Anesthesia (loss of pain and temperature sensations) Site of lesion: Affected side of body A, B, C, and D: Contralateral below the lesion; tract intact rostral to the lesion
D
Spinal cord 2
Dorsal horn
Ascend or descend 1–2 segments in Lissauer’s tract DRG 1
Receptor
Figure III-4-12. Spinothalamic Tract (Anterolateral System) Figure III-4-12. Spinothalamic Tract (Anterolateral System)
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Primary somatosensory cortex Neuron #3
To thalamus (VPL)
Thalamus (VPL) r Uppe lla u d e m
From arm
Lowe rm ed ul
la
Lissauer’s tract
Spinothalamic tract
Ce rv ic al
Spinothalamic tract
lc ina sp ord
A lesion here results in deficits that are contralateral and 1–2 segments below the lesion Ventral white commissure
Pain/temp fiber Spinothalamic tract
Neuron #2 in dorsal horn From leg Neuron #1
Lumba spinal cor rd
Pain/temp fiber Axons cross in ventral white commissure below central canal Spinothalamic tract
Figure III-4-13. Anterolateral System System in the Spinal Cord and Figure III-4-13. Anterolateral and Medulla Medulla
Spinocerebellar pathways The spinocerebellar tracts mainly carry unconscious proprioceptive input from muscle spindles and GTOs to the cerebellum, where this information is used to help monitor and modulate movements. There are 2 major spinocerebellar pathways: • Dorsal spinocerebellar tract—carries input from the lower extremities
and lower trunk.
• Cuneocerebellar tract—carries proprioceptive input to the cerebellum
from the upper extremities and upper trunk.
The cell bodies of the dorsal spinocerebellar tract are found in Clarke’s nucleus, which is situated in the spinal cord from T1 to L2. The cell bodies of the cuneocerebellar tract are found in the medulla in the external cuneate nucleus.
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Lesions that affect only the spinocerebellar tracts are Biochemistry uncommon, but there are a group of hereditary diseases in which degeneration of spinocerebellar pathways is a prominent feature. The Medical Genetics most common of these is Friedreich ataxia, which is usually inherited as an autosomal recessive trait. Behavioral Science/Social Sciences The spinocerebellar tracts, dorsal columns, corticospinal tracts, and cerebellum may be involved. Ataxia of gait is the most common initial symptom of this disease.
Right
Left Cerebellar cortex Cuneocerebellar tract
Inferior cerebellar peduncle
Brain stem
Dorsal spinocerebellar tract
2
External cuneate nucleus DRG 1
Dorsal horn 2
Clarke’s nucleus
From upper limb (muscle spindles)
Spinal cord DRG 1
From lower limb (muscle spindles)
Figure III-4-14. Spinocerebellar Figure III-4-14. Spinocerebellar TractsTracts
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Ipsilateral loss of vibratory sense in lower limb A Ipsilateral loss of vibratory B sense in upper limb
C
F
E
Ipsilateral spastic weakness
G
Horner’s syndrome (at T1)
D Ipsilateral flaccid paralysis
Contralateral loss of pain and temperature
Figure III-4-15. cord neural components and clinical Figure III-4-15. MajorMajor spinalspinal cord neural components and clinical anatomy anatomy depicted in myelin-stained section of upper thoracic depicted in myelin-stained section of upper thoracic cord.cord.
A Fasciculus Gracilis, B Fasciculus Cuneatus, C Corticospinal tract, D Anterolateral system, E Dorsal Horn, F Lateral horn (preganglionic sympathetic neurons), G Ventral horn (lower motor neurons)
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Features to look for to identify a cord section:
Cervical
• Is there a large ventral horn?
Physiology
Yes Pathology
Dorsal columns (DC) Corticospinal tract (CST) Lower motor neurons (LMN)
Medical Genetics
Fasciculus cuneatus
No
C 5 –T 1 , or L 2 –S 2
T 2 –L 1 , C 1 –C 4
Fasciculus gracilis
Spinothalamic tract (SpTh)
Behavioral Science/Social Sciences
• Are both dorsal columns present? Microbiology
Yes
No
Above T5
Below T5
Thoracic DC
Lateral horn (contains preganglionic sympathetic neurons from T1–L2)
• Is there a lateral horn present? Yes
No
T1–L2
C 1 –C 8 or L 3 –S 5
CST SpTh LMN Lumbar DC CST SpTh LMN Sacral DC CST SpTh LMN
FigureIII-4-16. III-4-16.Spinal Spinal Cord: Cord: Levels Figure Levels
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Spinal Cord Lesions UMN cell body Medial lemniscus
Dorsal spinocerebellar tract (unconscious proprioception from lower limb) Nucleus gracilis
Pyramidal decussation Midline
Loss of all sensation and flaccid weakness at level of lesion Ipsilateral and below lesion: impaired proprioception, vibration, 2-point discrimination, joint and position sensation (purple); spastic weakness (brown)
To skeletal muscles in upper limb
Corticospinal tract (UMN)
Contralateral and below lesion: impaired pain and temperature sensation begins 1–2 segments below lesion
Alpha motor neurons (LMN) in spinal nerves
Fasciculus gracilis (Vibration, touch, conscious proprioception from lower limb)
Spinothalamic tract (pain and temperature) 10
n at T
LMN
ectio Hemis
Muscle spindle afferent (la)
Clarke’s nucleus (T1–L2) Reflex synapse
Alpha motor neuron
Neuron in dorsal horn Pain, temperature
Fibers A-delta fiber
Vibration, touch, conscious proprioception Alpha motor neurons (LMN) to skeletal muscles in lower limb
Figure III-4-17. Spinal Cord Overview and Brown-Séquard Syndrome with Lesion at Left Tenth Thoracic Segment
Figure III-4-17. Spinal Cord Overview and Brown-Séquard Syndrome with Lesion at Left Tenth Thoracic Segment
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Brown-Séquard syndrome Hemisection of the cord results in a lesion of each of the 3 main neural systems: the principal upper motoneuron pathway of the corticospinal tract, one or both dorsal columns, and the spinothalamic tract. The hallmark of a lesion to these 3 long tracts is that the patient presents with 2 ipsilateral signs and 1 contralateral sign. • Lesion of the corticospinal tract results in an ipsilateral spastic paresis below the level of the injury. • Lesion of the fasciculus gracilis or cuneatus results in an ipsilateral loss
of joint position sense, tactile discrimination, and vibratory sensations below the lesion.
• Lesion of the spinothalamic tract results in a contralateral loss of pain Pathology
Behavioral Science/Social Sciences
Microbiology
and temperature sensation starting 1 or 2 segments below the level of the lesion.
At the level of the lesion, there will be an ipsilateral loss of all sensation, including touch modalities as well as pain and temperature, and an ipsilateral flaccid paralysis in muscles supplied by the injured spinal cord segments (Figure III-4-15). Polio a. Flaccid paralysis b. Muscle atrophy c. Fasciculations d. Areflexia e. Common at lumbar levels
Clinical Correlate Tabes patients present with paresthesias (pins-and-needles sensations), pain, polyuria, and Romberg sign.
Tabes Dorsalis a. “Paresthesias, pain, polyuria” b. Associated with late-stage syphilis, sensory ataxia, positive Romberg sign: sways with eyes closed, Argyll Robertson pupils, suppressed reflexes c. Common at lumbar cord levels
Clinical Correlate Spastic bladder results from lesions of the spinal cord above the sacral spinal cord levels. There is a loss of inhibition of the parasympathetic nerve fibers that innervate the detrusor muscle during the filling stage. Thus, the detrusor muscle responds to a minimum amount of stretch, causing urge incontinence.
Amyotrophic Lateral Sclerosis (ALS) a. Progressive spinal muscular atrophy (ventral horn) b. Primary lateral sclerosis (corticospinal tract) • Spastic paralysis in lower limbs • Increased tone and reflexes • Flaccid paralysis in upper limbs c. Common in cervical enlargement Anterior Spinal Artery (ASA) Occlusion
Clinical Correlate Atonic bladder results from lesions to the sacral spinal cord segments or the sacral spinal nerve roots. Loss of pelvic splanchnic motor innervation with loss of contraction of the detrusor muscle results in a full bladder with a continuous dribble of urine from the bladder.
a. DC spared b. All else bilateral signs c. Common at mid thoracic levels d. Spastic bladder ASA
Figure III-4-18. Lesions of of the the Spinal SpinalCord Cord II Figure III-4-18. Lesions
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Poliomyelitis Poliomyelitis results from a relatively selective destruction of lower motoneurons in the ventral horn by the poliovirus. The disease causes a flaccid paralysis of muscles with the accompanying hyporeflexia and hypotonicity. Some patients may recover most function, whereas others progress to muscle atrophy and permanent disability.
Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS, Lou Gehrig disease) is a relatively pure motor system disease that affects both upper and lower motoneurons. The disease typically begins at cervical levels of the cord and progresses either up or down the cord. Patients present with bilateral flaccid weakness of the upper limbs and bilateral spastic weakness of the lower limbs. Lower motoneurons in the brain-stem nuclei may be involved later. Subacute Combined Degeneration a. Vitamin B12, pernicious anemia b. Demyelination of the: • Dorsal columns (central and peripheral myelin) • Spinocerebellar tracts • Corticospinal tracts (CST) c. Upper thoracic or lower cervical cord
Clinical Correlate Subacute combined degeneration patients present paresthesias, bilateral spastic weakness, Babinski sign Babinski signs, and antibodies to intrinsic factor.
Syringomyelia a. Cavitation of the cord (usually cervical) b. Bilateral loss of pain and temperature at the level of the lesion c. As the disease progresses, there is muscle weakness; eventually flaccid paralysis and atrophy of the upper limb muscles due to destruction of ventral horn cells
Clinical Correlate Syringomyelia may present with hydrocephalus and Arnold-Chiari I malformation.
Hemisection: Brown-Séquard Syndrome (cervical) DC CST Spth LMN
a. DC: Ipsilateral loss of position and vibratory senses at and below level of the lesion b. Spinothalamic tract: Contralateral loss of pain and temp 1–2 segments below lesion and ipsilateral loss at the level of the lesion c. CST: Ipsilateral paresis below the level of the lesion d. LMN: Flaccid paralysis at the level of the lesion e. Descending hypothalamics: Ipsilateral Horner syndrome (if cord lesion is above T1) • Facial hemianhydrosis • Ptosis (slight) • Miosis
Note Syringomyelia results in a “beltlike” or “cape-like” loss of pain and temperature.
Figure III-4-19. Lesions II Figure III-4-19. Lesions of of the the Spinal Spinal Cord Cord II
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Occlusion of the anterior spinal artery This artery lies in the anterior median sulcus of the spinal cord. Occlusion of the anterior spinal artery interrupts blood supply to the ventrolateral parts of the cord, including the corticospinal tracts and spinothalamic tracts. Below the level of the lesion, the patient exhibits a bilateral spastic paresis and a bilateral loss of pain and temperature.
Syringomyelia Syringomyelia is a disease characterized by progressive cavitation of the central canal, usually in the cervical spinal cord but may involve other cord regions or the medulla. Early in the disease, there is a bilateral loss of pain and temperature sensation in the hands and forearms as a result of the destruction of spinothalamic fibers crossing in the anterior white commissure. When the cavitation expands, lower motoneurons in the ventral horns are compressed, resulting in bilateral flaccid paralysis of upper limb muscles. A late manifestation of cavitation is Horner syndrome, which occurs as a result of involvement of descending hypothalamic fibers innervating preganglionic sympathetic neurons in the T1 through T4 cord segments. Horner syndrome consists of miosis (pupillary constriction), ptosis (drooping eyelids), and anhidrosis (lack of sweating) in the face.
Tabes dorsalis Tabes dorsalis is one possible manifestation of neurosyphilis. It is caused by bilateral degeneration of the dorsal roots and secondary degeneration of the dorsal columns. There may be impaired vibration and position sense, astereognosis, paroxysmal pains, and ataxia, as well as diminished stretch reflexes or incontinence. Owing to the loss of proprioceptive pathways, individuals with tabes dorsalis are unsure of where the ground is and walk with a characteristic and almost diagnostic “high-step stride”. Tabetic patients may also present with abnormal pupillary responses (Argyll Robertson pupils).
Subacute combined degeneration Subacute combined degeneration is seen most commonly in cases of vitamin B12 deficiency, sometimes related to pernicious anemia. The disease is characterized by patchy losses of myelin in the dorsal columns and lateral corticospinal tracts, resulting in a bilateral spastic paresis and a bilateral alteration of touch, vibration, and pressure sensations below the lesion sites. Myelin in both CNS and PNS is affected.
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The Brain Stem
5
Learning Objectives ❏❏ Answer questions about cranial nerves ❏❏ Answer questions about sensory and motor neural systems ❏❏ Solve problems concerning medulla ❏❏ Demonstrate understanding of pons ❏❏ Interpret scenarios on midbrain ❏❏ Interpret scenarios on components of the ear, auditory, and vestibular systems ❏❏ Demonstrate understanding of horizontal conjugate gaze ❏❏ Solve problems concerning blood supply to the brain stem ❏❏ Interpret scenarios on brain-stem lesions ❏❏ Interpret scenarios on reticular formation
The brain stem is divisible into 3 continuous parts: the midbrain, the pons, and the medulla. The midbrain is most rostral and begins just below the diencephalon. The pons is in the middle and is overlain by the cerebellum. The medulla is caudal to the pons and is continuous with the spinal cord. The brain stem is the home of the origins or sites of termination of fibers in 9 of the 12 cranial nerves (CNs).
CRANIAL NERVES Two cranial nerves, the oculomotor and trochlear (CN III and IV), arise from the midbrain. Four cranial nerves, the trigeminal, abducens, facial, and vestibulocochlear nerves (CN V, VI, VII, and VIII), enter or exit from the pons. Three cranial nerves, the glossopharyngeal, vagus, and hypoglossal nerves (CN IX, X, and XII), enter or exit from the medulla. Fibers of the accessory nerve arise from the cervical spinal cord.
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Cingulate gyrus
Fornix
Thalamus
Corpus callosum
Pineal Biochemistry gland
Pharmacology
Septum pellucidum
Superior colliculus
Hypothalamus
Inferior colliculus
Physiology
Optic chiasm
Medical Genetics
Pituitary
Cerebral aqueduct Pathology
Midbrain
Tonsil
Behavioral Science/Social Sciences
Pons
Fourth ventricle
Medulla
Microbiology
Figure III-5-1. Mid-Sagittal Section Figure III-5-1. Brain:Brain: Mid-Sagittal Section
Olfactory bulb
Optic chiasm
Olfactory tract
Pituitary
Optic nerve (II)
Mammillary body
Oculomotor nerve (III)
Cerebral peduncle
Uncus
Abducens nerve (VI)
Trigeminal nerve (V)
Facial nerve (VII) Vestibulocochlear nerve (VIII)
Trochlear nerve (IV)
Glossopharyngeal nerve (IX)
Pyramid
Vagus nerve (X)
Olive
Accessory nerve (XI)
Cervical spinal nerves
Hypoglossal nerve (XII) Figure III-5-2. Brain: Inferior View Figure III-5-2. Brain: Inferior View
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Optic chiasm I (Olfactory tract)
Pineal body
II (Optic nerve)
Third ventricle
Superior colliculus
Mammillary body Optic tract
Thalamus
Inferior colliculus
III
Midbrain III, IV
IV
VIII IX
Lower medulla Crossing point of fibers forming medial lemniscus and corticospinal tracts
Dorsal column nuclei
X XII
Medial lemniscus Dorsal
Dorsal columns
V VI VII
Upper medulla IX, X, XII
Fourth ventricle
Cerebral peduncle IV
Pons V, VI, VII, VIII
Cerebellar peduncles
Spinothalamic tract and descending hypothalamic axons
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XI
Olive
Corticospinal tract (Pyramid) Ventral
FigureIII-5-3. III-5-3.Brain BrainStem Stemand andCranial CranialNerve: Nerve:Surface SurfaceAnatomy Anatomy Figure
Afferent fibers of cranial nerves enter the CNS and terminate in relation to aggregates of neurons in sensory nuclei. Motor or efferent components of cranial nerves arise from motor nuclei. All motor and sensory nuclei that contribute fibers to cranial nerves are organized in a series of discontinuous columns according to the functional component that they contain. Motor nuclei are situated medially, closest to the midline, and sensory nuclei are situated lateral to the motor nuclei. A cranial nerve nucleus or nerve will be found at virtually every transverse sectional level of the brain stem.
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Periaqueductal gray matter
III nucleus and nucleus of Edinger-Westphal
Cerebral aqueduct Pharmacology
Biochemistry
Note The descending hypothalamic fibers course with the Physiologyspinothalamic tract. Medical Genetics
Superior colliculus
Medial geniculate body (nucleus)
MLF
Spinothalamic tract and descending hypothalamic fibers
Red nucleus
Medial lemniscus
Substantia nigra
Corticospinal tract Pathology
Behavioral Science/Social Sciences
Corticobulbar tract
Cerebral peduncle
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Figure III-5-4A. Upper Midbrain; Level of Nerve III
Figure III-5-4A. Upper Midbrain; Level of Nerve III Microbiology
Inferior colliculus
Cerebral aqueduct
Trochlear nucleus
MLF
Superior cerebellar peduncle
Spinothalamic tract and descending hypothalamic fibers
Medial lemniscus
Corticospinal and corticobulbar tracts
Basis pontis
FigureIII-5-4B. III-5-4B.Lower Lower Midbrain; Midbrain; Level Level of IVIV Figure ofNucleus NucleusCN CN
Cerebellar hemisphere (cut section)
Vermis Superior cerebellar peduncle
Medial longitudinal fasciculus (MLF)
Fourth ventricle
Spinothalamic tract and descending hypothalamic fibers Medial lemniscus Corticospinal and corticobulbar tracts
Main sensory nucleus of V V
Motor nucleus of V
Figure Middle Pons; of Nerve NerveVV Figure III-5-4C. III-5-4C. Middle Pons; Level Level of
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Medial longitudinal fasciculus Fourth ventricle
Dentate nucleus
Spinal tract and nucleus of V
Cerebellum
Spinothalamic tract ng and descending hypothalamic fibers
Superior Su cerebellar peduncle ce
Superior olivary nucleuss
Facial colliculus Fa
Vermis Ve
Nucleus of nerve VI Nu
cus Medial lemniscus VII
Corticospinal and corticobulbar tracts
Nucleus of nerve VII Nu
VI
FigureIII-5-4D. III-5-4D.Lower Lower Pons; Pons; Level Level of Figure of Nerves NervesVI VIand andVII VII
Medial longitudinal fasciculus
Fourth ventricle
Hypoglossal nucleus
Vestibular/cochlear nuclei
Dorsal motor nucleus of nerve X Solitary nucleus and tract
Inferior cerebellar peduncle
Spinothalamic tract and descending Hypothalamic fibers
VIII Ambiguus nucleus
Spinal tract and nucleus of V
Inferior olivary nucleus
X (and IX)
Medial lemniscus
XII
Pyramid (corticospinal tract) Figure III-5-4E. Open Medulla
Figure III-5-4E. Open Medulla
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Nucleus gracilis
Internal arcuate fibers forming medial lemniscus Pharmacology
Nucleus cuneatus Spinal tract of V
Biochemistry
Spinal nucleus of V Physiology
Spinothalamic tract and descending hypothalamic fibers
Medical Genetics
Decussation of pyramids Pathology
Behavioral Science/Social Sciences
Figure III-5-4F. Closed Medulla Figure III-5-4F. Closed Medulla Table III-5-1. Cranial Nerves: Functional Features
Microbiology
CN
Name
Type
Function
Results of Lesions
I
Olfactory
Sensory
Smells
Anosmia
II
Optic
Sensory
Sees
Visual field deficits (anopsia) Loss of light reflex with III Only nerve to be affected by MS
III
Oculomotor
Motor
Innervates SR, IR, MR, IO extraocular muscles: adduction (MR) most important action Raises eyelid (levator palpebrae superioris) Constricts pupil (sphincter pupillae)
Diplopia, external strabismus Loss of parallel gaze Ptosis Dilated pupil, loss of light reflex with II Loss of near response
Accommodates (ciliary muscle) CN
Name
Type
Function
Results of Lesions
IV
Trochlear
Motor
Superior oblique—depresses and abducts eyeball (makes eyeball look down and out)
Weakness looking down with adducted eye
Intorts
Head tilts away from lesioned side
General sensation (touch, pain, temperature) of forehead/scalp/ cornea
V1—loss of general sensation in skin of forehead/scalp
General sensation of palate, nasal cavity, maxillary face, maxillary teeth
V2—loss of general sensation in skin over maxilla, maxillary teeth
General sensation of anterior twothirds of tongue, mandibular face, mandibular teeth
V3—loss of general sensation in skin over mandible, mandibular teeth, tongue, weakness in chewing
Motor to muscles of mastication (temporalis, masseter, medial and lateral pterygoids) and anterior belly of digastric, mylohyoid, tensor tympani, tensor palati
Jaw deviation toward weak side
V
Trigeminal Ophthalmic (V1) Maxillary (V2) Mandibular (V3)
Mixed
Trouble going down stairs
Loss of blink reflex with VII
Trigeminal neuralgia—intractable pain in V2 or V3 territory
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Table III-5-1. Cranial Nerves: Functional Features (continued) CN
Name
Type
Function
Results of Lesions
VI
Abducens
Motor
Lateral rectus—abducts eyeball
Diplopia, internal strabismus Loss of parallel gaze, “pseudoptosis”
VII
Facial
Mixed
To muscles of facial expression, posterior belly of digastric, stylohyoid, stapedius Salivation (submandibular, sublingual glands)
Corner of mouth droops, cannot close eye, cannot wrinkle forehead, loss of blink reflex, hyperacusis; Bell palsy— lesion of nerve in facial canal Pain behind ear
Skin behind ear
Alteration or loss of taste (ageusia)
Taste in anterior 2/3 of tongue/palate
Eye dry and red
Tears (lacrimal gland) VIII
Vestibulocochlear
Sensory
Hearing
Sensorineural hearing loss
Angular acceleration (head turning)
Loss of balance, nystagmus
Linear acceleration (gravity) IX
Glossopharyngeal
Mixed
Oropharynx sensation, carotid sinus/ body
Loss of gag reflex with X
Salivation (parotid gland) All sensation of posterior one-third of tongue Motor to one muscle— stylopharyngeus X
Vagus
Mixed
To muscles of palate and pharynx for swallowing except tensor palati (V) and stylopharyngeus (IX) To all muscles of larynx (phonates) Sensory of larynx and laryngopharynx Sensory of GI tract To GI tract smooth muscle and glands in foregut and midgut
Nasal speech, nasal regurgitation Dysphagia, palate droop Uvula pointing away from affected side Hoarseness/fixed vocal cord Loss of gag reflex with IX Loss of cough reflex
CN
Name
Type
Function
Results of Lesions
XI
Accessory
Motor
Head rotation to opposite side (sternocleidomastoid)
Weakness turning chin to opposite side Shoulder droop
Elevates and rotates scapula (trapezius) XII
Hypoglossal
Motor
Tongue movement (styloglossus, hyoglossus, genioglossus, and intrinsic tongue muscles— palatoglossus is by X)
Tongue pointing toward same (affected) side on protrusion
Abbreviations: CN, cranial nerve; IO, inferior oblique; IR, inferior rectus; MR, medial rectus; MS, multiple sclerosis; SR, superior rectus
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SENSORY AND MOTOR NEURAL SYSTEMS Each of the following 5 ascending or descending neural tracts, fibers, or fasciculi courses through the brain stem and is found at every transverse sectional level.
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
The medial lemniscus (ML) contains the axons from cell bodies found in the dorsal column nuclei (gracilis and cuneatus) in the caudal medulla and represents the second neuron in the pathway to the thalamus and cortex for discriminative touch, vibration, pressure, and conscious proprioception. The axons in the ML cross the midline of the medulla immediately after emerging from the dorsal column nuclei. Lesions in the ML, in any part of the brain stem, result in a loss of discriminative touch, vibration, pressure, and conscious proprioception from the contralateral side of the body. The spinothalamic tract (part of anterolateral system) has its cells of origin in the spinal cord and represents the crossed axons of the second neuron in the pathway conveying pain and temperature to the thalamus and cortex. Lesions of the spinothalamic tract, in any part of the brain stem, result in a loss of pain and temperature sensations from the contralateral side of the body. The corticospinal tract controls the activity of lower motoneurons, and interneuron pools for lower motoneurons course through the brain stem on their way to the spinal cord. Lesions of this tract produce a spastic paresis in skeletal muscles of the body contralateral to the lesion site in the brain stem. The descending hypothalamic fibers arise in the hypothalamus and course without crossing through the brain stem to terminate on preganglionic sympathetic neurons in the spinal cord. Lesions of this pathway produce an ipsilateral Horner syndrome. Horner syndrome consists of miosis (pupillary constriction), ptosis (drooping eyelid), and anhidrosis (lack of sweating) in the face ipsilateral to the side of the lesion. Descending hypothalamic fibers course with the spinothalamic fibers in the lateral part of the brain stem. Therefore, brain stem lesions producing Horner syndrome may also result in a contralateral loss of pain and temperature sensations from the limbs and body. The medial longitudinal fasciculus is a fiber bundle interconnecting centers for horizontal gaze, the vestibular nuclei, and the nerve nuclei of CN III, IV, and VI, which innervate skeletal muscles that move the eyeball. This fiber bundle courses close to the dorsal midline of the brain stem and also contains vestibulospinal fibers, which course through the medulla to the spinal cord. Lesions of the fasciculus produce internuclear ophthalmoplegia and disrupt the vestibulo-ocular reflex.
MEDULLA In the caudal medulla, 2 of the neural systems—the corticospinal and dorsal column–medial lemniscal pathways—send axons across the midline. The nucleus gracilis and nucleus cuneatus give rise to axons that decussate in the caudal medulla (the crossing axons are the internal arcuate fibers), which then form and ascend in the medial lemniscus.
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The corticospinal (pyramidal) tracts, which are contained in the pyramids, course ventromedially through the medulla. Most of these fibers decussate in the caudal medulla just below the crossing of axons from the dorsal column nuclei, and then travel down the spinal cord as the (lateral) corticospinal tract. The olives are located lateral to the pyramids in the rostral two-thirds of the medulla. The olives contain the convoluted inferior olivary nuclei. The olivary nuclei send climbing (olivocerebellar) fibers into the cerebellum through the inferior cerebellar peduncle. The olives are a key distinguishing feature of the medulla. The spinothalamic tract and the descending hypothalamic fibers course together in the lateral part of the medulla below the inferior cerebellar peduncle and near the spinal nucleus and tract of CN V.
Cranial Nerve Nuclei Spinal nucleus of V The spinal nucleus of the trigeminal nerve (CN V) is located in a position analogous to the dorsal horn of the spinal cord. The spinal tract of the trigeminal nerve lies just lateral to this nucleus and extends from the upper cervical cord (C2) to the point of entry of the fifth cranial nerve in the pons. Central processes from cells in the trigeminal ganglion conveying pain and temperature sensations from the face enter the brain stem in the rostral pons but descend in the spinal tract of CN V and synapse on cells in the spinal nucleus.
Solitary nucleus The solitary nucleus receives the axons of all general and special visceral afferent fibers carried into the CNS by CN VII, IX, and X. These include taste, cardiorespiratory, and gastrointestinal sensations carried by these cranial nerves. Taste and visceral sensory neurons all have their cell bodies in ganglia associated with CN VII, IX, and X outside the CNS.
Nucleus ambiguus The nucleus ambiguus is a column of large motoneurons situated dorsal to the inferior olive. Axons arising from cells in this nucleus course in the ninth and tenth cranial nerves. The component to the ninth nerve is insignificant. In the tenth nerve, these fibers supply muscles of the soft palate, larynx, pharynx, and upper esophagus. A unilateral lesion will produce ipsilateral paralysis of the soft palate causing the uvula to deviate away from the lesioned nerve and nasal regurgitation of liquids, weakness of laryngeal muscles causing hoarseness, and pharyngeal weakness resulting in difficulty in swallowing.
Dorsal motor nucleus of CN X These visceral motoneurons of CN X are located lateral to the hypoglossal nucleus in the floor of the fourth ventricle. This is a major parasympathetic nucleus of the brain stem, and it supplies preganglionic fibers innervating terminal ganglia in the thorax and the foregut and midgut parts of the gastrointestinal tract.
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Hypoglossal nucleus The hypoglossal nucleus is situated near the midline just beneath the central canal and fourth ventricle. This nucleus sends axons into the hypoglossal nerve to innervate all of the tongue muscles except the palatoglossus.
The accessory nucleus Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
The accessory nucleus is found in the cervical spinal cord. The axons of the spinal accessory nerve arise from the accessory nucleus, pass through the foramen magnum to enter the cranial cavity, and join the fibers of the vagus to exit the cranial cavity through the jugular foramen. As a result, intramedullary lesions do not affect fibers of the spinal accessory nerve. The spinal accessory nerve supplies the sternocleidomastoid and trapezius muscles. The rootlets of the glossopharyngeal (CN IX) and vagus (CN X) nerves exit between the olive and the fibers of the inferior cerebellar peduncle. The hypoglossal nerve (CN XII) exits more medially between the olive and the medullary pyramid.
PONS The pons is located between the medulla (caudally) and the midbrain (rostrally). The cerebellum overlies the pons. It is connected to the brain stem by 3 pairs of cerebellar peduncles. The fourth ventricle is found between the dorsal surface of the pons and the cerebellum. The ventral surface of the pons is dominated by fibers, which form a large ventral enlargement that carries fibers from pontine nuclei to the cerebellum in the middle cerebellar peduncle. This ventral enlargement is the key distinguishing feature of the pons. The corticospinal tracts are more diffuse in the pons than in the medulla and are embedded in the transversely coursing fibers that enter the cerebellum in the middle cerebellar peduncle. The medial lemniscus is still situated near the midline but is now separated from the corticospinal tracts by the fibers forming the middle cerebellar peduncle. The medial lemniscus has changed from a dorsoventral orientation in the medulla to a more horizontal orientation in the pons. The spinothalamic tract and the descending hypothalamic fibers continue to course together in the lateral pons. The lateral lemniscus, an ascending auditory pathway, is lateral and just dorsal to the medial lemniscus. The lateral lemniscus carries the bulk of ascending auditory fibers from both cochlear nuclei to the inferior colliculus of the midbrain. The medial longitudinal fasciculus (MLF) is located near the midline just beneath the fourth ventricle.
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Cranial Nerve Nuclei Abducens nucleus The abducens nucleus is found near the midline in the floor of the fourth ventricle just lateral to the MLF.
Facial motor nucleus The facial motor nucleus is located ventrolateral to the abducens nucleus. Fibers from the facial nucleus curve around the posterior side of the abducens nucleus (the curve forms the internal genu of the facial nerve), then pass ventrolaterally to exit the brain stem at the pontomedullary junction.
Superior olivary nucleus The superior olivary nucleus lies immediately ventral to the nucleus of CN VII and receives auditory impulses from both ears by way of the cochlear nuclei. The cochlear nuclei are found at the pontomedullary junction just lateral to the inferior cerebellar peduncle.
Vestibular nuclei The vestibular nuclei are located near the posterior surface of the pons lateral to the abducens nucleus, and extend into the medulla.
Cochlear nuclei The dorsal and ventral cochlear nuclei are found at the pontomedullary junction. All of the fibers of the cochlear part of CN VIII terminate here.
Trigeminal nuclei Motor Nucleus—Pons The motor nucleus of CN V is located in the pons just medial to the main sensory nucleus of the trigeminal and adjacent to the point of exit or entry of the trigeminal nerve fibers. These motor fibers supply the muscles of mastication (masseter, temporalis, and medial and lateral pterygoid (Figure IV-5-3). Main Sensory Nucleus—Pons The main sensory nucleus is located just lateral to the motor nucleus. The main sensory nucleus receives tactile and pressure sensations from the face, scalp, oral cavity, nasal cavity, and dura. Spinal Trigeminal Nucleus—Spinal cord to pons The spinal trigeminal nucleus is a caudal continuation of the main sensory nucleus, extending from the mid pons through the medulla to the cervical cord. Central processes from cells in the trigeminal ganglion conveying pain and temperature sensations from the face descend in the spinal tract of V and synapse on cells in the spinal nucleus.
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Note
Pharmacology
VPM relays touch, pain, temperature (CN V) and taste (CN VII, IX) sensationsBiochemistry to cortex.
Physiology
Mesencephalic Nucleus—Midbrain The mesencephalic nucleus of CN V is located at the point of entry of the fifth nerve and extends into the midbrain. It receives proprioceptive input from joints, muscles of mastication, extraocular muscles, teeth, and the periodontium. Some of these fibers synapse monosynaptically on the motoneurons, forming the sensory limb of the jaw jerk reflex.
Medical Genetics
Pathology
Ophthalmic (CN V1)
Behavioral Science/Social Sciences
Somatosensory cortex VPM (neuron #3) in thalamus)
Microbiology
Maxillary (CN V2)
1
2
3
4
Mandibular (CN V3)
Ventral trigeminal tract
Mesencephalic nucleus of V Muscle spindle afferent
Motor nucleus of V
Main sensory nucleus of V Tactile afferent To muscles of mastication Pain afferent CN V V3 V2 V1
Nerves VII, IX, and X (from skin in or near external auditory meatus) Spinal tract of V
Spinal trigeminal nucleus Figure III.5.5 Shaded areas indicate regions of face and scalp innervated branches the 3 divisions Figure III-5-5. Shaded areas indicate regions of facebyand scalpof innervated by of CN V. branches the 3 divisions of “onion-skin” CN V. Dottedregions lines indicate concentric numbered Dotted lines indicateofconcentric numbered emanating posteriorly from nose “onion-skin” regions emanating posteriorly from nose and mouth that have a rostral and mouth that have a rostral to caudal representation in the spinal nucleus of V in the brain stem.to caudal representation in the spinal nucleus of V in the brain stem.
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Cranial Nerves V, VI, VII, and VIII Four cranial nerves emerge from the pons. Cranial nerves VI, VII, and VIII emerge from the pontomedullary junction. The facial nerve is located medial to the vestibulocochlear nerve. The abducens nerve (CN VI) emerges near the midline lateral to the corticospinal tract. The trigeminal nerve (CN V) emerges from the middle of the pons.
MIDBRAIN The midbrain (mesencephalon) is located between the pons and diencephalon. The cerebral aqueduct, a narrow channel that connects the third and fourth ventricles, passes through the midbrain. The inferior colliculi and superior colliculi are found on the dorsal aspect of the midbrain above the cerebral aqueduct. The inferior colliculus processes auditory information received bilaterally from the cochlear nuclei by axon fibers of the lateral lemniscus. The superior colliculi help direct movements of both eyes in gaze. The pretectal region is located just beneath the superior colliculi and in front of the oculomotor complex. This area contains interneurons involved in the pupillary light reflex. The massive cerebral peduncles extend ventrally from the midbrain. The cerebral peduncles contain corticospinal and corticobulbar fibers. The interpeduncular fossa is the space between the cerebral peduncles. The substantia nigra is the largest nucleus of the midbrain. It appears black to dark brown in the freshly cut brain because nigral cells contain melanin pigments. Neurons in the substantia nigra utilize Dopamine and GABA as neurotransmitters. The medial lemniscus and spinothalamic tract and descending hypothalamic fibers course together ventrolateral to the periaqueductal gray. The MLF continues to be located near the midline, just beneath the cerebral aqueduct. The mesencephalic nuclei of the trigeminal nerve are located on either side of the central gray.
Cranial Nerve Nuclei The trochlear nucleus is located just beneath the periaqueductal gray near the midline between the superior and inferior colliculi. The oculomotor nucleus and the nucleus of Edinger-Westphal are found just beneath the periaqueductal gray near the midline at the level of the superior colliculi. Two cranial nerves emerge from the midbrain: the oculomotor (CN III) and the trochlear (CN IV) nerves. The oculomotor nerve arises from the oculomotor nucleus and exits ventrally from the midbrain in the interpeduncular fossa. CN III also contains preganglionic parasympathetic axons that arise from the nucleus of EdingerWestphal, which lies adjacent to the oculomotor nucleus. Axons of the trochlear nerve decussate in the superior medullary velum and exit the brain stem near the posterior midline just inferior to the inferior colliculi.
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Corticobulbar (Corticonuclear) Innervation of Cranial Nerve Nuclei Pharmacology
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Physiology
Medical Genetics
Corticobulbar fibers serve as the source of upper motoneuron innervation of lower motoneurons in cranial nerve nuclei. Corticobulbar fibers arise in the motor cortex and influence lower motoneurons in all brain stem nuclei that innervate skeletal muscles. This includes: • Muscles of mastication (CN V) • Muscles of facial expression (CN VII) – (partially bilateral) • Palate, pharynx, and larynx (CN X)
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• Tongue (CN XII) • Sternocleidomastoid and trapezius muscles (CN XI)
Right
Microbiology
UMN innervation to LMN in cranial nerves is bilateral
Left
Cerebral cortex
Upper motor neuron (UMN) UMN innervation to LMN in spinal nerves is contralateral
Precentral gyrus
A
B Caudal medulla (decussation)
Brain stem
Lateral corticospinal tract Function: Voluntary refined movements of the distal extremities
D
Lower motor neuron in a CN
Spinal cord C
Lower motor neuron (LMN)
Skeletal muscle E
FigureIII-5-6. III-5-6.Upper UpperMotor MotorNeuron NeuronInnervation Innervationofof Figure Spinal Nerves and Cranial Nerves Spinal Nerves and Cranial Nerves
The corticobulbar innervation of cranial nerve lower motoneurons is predominantly bilateral, in that each lower motoneuron in a cranial nerve nucleus receives input from corticobulbar axons arising from both the right and the left cerebral cortex. T he major exception is that only some of the LMNs of the facial nerve (CN VII) receive a contralateral innervation.
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Clinical Correlate Facial Paralysis The upper motoneuron innervation of lower motoneurons in the facial motor nucleus is different and clinically significant. Like most cranial nerve lower motoneurons, the corticobulbar innervation of facial motoneurons to muscles of the upper face (which wrinkle the forehead and shut the eyes) is bilateral. The corticobulbar innervation of facial motoneurons to muscles of the mouth, however, is contralateral only. Clinically, this means that one can differentiate between a lesion of the seventh nerve and a lesion of the corticobulbar fibers to the facial motor nucleus. A facial nerve lesion (as in Bell Palsy) will result in a complete ipsilateral paralysis of muscles of facial expression, including an inability to wrinkle the forehead or shut the eyes and a drooping of the corner of the mouth. A corticobulbar lesion will result in only a drooping of the corner of the mouth on the contralateral side of the face and no other facial motor deficits. Generally, no other cranial deficits will be seen with corticobulbar lesions because virtually every other cranial nerve nucleus is bilaterally innervated. In some individuals, the hypoglossal nucleus may receive mainly contralateral corticobulbar innervation. If these corticobulbar fibers are lesioned, the tongue muscles undergo transient weakness without atrophy or fasciculations and may deviate away from the injured corticobulbar fibers. If, for example, the lesion is in corticobulbar fibers on the left, there is transient weakness of the right tongue muscles, causing a deviation of the tongue toward the right side upon protrusion.
Cortex
UMN
UMN
A
UMN
Cortex Facial nucleus of pons (LMN) Upper face division
Normal:
Lower face division
Wrinkles forehead
Clinical Correlate Lesion A: left lower face weakness Lesion B: complete left face weakness
Abbreviations UMN = upper motoneuron LMN = lower motoneuron
Shuts eye Flares nostrils
B
Smiles R
L
Figure III-5-7. Corticobulbar Innervation of the Facial Motor Nucleus Figure III-5-7. Corticobulbar Innervation of the Facial Motor Nucleus
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EAR, AUDITORY, AND VESTIBULAR SYSTEMS Each ear consists of 3 components: 2 air-filled spaces, the external ear and the middle ear; and the fluid-filled spaces of the inner ear.
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Biochemistry
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Medical Genetics
Pathology
The external ear includes the pinna and the external auditory meatus, which extends to the tympanic membrane. Sound waves travel through the external auditory canal and cause the tympanic membrane (eardrum) to vibrate. Movement of the eardrum causes vibrations of the ossicles in the middle ear (i.e., the malleus, incus, and stapes). Vibrations of the ossicles are transferred through the oval window and into the inner ear.
Behavioral Science/Social Sciences
Microbiology
The middle ear lies in the temporal bone, where the chain of 3 ossicles connects the tympanic membrane to the oval window. These auditory ossicles amplify the vibrations received by the tympanic membrane and transmit them to the fluid of the inner ear with minimal energy loss. The malleus is inserted in the tympanic membrane, and the stapes is inserted into the membrane of the oval window. Two small skeletal muscles, the tensor tympani and the stapedius, contract to prevent damage to the inner ear when the ear is exposed to loud sounds. The middleear cavity communicates with the nasopharynx via the eustachian tube, which allows air pressure to be equalized on both sides of the tympanic membrane. The inner ear consists of a labyrinth (osseous and membranous) of interconnected sacs (utricle and saccule) and channels (semicircular ducts and the cochlear duct) that contain patches of receptor or hair cells that respond to airborne vibrations or movements of the head. Both the cochlear duct and the sacs and channels of the vestibular labyrinth are filled with endolymph, which bathes the hairs of the hair cells. Endolymph is unique because it has the inorganic ionic composition of an intracellular fluid but it lies in an extracellular space. The intracellular ionic composition of endolymph is important for the function of hair cells. Perilymph, ionically like a typical extracellular fluid, lies outside the endolymph-filled labyrinth. Spiral Scala vestibuli ganglion (perilymph)
Ampulla Ossicles
Tympanic membrane
Stria vascularis (endolymph production)
Semicircular duct
Tectorial membrane
Semicircular canal
B
Oval window
Round window
Scala media (endolymph)
Basilar membrane
Cross section through one turn of the cochlea
A
Eustachian tube
B Base (High pitch)
Organ of Corti Scala tympani (perilymph) VIII nerve (cochlear division)
A Apex (Low pitch)
Figure III-5-8. Structures of the Inner Ear Figure III-5-8. Structures of the Inner Ear
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Semicircular canals (perilymph) Utricle (endolymph)
Malleus Saccule (endolymph)
Incus
Scala vestibuli (perilymph)
Stapes
Scala media (endolymph)
Tympanic membrane Oval window Endolymph Perilymph
High K+ Low Na+
Vestibule
Scala tympani (perilymph)
Round window Eustachian tube
Figure III-5-9. Distribution of Endolymph and Perilymph in Inner Ear Figure III-5-9. Distribution of Endolymph and Perilymph in Inner Ear
Auditory System
Clinical Correlate
The cochlear duct is the auditory receptor of the inner ear. It contains hair cells, which respond to airborne vibrations transmitted by the ossicles to the oval window. The cochlear duct coils 2 and a quarter turns within the bony cochlea and contains hair cells situated on an elongated, highly flexible, basilar membrane. High-frequency sound waves cause maximum displacement of the basilar membrane and stimulation of hair cells at the base of the cochlea, whereas low-frequency sounds maximally stimulate hair cells at the apex of the cochlea.
Middle-ear diseases (otitis media, otosclerosis) result in a conductive hearing loss because of a reduction in amplification provided by the ossicles.
The spiral ganglion contains cell bodies whose peripheral axons innervate auditory hair cells of the organ of Corti. The central axons from these bipolar cells form the cochlear part of the eighth cranial nerve. All of the axons in the cochlear part of the eighth nerve enter the pontomedullary junction and synapse in the ventral and dorsal cochlear nuclei. Axons of cells in the ventral cochlear nuclei bilaterally innervate the superior olivary nuclei in the pons. The superior olivary nuclei are the first auditory nuclei to receive binaural input and use the binaural input to localize sound sources. The lateral lemniscus carries auditory input from the cochlear nuclei and the superior olivary nuclei to the inferior colliculus in the midbrain. Each lateral lemniscus carries information derived from both ears; however, input from the contralateral ear predominates.
Lesions of the facial nerve in the brain stem or temporal bone (Bell palsy) may result in hyperacusis, an increased sensitivity to loud sounds.
Clinical Correlate Presbycusis results from a loss of hair cells at the base of the cochlea.
Clinical Correlate Sensorineural hearing loss: air conduction bone conduction Conductive hearing loss: bone conduction air conduction
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The inferior colliculus sends auditory information to the medial geniculate body (MGB) of the thalamus. From the MGB, the auditory radiation projects to the primary auditory cortex located on the posterior portion of the transverse temporal gyrus (Heschl’s gyrus; Brodmann areas 41 and 42). The adjacent auditory association area makes connections with other parts of the cortex, including Wernicke’s area, the cortical area for the comprehension of language.
Lesions Causing Hearing Loss Lesions of the cochlear part of the Medical Genetics eighth nerve or cochlear nuclei inside the brain stem at the pontomedullary junction result in a profound unilateral sensorineural hearing loss (A). All Pathology Behavioral Science/Social Sciences other lesions to auditory structures in the brain stem, thalamus, or cortex result in a bilateral suppression of hearing and a decreased ability to Microbiology localize a sound source (B). If a patient presents with a significant hearing loss in one ear, the lesion is most likely in the middle ear, inner ear, eighth nerve, or cochlear nuclei, and not at higher
Right
Physiology
levels of the auditory system.
Left
Superior temporal gyrus
Medial geniculate body
Lesion B
Cerebral cortex
Thalamus
Inferior colliculus Midbrain Lateral lemniscus
Superior olivary nucleus
Pons
Spiral ganglion
Trapezoid body Cochlear nucleus
Lesion A
Cochlear hair cell
Figure III-5-10. Auditory System igure Auditory System
Hearing Loss Conductive: passage of sound waves through external or middle ear is interrupted. Causes: obstruction, otosclerosis, otitis media Sensorineural: damage to cochlea, CN VIII, or central auditory connections
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Auditory Tests Weber test: place tuning fork on vertex of skull. If unilateral conductive loss → vibration is louder in affected ear; if unilateral sensorineural loss → vibration is louder in normal ear. Rinne test: place tuning fork on mastoid process (bone conduction) until vibration is not heard, then place fork in front of ear (air conduction). If unilateral conductive loss → no air conduction after bone conduction is gone; if unilateral sensorineural loss → air conduction present after bone conduction is gone.
Vestibular System Sensory receptors The vestibular system contains 2 kinds of sensory receptors, one kind in the utricle and the saccule and the other in the semicircular ducts. The utricle and the saccule are 2 large sacs, each containing a patch of hair cells in a macula. Each macula responds to linear acceleration and detects positional changes in the head relative to gravity. There are 3 semicircular ducts in the inner ear, each lying in a bony semicircular canal. Each semicircular duct contains an ampullary crest of hair cells that detect changes in angular acceleration resulting from circular movements of the head. The 3 semicircular ducts—anterior, posterior, and horizontal—are oriented such that they lie in the 3 planes of space. Circular movements of the head in any plane will depolarize hair cells in a semicircular duct in one labyrinth and hyperpolarize hair cells in the corresponding duct in the opposite labyrinth.
Vestibular nuclei There are 4 vestibular nuclei located in the rostral medulla and caudal pons. The vestibular nuclei receive afferents from the vestibular nerve, which innervates receptors located in the semicircular ducts, utricle, and saccule. Primary vestibular fibers terminate in the vestibular nuclei and the flocculonodular lobe of the cerebellum.
Vestibular fibers Secondary vestibular fibers, originating in the vestibular nuclei, join the MLF and supply the motor nuclei of CN III, IV, and VI. These fibers are involved in the production of conjugate eye movements. These compensatory eye movements represent the efferent limb of the vestibulo-ocular reflex, which enables the eye to remain focused on a stationary target during movement of the head or neck. Most of our understanding of the vestibulo-ocular reflex is based on horizontal head turning and a corresponding horizontal movement of the eyes in the direction opposite to that of head turning. For example, when the head turns horizontally to the right, both eyes will move to the left using the following vestibulo-ocular structures. Head turning to the right stimulates hairs cells in the right semicircular ducts. The right eighth nerve increases its firing rate to the right vestibular nuclei. These nuclei then send axons by way of the MLF to the right oculomotor nucleus and to the left abducens nucleus. The right oculomotor nerve to the right medial rectus adducts the right eye, and the left abducens nerve to the left lateral rectus abducts the left eye. The net effect of stimulating these nuclei is that both eyes will look to the left.
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Note
Vestibular System (VIII)
Vestibular Functions:
Three semicircular ducts respond to angular acceleration and deceleration of the head. The utricle and saccule respond to linear acceleration and the pull of gravity. There are 4 vestibular nuclei in the medulla and pons, which receive information from CN VIII. Fibers from the vestibular nuclei join the MLF and supply the motor nuclei of CNs III, IV, and VI, thereby regulating conjugate eye movements. Vestibular nuclei also receive and send information to the flocculonodular lobe of the cerebellum.
Equilibrium Pharmacology
Posture
Biochemistry
VOR
Physiology
Medical Genetics
Clinical Correlate A lesion of the vestibular nuclei or nerve (in this example, on the left) Pathology Behavioral Science/Social Sciences produces a vestibular nystagmus with a slow deviation of the eyes toward the lesion and a fast correction back to the right. Microbiology
Vestibulo-Ocular Reflex Head rotates to right gmus (fast component ) Nysta
track (slow component) Eyes
VOR
➍ Both eyes look left
Lateral rectus muscle
Medial rectus muscle
III VI
Medial longitudinal fasciculus Cerebellar peduncles Vestibular nuclei Lesion site (see Clinical Correlate)
VIII
➊ Endolymph flow stimulates hair cells
Vestibular ganglion
➋ Increases nerve firing rate ➌ Stimulates vestibular nuclei Lateral vestibulospinal tract (to antigravity muscles) Figure III-5-11. Vestibulo-Ocular Reflex (VOR) Figure III-5-11. Vestibulo-Ocular Reflex (VOR)
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Caloric Test
Note
This stimulates the horizontal semicircular ducts; can be used as a test of brainstem function in unconscious patients.
Cold water mimics a lesion of the vestibular system.
Normal results: • Cold water irrigation of ear → nystagmus to opposite side • Warm water irrigation of ear → nystagmus to same side • COWS: cold opposite, warm same
First—Slow Component (Slow Tracking)
R
L
Second—Fast Component (Nystagmus)
R
L (Left side lesion)
Figure III-5-12. Vestibular System
Figure III-5-12. Vestibular System
Clinical Correlate Vestibular dysfunction may result from a peripheral or central lesion. Vertigo may result from a lesion of the peripheral (end organ, nerve) or central (nuclear, brain-stem pathways) vestibular structures. Vertigo refers to the perception of rotation, which may involve either the subject or the external space. The vertigo is usually severe in peripheral disease and mild in brain-stem disease. Chronic vertigo (i.e., persisting longer than 2–3 weeks) strongly suggests a central lesion. Vertigo may also be caused by a variety of drugs, including anticonvulsants, aspirin, alcohol, and certain sedatives and antibiotics. Ménière disease is characterized by abrupt, recurrent attacks of vertigo lasting minutes to hours accompanied by tinnitus or deafness and usually involving only one ear. Nausea and vomiting and a sensation of fullness or pressure in the ear also are common during the acute episode. The attacks are often severe, and the patient may be unable to stand. The disease usually occurs in middle age and results from distention of the fluid spaces in the cochlear and vestibular parts of the labyrinth.
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Eye Movement Control Systems For the eyes to move together (conjugate gaze), the oculomotor nuclei and abducens nuclei are interconnected by the medial longitudinal fasciculus (MLF). Horizontal gaze is controlled by 2 gaze centers: frontal eye field (contralateral gaze), and PPRF (paramedian pontine reticular formation, ipsilateral gaze).
Physiology
Pathology
Medical Genetics
Behavioral Science/Social Sciences
Microbiology
Note To remember the direction of the fast phase of vestibular nystagmus in a caloric test toward the warm-water side and away from the cool-water side, remember the mnemonic COWS: • Cool • Opposite • Warm • Same
Nystagmus Nystagmus refers to rhythmic oscillations of the eyes slowly to one side followed by a rapid reflex movement in the opposite direction. Nystagmus is defined by the direction of the rapid reflex movement or the fast phase. It is usually horizontal, although rotatory or vertical nystagmus may also occur. Unilateral vestibular nerve or vestibular nucleus lesions may result in a vestibular nystagmus. In a pathologic vestibular nystagmus, the initial slow phase is the response to the pathology, and the fast phase is the correction attempt made by the cortex in response to the pathology. Consider this example: if the left vestibular nerve or nuclei are lesioned, because of the loss of balance between the 2 sides, the right vestibular nuclei are unopposed and act as if they have been stimulated, causing both eyes to look slowly to the left. This is the slow phase of a pathologic vestibular nystagmus. Because the head did not move, the cortex responds by moving both eyes quickly back to the right, the direction of the fast phase of the nystagmus. The integrity of the vestibulo-ocular reflex can be an indicator of brain-stem integrity in comatose patients. To test this reflex, a vestibular nystagmus is induced by performing a caloric test in which an examiner introduces warm or cool water into an external auditory meatus. Warm water introduced into the external ear stimulates the horizontal semicircular duct and causes the eyes to move slowly in the opposite direction. Because the head did not turn, the eyes are moved quickly back by the cortex (if intact) toward the same ear where the warm water was introduced, producing a fast phase of nystagmus to the same side. Introduction of cool water into the external ear mimics a lesion; the horizontal duct activity is inhibited on the cool water side, and the opposite vestibular complex moves the eyes slowly toward the cool-water ear. The corrective or fast phase of the nystagmus moves the eyes quickly away from the ear where the cool water was introduced.
HORIZONTAL CONJUGATE GAZE The eyeballs move together in conjugate gaze. The ocular muscles function to move and position both eyes as a unit so that an image falls on a corresponding spot on the retina of each eye. The slightest weakness in the movements of one eye causes diplopia, the presence of a double image, indicating that the image has been shifted to a different position on the retina of the affected side. Although gaze in all planes is possible, the muscles and cranial nerves involved in horizontal conjugate gaze, or abduction and adduction of both eyes together, are the most important eye movements.
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Abduction of each eyeball is performed largely by the lateral rectus muscle, which is innervated by the abducens nerve (CN VI). Adduction of the eyeball is performed by the medial rectus muscle, which is innervated by the oculomotor nerve (CN III). Therefore, for both eyes to look to the right in horizontal gaze, the right abducens nerve and the right lateral rectus muscle must be active to abduct the right eye, and the left oculomotor nerve and the left medial rectus muscle must be active to adduct the left eye. The net effect is that both eyes will look to the right. In the brain stem, the abducens nucleus (CN VI) and the oculomotor nucleus (CN III) are situated close to the midline just beneath the fourth ventricle or the cerebral aqueduct, in the pons and midbrain. These nuclei are interconnected by the fibers in the MLF. It is the fibers in the MLF that permit conjugate gaze, either when the target moves or when the head moves, through their interconnections to gaze centers and the vestibular system.
Control of Horizontal Gaze Horizontal gaze is controlled by 2 interconnected gaze centers. One control center is in the frontal lobe, the frontal eye field (Brodmann area 8). This area acts as a center for contralateral horizontal gaze. In the pons is a second gaze center, known as the pontine gaze center or the PPRF, the paramedian pontine reticular formation. This is a center for ipsilateral horizontal gaze. When activated by neurons in the frontal eye field, the pontine gaze center neurons send axons to synapse with cell bodies in the abducens nucleus, which is actually contained within the pontine gaze center. The pontine gaze center also sends axons that cross immediately and course in the contralateral MLF to reach the contralateral oculomotor nucleus. The net effect of stimulation of the left frontal eye field, therefore, is activation of the pontine gaze center on the right and a saccadic horizontal eye movement of both eyes to the right. Horizontal gaze to the right results from activation of the right abducens nucleus and the left oculomotor nucleus by fibers in the MLF. Lesions in the MLF result in an internuclear ophthalmoplegia in which there is an inability to adduct one eye on attempted gaze to the opposite side. For example, a lesion in the right MLF results in an inability to adduct the right eye on an attempted gaze to the left. The left eye abducts normally but exhibits a nystagmus. If the MLF is lesioned bilaterally (as might be the case in multiple sclerosis), neither eye adducts on attempted gaze (Figures III-5-13 and III-514), and the abducting eye exhibits a nystagmus.
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Lesion sites are indicated by 1–4. Pharmacology
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Right
Left
Paramedian pontine reticular formation (PPRF)
Abducens nucleus
Pathology
Cerebral cortex frontal eye fields (Area 8)
Behavioral Science/Social Sciences
Medial longitudinal fasciculus (MLF) Oculomotor nucleus
Lesion s indicated
Microbiology
Right lateral rectus muscle
Left medial rectus muscle
Abducts
Adducts
Right eye
Left eye
Figure III-5-13. Voluntary Horizontal Conjugate Gaze Figure III-5-13. Voluntary Horizontal Conjugate Gaze Table III-5-2. Clinical Correlate Lesion Examples
Symptoms
1. Right CN VI
Right eye cannot look right
2. Right PPRF
Neither eye can look right
3. Left MLF
Internuclear ophthalmoplegia (INO) Left eye cannot look right; convergence is intact (this is how to distinguish an INO from an oculomotor lesion); right eye has nystagmus; seen in multiple sclerosis
4. Left frontal eye field
Neither eye can look right; but slow drift to left
Abbreviations: MLF, medial longitudinal fasciculus; PPRF, paramedian pontine reticular formation
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Chapter 5 Ask patient to look to the right—response shown below Normal
R
L ABDUCT
1
ADDUCT
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Clinical Correlate The abducens nucleus is coexistent with the PPRF, the center for ipsilateral horizontal gaze. Lesions result in an inability to look to the lesion side, and may include a complete ipsilateral facial paralysis because the VIIth nerve fibers loop over the CN VI nucleus.
2
Figure III-5-14. Normal and Abnormal Horizontal Gaze Figure III-5-14. Normal and Abnormal Horizontal Gaze
Table III-5-3. Normal/Abnormal Responses to Horizontal Conjugate Gaze: Part 1 Lesion Location
Symptoms (Results)
Right Abducens nerve, #1
Right eye cannot look right (abduct)
Right Abducens nucleus, #2
Neither eye can look right (lateral gaze paralysis)—may be slow drift left and complete right facial paralysis
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Ask patient to look to the right—response shown below Normal Pharmacology
Biochemistry
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Medical Genetics
Pathology
Behavioral Science/Social Sciences
L
3
4
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Figure III-5-15. Horizontal Gaze Figure III-5-15.Normal Normaland and Abnormal Abnormal Horizontal Gaze Table III-5-4. Normal/Abnormal Responses to Horizontal Gaze: Part 2 Lesion Location
Symptoms (Results)
Left MLF, #3
Left eye cannot look right; convergence intact; right eye exhibits nystagmus
Internuclear ophthalmoplegia Left cerebral cortex, #4
Neither eye can look right: but slow drift to left; may be seen with right lower face weakness and right upper limb weakness
Abbreviation: MLF, medial longitudinal fasciculus
BLOOD SUPPLY TO THE BRAIN STEM Vertebral Artery This artery is a branch of the subclavian that ascends through the foramina of the transverse processes of the upper 6 cervical vertebrae. It enters the posterior fossa by passing through the foramen magnum. The vertebral arteries continue up the ventral surface of the medulla and, at the caudal border of the pons, join to form the basilar artery.
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Circle of Willis Anterior communicating Anterior cerebral Internal carotid
Middle cerebral
Posterior communicating
Superior cerebellar (lateral pons)
Posterior cerebral (medial midbrain) Paramedian (medial pons)
Basilar
Anterior inferior cerebellar (lateral pons)
Vertebral Anterior spinal (medial medulla)
Posterior inferior cerebellar (lateral medulla)
Figure III-5-16. Arterial Supply of the Brain Figure III-5-16. Arterial Supply of the Brain
Branches of the vertebral artery include: the anterior spinal artery, which supplies the ventrolateral two-thirds of the cervical spinal cord and the ventromedial part of the medulla; and the posterior inferior cerebellar artery (PICA), which supplies the cerebellum and the dorsolateral part of the medulla.
Basilar Artery The basilar artery is formed by the joining of the 2 vertebral arteries at the pontomedullary junction. It ascends along the ventral midline of the pons and terminates near the rostral border of the pons by dividing into the 2 posterior cerebral arteries. Branches include the anterior inferior cerebellar arteries (AICA) and the paramedian arteries. Branches of the basilar artery include:the labyrinthine artery, which follows the course of the eighth cranial nerve and supplies the inner ear; the anterior inferior cerebellar artery, which supplies part of the pons and the anterior and inferior regions of the cerebellum; the superior cerebellar artery, which supplies part of the rostral pons and the superior region of the cerebellum; and pontine branches, which supply much of the pons via paramedian and circumferential vessels. At the rostral end of the midbrain, the basilar artery divides into a pair of posterior cerebral arteries. Paramedian and circumferential branches of the posterior cerebral artery supply the midbrain.
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BRAIN-STEM LESIONS There are 2 keys to localizing brain-stem lesions. First, it is uncommon to injure parts of the brain stem without involving one or more cranial nerves. The cranial nerve signs will localize the lesion to the midbrain (CN III or IV), upper pons (CN V), lower pons (CN VI, VII, or VIII), or upper medulla (CN IX, X, or XII). Second, if the lesion is in the brain stem, the cranial nerve deficits will be seen with a lesion to one or more of the descending or ascending long tracts (corticospinal, medial lemniscus, spinothalamic, descending hypothalamic fibers). Lesions in the brain stem to any of the long tracts except for the descending hypothalamic fibers will result in a contralateral deficit. A unilateral lesion to the descending hypothalamic fibers that results in Horner syndrome is always seen ipsilateral to the side of the lesion.
Medial Medullary Syndrome Microbiology
Medial medullary syndrome is most frequently the result of occlusion of the vertebral artery or the anterior spinal artery (Figure III-5-17). Medial medullary syndrome presents with a lesion of the hypoglossal nerve as the cranial nerve sign and lesions to both the medial lemniscus and the corticospinal tract. Corticospinal tract lesions produce contralateral spastic hemiparesis of both limbs. Medial lemniscus lesions produce a contralateral deficit of proprioception and touch, pressure, and vibratory sensations in the limbs and body. Lesions of the hypoglossal nerve in the medulla produce an ipsilateral paralysis of half the tongue with atrophy. Upon protrusion, the tongue deviates toward the side of the lesion.
Medulla Nucleus of solitary tract
Vestibular nuclei
Dorsal motor nucleus of CN X
Inferior cerebellar peduncle
Hypoglossal nucleus B
Spinal trigeminal tract and nucleus CNs IX, X Nucleus ambiguus Descending hypo- and spino-thalamic tracts Inferior olivary nucleus
Medial lemniscus
CN XII
A
Pyramid
Figure III-5-17. Medulla Lesions Figure III-5-17. Medulla Lesions
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Medial Medullary Syndrome A Anterior Spinal Artery • Pyramid: contralateral spastic paresis • Medial lemniscus: contralateral loss of tactile, vibration, conscious
proprioception
• XII nucleus/fibers: ipsilateral flaccid paralysis of tongue with tongue
deviation on protrusion to lesion side.
Lateral Medullary Syndrome B PICA, Wallenberg Syndrome • Inferior cerebellar peduncle: ipsilateral limb ataxia • Vestibular nuclei: vertigo, nausea/vomiting, nystagmus (away from
lesion)
• Nucleus ambiguus (CN IX, X): ipsilateral paralysis of larynx, pharynx,
palate → dysarthria, dysphagia, loss of gag reflex
• Spinal V: ipsilateral pain/temperature loss (face) • Spinothalamic tract: Contralateral pain/temperature loss (body) • Descending hypothalamics: ipsilateral Horner syndrome
Lateral Medullary (Wallenberg) Syndrome Lateral medullary syndrome results from occlusion of the PICA. The cranial nerves or nuclei involved in the lesion are the vestibular or the cochlear parts of CN VIII, the glossopharyngeal and the vagus nerves, and the spinal nucleus or tract of V. The long tracts involved are the spinothalamic tract and the descending hypothalamic fibers. Spinothalamic tract lesions produce a pain and temperature sensation deficit in the contralateral limbs and body. Lesions of descending hypothalamic fibers produce an ipsilateral Horner syndrome (i.e., miosis, ptosis, and anhidrosis). Lesions of the vestibular nuclei and pathways may produce nystagmus, vertigo, nausea, and vomiting. If there is a vestibular nystagmus, the fast component will be away from the side of the lesion. Lesions of the vagus nerves exiting the medulla may produce dysphagia (difficulty in swallowing) or hoarseness. The palate will droop on the affected side, and the uvula will deviate away from the side of the lesion. Lesions of the glossopharyngeal nerve result in a diminished or absent gag reflex. Lesions of the spinal tract and nucleus of the trigeminal nerve produce a loss of just pain and temperature sensations on the ipsilateral side of half the face. Touch sensations from the face and the corneal blink reflex will be intact. In lateral medullary syndrome, the pain and temperature losses are alternating; these sensations are lost from the face and scalp ipsilateral to the lesion but are lost from the contralateral limbs and trunk. Taste sensations may be altered if the solitary nucleus is involved.
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Medial Pontine Syndrome Medial pontine syndrome results from occlusion of paramedian branches of the basilar artery. At a minimum, this lesion affects the exiting fibers of the abducens nerve and the corticospinal tract. The medial lemniscus may be affected if the lesion is deeper into the pons, and the facial nerve may be affected if the lesion extends laterally. The long tract signs will be the same as in medial medullary syndrome, involving the corticospinal and medial lemniscus, but the abducens nerve and the facial nerve lesions localize the lesion to the caudal pons. Corticospinal tract lesions produce contralateral spastic hemiparesis of both limbs. Medial lemniscus lesions produce a contralateral deficit of proprioception and touch, pressure, and vibratory sensations in the limbs and body.
Microbiology
Lesions of the abducens nerve exiting the caudal pons produce an internal strabismus of the ipsilateral eye (from paralysis of the lateral rectus). This results in diplopia on attempted lateral gaze to the affected side. Lesions of the facial nerve exiting the caudal pons produce complete weakness of the muscles of facial expression on the side of the lesion. Lesions of the facial nerve may also include an alteration of taste from the anterior two-thirds of the tongue, loss of lacrimation (eye dry and red), and loss of the motor limb of the corneal blink reflex. If a lesion extends dorsally to include the abducens nucleus (which includes the horizontal gaze center in the PPRF), there may be a lateral gaze paralysis in which both eyes are forcefully directed to the side contralateral to the lesion.
Lateral Pontine Syndrome Lesions of the dorsolateral pons usually result from occlusion of the anterior inferior cerebellar artery (caudal pons) or superior cerebellar artery (rostral pons). The long tracts involved will be the same as in lateral medullary syndrome, the spinothalamic tract and the descending hypothalamic fibers. The cranial nerves involved will be the facial and vestibulocochlear in the caudal pons, the trigeminal nerve in the rostral pons, and the spinal nucleus and tract of V in both lesions. Spinothalamic tract lesions produce a pain and temperature sensation deficit in the contralateral limbs and body. Lesions of descending hypothalamic fibers produce an ipsilateral Horner syndrome (i.e., miosis, ptosis, and anhidrosis). Lesions of the vestibular nuclei and pathways (caudal pons) produce nystagmus, vertigo, nausea, and vomiting. Again, the fast phase of the nystagmus will be away from the side of the lesion. Lesions of the cochlear nucleus or auditory nerve produce an ipsilateral sensorineural hearing loss. Lesions of the spinal tract and nucleus of the trigeminal nerve result only in a loss of pain and temperature sensations on the ipsilateral side of half the face.
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Lesions of the facial nerve and associated structures produce ipsilateral facial paralysis, loss of taste from the anterior two-thirds of the tongue, loss of lacrimation and salivation, and loss of the corneal reflex. Lesions of the trigeminal nerve (rostral pons) result in complete anesthesia of the face on the side of the lesion, weakness of muscles of mastication, and deviation of the jaw toward the lesioned side.
Pons Abducent nucleus
Vestibular nuclei
MLF
Inferior cerebellar peduncle Spinal trigeminal nucleus and tract
B
CN VIII (vestibular nerve) CN VII Nucleus CN VII Lateral spinothalamic tract
Medial lemniscus CN VI
Corticospinal tract A
FigureIII-5-18. III-5-18.Pons Pons Figure
Medial Pontine Syndrome (A) Paramedian Branches of Basilar Artery • Corticospinal tract: contralateral spastic hemiparesis • Medial lemniscus: contralateral loss of tactile/position/vibration
sensation
• Fibers of VI: medial strabismus
Lateral Pontine Syndrome (B) AICA • Middle cerebellar peduncle: ipsilateral ataxia • Vestibular nuclei: vertigo, nausea and vomiting, nystagmus • Facial nucleus and fibers: ipsilateral facial paralysis; ipsilateral loss
of taste (anterior two-thirds of tongue), lacrimation, salivation, and corneal reflex; hyperacusis
• Spinal trigeminal nucleus/tract: ipsilateral pain/temperature loss
(face)
• Spinothalamic tract: contralateral pain/temperature loss (body) • Cochlear nucleus/VIII fibers: ipsilateral hearing loss • Descending hypothalamics: ipsilateral Horner syndrome
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Pontocerebellar Angle Syndrome Pontocerebellar angle syndrome is usually caused by an acoustic neuroma (schwannoma) of CN VIII. This is a slow-growing tumor, which originates from Schwann cells in the vestibular nerve (or less commonly the auditory nerve). As the tumor grows, it exerts pressure on the lateral part of the caudal pons where CN VII emerges and may expand anteriorly to compress the fifth nerve. The cranial nerve deficits seen together localize the lesion to the brain stem, but the absence of long tract signs indicates that the lesion must be outside of the brain stem.
Medial Midbrain (Weber) Syndrome Pathology
Microbiology
Behavioral Science/Social Sciences
Medial midbrain (Weber) syndrome results from occlusion of branches of the posterior cerebral artery. Exiting fibers of CN III are affected, along with corticobulbar and corticospinal fibers in the medial aspect of the cerebral peduncle. Third-nerve lesions result in a ptosis, mydriasis (dilated pupil), and an external strabismus. As with any brain-stem lesion affecting CN III, accommodation and convergence will also be affected. Corticospinal tract lesions produce contralateral spastic hemiparesis of both limbs. The involvement of the cortico-bulbar fibers results in a contralateral lower face weakness seen as a drooping of the corner of the mouth. The patient will be able to shut the eye (blink reflex is intact) and wrinkle the forehead.
Midbrain Posterior commissure and center for vertical conjugate gaze Superior colliculus
A
Nucleus of CN III
Medial geniculate body
Spinothalamic tract
Substantia nigra
Medial lemniscus
Corticospinal tract
Red nucleus B
Corticobulbar tract
CN III
Figure III-5-19. Figure III-5-19. Midbrain Midbrain
Dorsal Midbrain (Parinaud) Syndrome (A) Tumor in Pineal Region • Superior colliculus/pretectal area: paralysis of upward gaze, various
pupillary abnormalities
• Cerebral aqueduct: noncommunicating hydrocephalus
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The Brain Stem
Medial Midbrain (Weber) Syndrome (B) Branches of PCA • Fibers of III: ipsilateral oculomotor palsy (lateral strabismus, dilated pupil, ptosis) • Corticospinal tract: contralateral spastic hemiparesis • Corticobulbar tract: contralateral hemiparesis of lower face
Cortex or Capsular Lesions
Brain-stem Lesions
Spinal Cord Hemisection Corticospinal tract (CST)
Dorsal columns (DC)
Spinothalamic tract (SpTh)
All long tract signs produce contralateral deficits except for ipsilateral Horner’s syndrome
Complete anesthesia and lower face weakness contralateral
All sensory system lesions from face or body produce contralateral deficits.
CN signs ipsilateral to lesion
Long track findings: All give rise to contralateral deficits.
Lesion of corticobulbar fibers produces contralateral lower face weakness.
Lesion is at brain stem: at level of cranial nerve affected and on same side as cranial nerve findings.
Two signs ipsilateral and below lesion
One sign contralateral and below lesion
• Spastic weakness • Altered vibratory sense
• Loss of pain and temperature No CN signs
Long track findings: NOT ALL on one side; loss of pain and temperature (P&T) separate from others. Lesion is at spinal cord level on side opposite P&T loss.
Figure III-5-20. Figure III-5-20. Strategy Strategy for for the the Study Study of of Lesions Lesions
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Parinaud Syndrome Parinaud syndrome usually occurs as a result of a pineal tumor compressing the superior colliculi. The most common sign is paralysis of upward or vertical gaze, combined with bilateral pupillary abnormalities (e.g., slightly dilated pupils, which may show an impaired light or accommodation reaction) and signs of elevated intracranial pressure. Compression of the cerebral aqueduct can result in noncommunicating hydrocephalus.
RETICULAR FORMATION Pathology
Microbiology
Behavioral Science/Social Sciences
The reticular formation is located in the brain stem and functions to coordinate and integrate the actions of different parts of the CNS. It plays an important role in the regulation of muscle and reflex activity and control of respiration, cardiovascular responses, behavioral arousal, and sleep.
Clinical Correlate
Reticular Nuclei
Neurons in both the raphe and locus caeruleus degenerate in Alzheimer disease.
The raphe nuclei are a narrow column of cells in the midline of the brain stem, extending from the medulla to the midbrain. Cells in some of the raphe nuclei (e.g., the dorsal raphe nucleus) synthesize serotonin (5-hydroxytryptamine [5HT]) from l-tryptophan and project to vast areas of the CNS. They play a role in mood, aggression, and the induction of non–rapid eye movement (non-REM) sleep. Cells in the locus caeruleus synthesize norepinephrine and send projections to most brain areas involved in the control of cortical activation (arousal). Decreased levels of norepinephrine are evident in REM (paradoxic) sleep. The periaqueductal (central) gray is a collection of nuclei surrounding the cerebral aqueduct in the midbrain. Opioid receptors are present on many periaqueductal gray cells, the projections from which descend to modulate pain at the level of the dorsal horn of the spinal cord.
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The Cerebellum
6
Learning Objectives ❏❏ Use knowledge of general features ❏❏ Use knowledge of cerebellar cytoarchitecture ❏❏ Solve problems concerning circuitry
GENERAL FEATURES The cerebellum, located dorsal to the pons and the medulla, is derived from the metencephalon. The fourth ventricle is found between the cerebellum and the dorsal aspect of the pons. The cerebellum functions in the planning and finetuning of skeletal muscle contractions; it performs these tasks by comparing an intended with an actual performance. The cerebellum consists of a midline vermis and 2 lateral cerebellar hemispheres. The cerebellar cortex consists of multiple parallel folds (or folia) and contains several maps of the skeletal muscles in the body. The topographic arrangement of these maps indicates that the vermis controls the axial and proximal musculature of the limbs, the intermediate part of the hemisphere controls distal musculature, and the lateral part of the hemisphere is involved in motor planning. The flocculonodular lobe is involved in control of balance and eye movements.
Vermis Superior vermis
Intermediate hemisphere Lateral hemisphere
Cerebellar peduncle
Anterior lobe Flocculonodular lobe Posterior lobe
Inferior vermis
Figure III-6-1. Cerebellum Figure III-6-1. Cerebellum
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Table III-6-1. Cerebellum Region
Function
Principle Input
Vermis and intermediate zones
Ongoing motor execution
Spinal cord
Hemisphere (lateral)
Planning/coordination
Cerebral cortex and inferior olivary nucleus
Flocculonodular lobe
Balance and eye movements
Vestibular nuclei (VIII)
Medical Genetics
Behavioral Science/Social Sciences
Major input to the cerebellum travels in the inferior cerebellar peduncle (ICP) (restiform body) and middle cerebellar peduncle (MCP). Major outflow from the cerebellum travels in the superior cerebellar peduncle (SCP). Microbiology
Cerebellar Cytoarchitecture All afferent and efferent projections of the cerebellum traverse the ICP, MCP, or SCP. Most afferent input enters the cerebellum in the ICP and MCP; most efferent outflow leaves in the SCP.
Table III-6-2. Major Afferents to the Cerebellum Name
Tract
Enter Cerebellum Via
Target and Function
Mossy fibers
Vestibulocerebellar
ICP
Spinocerebellar (Cortico) pontocerebellar
ICP and SCP
Excitatory terminals on granule cells (glutamate)
Olivocerebellar
ICP (decussate)
Climbing fibers
MCP (decussate)
Excitatory terminals on Purkinje cells
Abbreviations: ICP, inferior cerebellar peduncle; MCP, middle cerebellar peduncle; SCP, superior cerebellar peduncle
Internally, the cerebellum consists of an outer cortex and an internal white matter (medullary substance). The 3 cell layers of the cortex are the molecular layer, the Purkinje layer, and the granule cell layer. The molecular layer is the outer layer and is made up of basket and stellate cells as well as parallel fibers, which are the axons of the granule cells. The extensive dendritic tree of the Purkinje cell extends into the molecular layer. The Purkinje layer is the middle and most important layer of the cerebellar cortex. All of the inputs to the cerebellum are directed toward influencing the firing of Purkinje cells, and only axons of Purkinje cells leave the cerebellar cortex.
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A single axon exits from each Purkinje cell and projects to one of the deep cerebellar nuclei or to vestibular nuclei of the brain stem. The granule cell layer is the innermost layer of cerebellar cortex and contains Golgi cells, granule cells, and glomeruli. Each glomerulus is surrounded by a glial capsule and contains a granule cell and axons of Golgi cells, which synapse with granule cells. The granule cell is the only excitatory neuron within the cerebellar cortex. All other neurons in the cerebellar cortex, including Purkinje, Golgi, basket, and stellate cells, are inhibitory.
Table III-6-3. Cerebellum: Cell Types Name
Target (Axon Termination)
Transmitter
Function
Purkinje cell
Deep cerebellar nuclei
GABA
Inhibitory*
Granule cell
Purkinje cell
Glutamate
Excitatory
Stellate cell
Purkinje cell
GABA
Inhibitory
Basket cell
Purkinje cell
GABA
Inhibitory
Golgi cell
Granule cell
GABA
Inhibitory
*Purkinje cells are the only outflow from the cerebellar cortex.
The internal white matter contains the deep cerebellar nuclei.
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Anterior lobe Posterior lobe Flocculonodular lobe Biochemistry
Pharmacology
Paravermal
Vermal
Anterior
Hemisphere (lateral) Physiology
Primary fissure
Posterior Posterolateral fissure
Medical Genetics
Dentate nucleus
Flocculus Nodulus
Pathology
Microbiology
Behavioral Science/Social Sciences
Emboliform nucleus Globose nucleus
A
GC: Golgi cell
Purkinje cell axons
Fastigial nucleus
BC: Basket cell GrC: Granule cell
Interposed nuclei Parallel fiber Cerebellar cortex Climbing fiber (from olivary nuclei)
Deep CB nuclei B
+
+
+
+
BC PC
– + +
+
+
Purkinje cell layer
GC GrC
–
–
Molecular layer
+
Granule cell layer
Mossy fiber (from spinal cord, pontine nuclei, or vestibular nuclei)
Figure III-6-2. Cerebellar Organization III-6-2. (A) Parts of the cerebellar cortexFigure and the deepCerebellar cerebellarOrganization nuclei linked together by Purkinje cells (B) Topographic arrangement of skeletal muscles controlled by parts of the cerebellum Parts ofofthe (C)(A) Cytology thecerebellar cerebellarcortex cortexand the deep cerebellar nuclei linked together by Purkinje cells
(B) Topographic arrangement of skeletal muscles controlled by parts of the cerebellum (C) Cytology of the cerebellar cortex
From medial to lateral, the deep cerebellar nuclei in the internal white matter are the fastigial nucleus, interposed nuclei, and dentate nucleus. Two kinds of excitatory input enter the cerebellum in the form of climbing fibers and mossy fibers. Both types influence the firing of deep cerebellar nuclei by axon collaterals. Climbing fibers originate exclusively from the inferior olivary complex of nuclei on the contralateral side of the medulla. Climbing fibers provide a direct powerful monosynaptic excitatory input to Purkinje cells. Mossy fibers represent the axons from all other sources of cerebellar input. Mossy fibers provide an indirect, more diffuse excitatory input to Purkinje cells.
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All mossy fibers exert an excitatory effect on granule cells. Each granule cell sends its axon into the molecular layer, where it gives off collaterals at a 90-degree angle that run parallel to the cortical surface (i.e., parallel fibers). These granule cell axons stimulate the apical dendrites of the Purkinje cells. Golgi cells receive excitatory input from mossy fibers and from the parallel fibers of the granule cells. The Golgi cell in turn inhibits the granule cell, which activated it in the first place. The basket and stellate cells, which also receive excitatory input from parallel fibers of granule cells, inhibit Purkinje cells.
Circuitry The basic cerebellar circuits begin with Purkinje cells that receive excitatory input directly from climbing fibers and from parallel fibers of granule cells. Purkinje cell axons project to and inhibit the deep cerebellar nuclei or the vestibular nuclei in an orderly fashion. • Purkinje cells in the flocculonodular lobe project to the lateral vestibu-
lar nucleus.
• Purkinje cells in the vermis project to the fastigial nuclei. • Purkinje cells in the intermediate hemisphere primarily project to the
interposed (globose and emboliform) nuclei.
• Purkinje cells in the lateral cerebellar hemisphere project to the dentate
nucleus.
Dysfunction • Hemisphere lesions → ipsilateral symptoms: intention tremor,
ysmetria, dysdiadochokinesia, scanning dysarthria, nystagmus, d hypotonia
• Vermal lesions → truncal ataxia
Major Pathway Purkinje cells → deep cerebellar nucleus; dentate nucleus → contralateral VL → first-degree motor cortex → pontine nuclei → contralateral cerebellar cortex
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Upper motor neurons Pharmacology
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Physiology
Medical Genetics
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Precentral gyrus
Net effect: Right side of Cb controls muscles on right side of the body
VL /VA (thalamus)
Red nucleus (midbrain)
Fastigial nucleus
Superior Cb peduncle
Interpositus nucleus Microbiology
Dentate nucleus
Purkinje cell axons Lateral hemisphere Paravermal hemisphere
Vermis
Left
Rubrospinal tract
Right
Corticospinal tract Figure Efferents FigureIII-6-3. III-6-3.Cerebellar Cerebellar Efferents
Table III-6-4. Major Efferents From the Cerebellum Cerebellar Areas
Deep Cerebellar Nucleus
Efferents to:
Function
Vestibulocerebellum (flocculonodular lobe)
Fastigial nucleus
Vestibular nucleus
Elicit positional changes of eyes and trunk in response to movement of the head
Spinocerebellum (intermediate hemisphere)
Interpositus nucleus
Red nucleus
Influence LMNs via the reticulospinal and rubrospinal tracts to adjust posture and effect movement
Pontocerebellum (lateral hemispheres)
Dentate nucleus
Thalamus (VA, VL) then cortex
Reticular formation
Influence on LMNs via the corticospinal tract, which effect voluntary movements, especially sequence and precision
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Efferents from the deep cerebellar nuclei leave mainly through the SCP and influence all upper motoneurons. In particular, axons from the dentate and interposed nuclei leave through the SCP, cross the midline, and terminate in the ventrolateral (VL) nucleus of the thalamus. The VL nucleus of the thalamus projects to primary motor cortex and influences the firing of corticospinal and corticobulbar neurons. Axons from other deep cerebellar nuclei influence upper motoneurons in the red nucleus and in the reticular formation and vestibular nuclei.
Cerebellar Lesions The hallmark of cerebellar dysfunction is a tremor with intended movement without paralysis or paresis. Symptoms associated with cerebellar lesions are expressed ipsilaterally because the major outflow of the cerebellum projects to the contralateral motor cortex, and then the corticospinal fibers cross on their way to the spinal cord. Thus, unilateral lesions of the cerebellum will result in a patient falling toward the side of the lesion.
Clinical Correlate Anterior vermis lesions are usually the result of degeneration from alcohol abuse and are present with gait ataxia. Posterior vermis lesions result from medulloblastomas or ependymomas and present with truncal ataxia.
Lesions that include the hemisphere Lesions that include the hemisphere produce a number of dysfunctions, mostly involving distal musculature. An intention tremor is seen when voluntary movements are performed. For example, if a patient with a cerebellar lesion is asked to pick up a penny, a slight tremor of the fingers is evident and increases as the penny is approached. The tremor is barely noticeable or is absent at rest. Dysmetria (past pointing) is the inability to stop a movement at the proper place. The patient has difficulty performing the finger-to-nose test. Dysdiadochokinesia (adiadochokinesia) is the reduced ability to perform alternating movements, such as pronation and supination of the forearm, at a moderately quick pace. Scanning dysarthria is caused by asynergy of the muscles responsible for speech. In scanning dysarthria, patients divide words into syllables, thereby disrupting the melody of speech. Gaze dysfunction occurs when the eyes try to fix on a point: They may pass it or stop too soon and then oscillate a few times before they settle on the target. A nystagmus may be present, particularly with acute cerebellar damage. The nystagmus is often coarse, with the fast component usually directed toward the involved cerebellar hemisphere. Hypotonia usually occurs with an acute cerebellar insult that includes the deep cerebellar nuclei. The muscles feel flabby on palpation, and deep tendon reflexes are usually diminished.
Lesions to the vermal region Vermal lesions result in difficulty maintaining posture, gait, or balance (an ataxic gait). Patients with vermal damage may be differentiated from those with a lesion of the dorsal columns by the Romberg sign. In cerebellar lesions, patients will sway or lose their balance with their eyes open; in dorsal column lesions, patients sway with their eyes closed.
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Basal Ganglia
7
Learning Objectives ❏❏ Solve problems concerning general features of the basal ganglia
GENERAL FEATURES The basal ganglia initiate and provide gross control over skeletal muscle movements. The major components of the basal ganglia include: • Striatum, which consists of the caudate nucleus and the putamen (tel-
encephalon)
• External and internal segments of the globus pallidus (telencephalon) • Substantia nigra (in midbrain) • Subthalamic nucleus (in diencephalon)
Together with the cerebral cortex and the ventrolateral (VL) nucleus of the thalamus, these structures are interconnected to form 2 parallel but antagonistic circuits known as the direct and indirect basal ganglia pathways. Both pathways are driven by extensive inputs from large areas of cerebral cortex, and both project back to the motor cortex after a relay in the VL nucleus of the thalamus. Both pathways use a process known as “disinhibition” to mediate their effects, whereby one population of inhibitory neurons inhibits a second population of inhibitory neurons.
Direct Basal Ganglia Pathway In the direct pathway, excitatory input from the cerebral cortex projects to striatal neurons in the caudate nucleus and putamen. Through disinhibition, activated inhibitory neurons in the striatum, which use γ-aminobutyric acid (GABA) as their neurotransmitter, project to and inhibit additional GABA neurons in the internal segment of the globus pallidus. The GABA axons of the internal segment of the globus pallidus project to the thalamus (VL). Because their input to the thalamus is disinhibited, the thalamic input excites the motor cortex. The net effect of the disinhibition in the direct pathway results in an increased level of cortical excitation and the promotion of movement.
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Indirect Basal Ganglia Pathway In the indirect pathway, excitatory input from the cerebral cortex also projects to striatal neurons in the caudate nucleus and putamen. These inhibitory neurons in the striatum, which also use GABA as their neurotransmitter, project to and inhibit additional GABA neurons in the external segment of the globus pallidus. The GABA axons of the external segment of the globus pallidus project to the subthalamic nucleus. Through disinhibition, the subthalamic nucleus excites inhibitory GABA neurons in the internal segment of the globus pallidus, which inhibits the thalamus. This decreases the level of cortical excitation, inhibiting movement. The net effect of the disinhibition in the indirect pathway results in a decreased level of cortical excitation, and a suppression of unwanted movement.
Plane of section
Microbiology
Corpus callosum Lateral ventricle
Internal capsule:
Caudate nucleus
Anterior limb
Putamen
Genu
Globus pallidus
Posterior limb
Thalamus Third ventricle
Figure III-7-1. Figure III-7-1. Horizontal or Axial Section through Basal Ganglia
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Globus pallidus external segment
Glutamate Striatum (acetylcholine)
Direct
GABA
Subthalamic nucleus
Input center
GABA/Enkephalin
Glutamate
GABA/ Substance P
Output center
Both basal ganglia pathways utilize 2 GABA neurons in series, and a “disinhibition.”
Note Dopamine drives the direct pathway; acetylcholine (ACh) drives the indirect pathway.
Substantia nigra pars reticulata
GABA Thalamus
Clear arrows: excitatory Shaded arrows: inhibitory
Dopamine
Substantia nigra pars compacta
Globus pallidus internal segment
Basal Ganglia
Note
Cortex Indirect
l
Ventral anterior/ ventral lateral thalamic nuclei
Supplementary motor area
Figure III-7-2. BasalIII-7-2. Ganglia Pathways Figure
Dopamine and cholinergic effects In addition to the GABA neurons, 2 other sources of chemically significant neurons enhance the effects of the direct or indirect pathways. Dopaminergic neurons in the substantia nigra in the midbrain project to the striatum. The effect of dopamine excites or drives the direct pathway, increasing cortical excitation. Dopamine excites the direct pathway through D1 receptors and inhibits the indirect pathway through D2 receptors. Cholinergic neurons found within the striatum have the opposite effect. Acetylcholine (Ach) drives the indirect pathway, decreasing cortical excitation.
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Note Medical Genetics All basal ganglia connections are with ipsilateral cortex.
Physiology
Pathology
Behavioral Science/Social Sciences
Microbiology
of Horizontal Section Diencephalon, through FigureFigure III-7-3.III-7-3. MRI of MRI Horizontal Section through Diencephalon, Basal Ganglia, and Cortex. Basal Ganglia, and Cortex Thalamus (b) Head of Caudate Nucleus (c)ofGenu of Internal (a) (a) Thalamus (b) Head of Caudate Nucleus (c) Genu Internal Capsule ConCapsule Containing Corticobulbar Axons (d) Posterior Limb(e) of Primary taining Corticobulbar Axons (d) Posterior Limb of Internal Capsule Internal Capsule (e) Primary Visual Cortex (f) Splenium of Corpus Visual Cortex (f) Splenium of Corpus Callosum (g) Putamen (h) Broca’s Motor Callosum (g) Putamen (h) Broca’sOral Motor Speech AreaArea Speech Area (i) Wernicke’s Comprehension (i) Wernicke’s Oral Comprehension Area
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Figure III-7-4. Gangliaand andOther OtherSubcortical Subcortical Structures Figure III-7-4.Coronal CoronalSection Section through through Basal Basal Ganglia Structures (A) nucleus (B)(B) putamen (C) globus pallidus external segment (D) globus (A)caudate caudate nucleus putamen (C) globus pallidus external segment pallidus internal segment (E) septal nuclei (F) fornix (G) lateral ventricle (H) (D) globus pallidus internal segment (E) septal nuclei (F) fornix (G) anterior lateral commissure (I) optic chiasm (J) basal nucleus of Meynert (K) preoptic hypothalamus ventricle (H) anterior commissure (I) optic chiasm (J) basal nucleus of (L) internal capsule, anteriorcapsule, limb anterior limb Meynert (K) preoptic hypothalamus (L) internal
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Table III-7-1. Diseases of the Basal Ganglia
Pharmacology
Disease
Clinical Manifestations
Notes
Parkinson disease
Bradykinesia, cogwheel rigidity, pillBiochemistry rolling (resting) tremor, shuffling gate, stooped posture, masked face, depression, dementia
Loss of pigmented dopaminergic neurons from substantia nigra
Physiology
Medical Genetics
Disease
Pathology
Huntington disease
Lewy bodies: intracytoplasmic eosinophilic inclusions, contain α-synuclein Known causes of parkinsonism: infections, vascular, and toxic insults (e.g., MPTP)
Clinical Manifestations
Notes
Chorea (multiple, rapid, random movements), athetosis (slow, writhing movements), personality changes, dementia
Degeneration of GABAergic neurons in neostriatum, causing atrophy of head of caudate nucleus (and ventricular dilatation)
Onset: 20−40 years
Unstable nucleotide repeat on gene in chromosome 4, which codes for huntingtin protein
Behavioral Science/Social Sciences
Microbiology
Autosomal dominant
Disease shows anticipation and genomic imprinting Treatment: antipsychotic agents, benzodiazepines, anticonvulsants Wilson disease (hepatolenticular degeneration)
Tremor, asterixis, parkinsonian symptoms, chorea, neuropsychiatric symptoms; fatty change, hepatitis, or cirrhosis of liver, tremor may be “wing beating”
Autosomal recessive defect in copper transport Accumulation of copper in liver, brain, and eye (Descemet membrane, producing Kayser-Fleischer ring) Lesions in basal ganglia (especially putamen) Treatment: penicillamine (a chelator), zinc acetate (blocks absorption)
Hemiballism
Wild, flinging movements of limbs
Hemorrhagic destruction of contralateral subthalamic nucleus Hypertensive patients
Tourette syndrome
Motor tics and vocal tics (e.g., snorting, sniffing, uncontrolled and often obscene vocalizations), commonly associated with OCD and ADHD
Treatment: Antipsychotic agents
Abbreviations: ADHD, attention deficit hyperactivity disorder; MPTP, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine; OCD, obsessive-compulsive disorder
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Clinical Correlate Lesions or diseases of the basal ganglia generally present with movement disorders, known as dyskinesias, and an involuntary tremor or tremor at rest. Most basal ganglia disorders seem to preferentially affect either the direct or the indirect pathway, altering the balance between the two. Lesions of the direct pathway result in an underactive cortex and hypokinetic disturbances in which there is a slowing or absence of spontaneous movements. The bestknown disorder is caused by the degeneration of dopaminergic neurons of the substantia nigra in Parkinson disease. Because the cortex is underactive, Parkinson patients have problems initiating movements, combined with a reduction in the velocity and amplitude of the movements. The tremor at rest is the classic pill-rolling tremor seen in the fingers. Skeletal muscles in the upper limbs exhibit a cogwheel rigidity because of increased muscle tone. Patients also present with stooped posture, an expressionless face, and a festinating or accelerating gait during which individuals seem to chase their center of gravity. Strategies for Parkinson are L-dopa, a dopamine precursor that crosses the blood–brain barrier, anticholinergic drugs, which inhibit the effects of acetylcholine on the indirect pathway. Other common disorders of the basal ganglia (chorea, athetosis, dystonia, tics) result from lesions to parts of the indirect pathway, which result in an overactive motor cortex. An overactive cortex produces hyperkinetic disturbances, expressed in numerous spontaneous movements. The involuntary tremors seen in these diseases range from being dancelike in chorea to ballistic with lesions to the subthalamic nucleus. Chorea produces involuntary movements that are purposeless, quick jerks that may be superimposed on voluntary movements. Huntington chorea exhibits autosomal dominant inheritance (chromosome 4) and is characterized by severe degeneration of GABA neurons in the striatum. Patients suffer from athetoid movements, progressive dementia, and behavioral disorders. Sydenham chorea is a transient complication in some children with rheumatic fever. Athetosis refers to slow, wormlike, involuntary movements that are most noticeable in the fingers and hands but may involve any muscle group. It is present in Huntington disease and may be observed in many diseases that involve the basal ganglia. Dystonia refers to a slow, prolonged movement involving predominantly the truncal musculature. Dystonia often occurs with athetosis. Blepharospasm (contraction of the orbicularis oculi causing the eyelids to close), spasmodic torticollis (in which the head is pulled toward the shoulder), and writer’s cramp (contraction of arm and hand muscles on attempting to write) are all examples of dystonic movements. Hemiballismus results from a lesion of the subthalamic nucleus usually seen in hypertensive patients. Hemiballismus refers to a violent projectile movement of a limb and is typically observed in the upper limb contralateral to the involved subthalamic nucleus. Tourette syndrome involves facial and vocal tics that progress to jerking movements of the limbs. It is frequently associated with explosive, vulgar speech. Wilson disease results from an abnormality of copper metabolism, causing the accumulation of copper in the liver and basal ganglia. Personality changes, tremor, dystonia, and athetoid movements develop. Untreated patients usually succumb because of hepatic cirrhosis. A thin brown ring around the outer cornea, the Kayser-Fleischer ring, may be present and aid in the diagnosis.
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Visual Pathways
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Learning Objectives ❏❏ Use knowledge of eyeball and optic nerve ❏❏ Solve problems concerning visual reflexes ❏❏ Answer questions about lesions of the visual pathways
EYEBALL AND OPTIC NERVE Light must pass through the cornea, aqueous humor, pupil, lens, and vitreous humor before reaching the retina. It must then pass through the layers of the retina to reach the photoreceptive layer of rods and cones. The outer segments of rods and cones transduce light energy from photons into membrane potentials. Photopigments in rods and cones absorb photons, and this causes a conformational change in the molecular structure of these pigments. This molecular alteration causes sodium channels to close, a hyperpolarization of the membranes of the rods and cones, and a reduction in the amount of neurotransmitter released. Thus, rods and cones release less neurotransmitter in the light and more neurotransmitter in the dark.
Clinical Correlate Vitamin A, necessary for retinal transduction, cannot be synthesized by humans. Dietary deficiency of vitamin A causes visual impairment resulting in night blindness.
Rods and cones have synaptic contacts on bipolar cells that project to ganglion cells (Figure III-8-2). Axons from the ganglion cells converge at the optic disc to form the optic nerve, which enters the cranial cavity through the optic foramen. At the optic disc, these axons acquire a myelin sheath from the oligodendrocytes of the central nervous system (CNS).
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Ciliary muscle (CN III parasympathetics)
Clinical Correlate Decreased drainage into the canal of Schlemm is the most common cause Pharmacology of open-angle glaucoma. Biochemistry
Dilator pupillae (sympathetics)
Sclera Choroid
Constrictor pupillae (CN III parasympathetics)
Retina Physiology
Pathology
Medical Genetics
Behavioral Science/Social Sciences
Fovea (in macula) (cones only) Lens
Cornea (V1) Anterior chamber
Optic disc
Iris Posterior chamber (production of aqueous humor)
Vitreous humor Microbiology
Canal of Schlemm (drains aqueous humor) Figure III-8-1. Figure III-8-1. The TheEyeball Eyeball
Open-Angle Glaucoma A chronic condition (often with increased intraocular pressure [IOP]) due to decreased reabsorption of aqueous humor, leading to progressive (painless) visual loss and, if left untreated, blindness. IOP is a balance between fluid formation and its drainage from the globe.
Narrow-Angle Glaucoma An acute (painful) or chronic (genetic) condition with increased IOP due to blockade of the canal of Schlemm. Emergency treatment prior to surgery often involves cholinomimetics, carbonic anhydrase inhibitors, and/or mannitol.
VISUAL REFLEXES Pupillary Light Reflex When light is directed into an eye, it stimulates retinal photoreceptors and results in impulses carried in the optic nerve to the pretectal area. Cells in the pretectal area send axons to the Edinger-Westphal nuclei on both sides. The Edinger-Westphal nucleus is the parasympathetic nucleus of the oculomotor nerve and gives rise to preganglionic parasympathetic fibers that pass in the third cranial nerve to the ciliary ganglion. Because cells in the pretectal area supply both Edinger-Westphal nuclei, shining light into one eye results in constriction of both the ipsilateral pupil (direct light reflex) and contralateral pupil (consensual light reflex).
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Accommodation-Convergence Reaction This reaction occurs when an individual attempts to focus on a nearby object after looking at a distant object. The oculomotor nerve carries the efferent fibers from the accommodation–convergence reaction, which consists of 3 components: accommodation, convergence, and pupillary constriction. Accommodation refers to the reflex that increases the curvature of the lens needed for near vision. Preganglionic parasympathetic fibers arise in the Edinger-Westphal nucleus and pass via the oculomotor nerve to the ciliary ganglion. Postganglionic parasympathetic fibers from the ciliary ganglion supply the ciliary muscle. Contraction of this muscle relaxes the suspensory ligaments and allows the lens to increase its convexity (become more round). This increases the refractive index of the lens, permitting the image of a nearby object to focus on the retina. Convergence results from contraction of both medial rectus muscles, which pull the eyes to look toward the nose. This allows the image of the near object to focus on the same part of the retina in each eye. Pupillary constriction (miosis) results from contraction of the constrictor muscle of the iris. A smaller aperture gives the optic apparatus a greater depth of field. With Argyll Robertson pupils, both direct and consensual light reflexes are lost, but the accommodation–convergence reaction remains intact. This type of pupil is often seen in cases of neurosyphilis; however, it is sometimes seen in patients with multiple sclerosis, pineal tumors, or tabes dorsalis. The lesion site is believed to occur near the pretectal nuclei just rostral to the superior colliculi.
Table III-8-1. Pupillary Light Reflex Pathway Afferent Limb: CN II Pretectal area
EdingerWestphal nucleus Ciliary Ganglion Pupil
Light stimulates ganglion retinal cells → impulses travel up CNII which projects bilaterally to the pretectal nuclei (midbrain) The pretectal nucleus projects bilaterally → Edinger-Westphal nuclei (CN III) Efferent Limb: CN III Edinger-Westphal nucleus (preganglionic parasympathetic) → ciliary ganglion (postganglionic parasympathetic) → pupillary sphincter muscle → miosis
Because cells in the pretectal area supply the Edinger-Westphal nuclei bilaterally, shining light in one eye → constriction in the ipsilateral pupil (direct light reflex) and the contralateral pupil (consensual light reflex). Because this reflex does not involve the visual cortex, a person who is cortically blind can still have this reflex.
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The eye is predominantly innervated by the parasympathetic nervous system. Therefore, application of muscarinic antagonists or ganglionic blockers has a large effect by blocking the parasympathetic nervous system.
Table III-8-2. Pharmacology of the Eye
Physiology
Pathology
Structure
Predominant Receptor
Receptor Stimulation
Receptor Blockade
Pupillary sphincter ms. (iris)
M3 receptor (PANS)
Contraction → miosis
Relaxation → mydriasis
Radial dilator ms. (iris)
α receptor (SANS)
Contraction → mydriasis
Relaxation → miosis
Ciliary ms.
M3 receptor (PANS)
Contraction → accommodation for near vision
Relaxation → focus for far vision
Ciliary body epithelium
β receptor (SANS)
Secretion of aqueous humor
Decreased aqueous humor production
Medical Genetics
Behavioral Science/Social Sciences
Microbiology
Abbreviations: ms., muscle; PANS, parasympathetic nervous system; SANS, sympathetic nervous system
Table III-8-3. Accommodation-Convergence Reaction When an individual focuses on a nearby object after looking at a distant object, 3 events occur: 1. Accommodation 2. Convergence 3. Pupillary constriction (miosis) In general, stimuli from light → visual cortex → superior colliculus and pretectal nucleus → Edinger-Westphal nucleus (1, 3) and oculomotor nucleus (2). Accommodation: Parasympathetic fibers contract the ciliary muscle, which relaxes suspensory ligaments, allowing the lens to increase its convexity (become more round). This increases the refractive index of the lens, thereby focusing a nearby object on the retina. Convergence: Both medial rectus muscles contract, adducting both eyes. Pupillary constriction: Parasympathetic fibers contract the pupillary sphincter muscle → miosis.
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Table III-8-4. Clinical Correlates Pupillary Abnormalities Argyll Robertson pupil (pupillary light-near dissociation)
• N o direct or consensual light reflex; accommodation-convergence intact
Relative afferent (Marcus Gunn) pupil
• L esion of afferent limb of pupillary light reflex; diagnosis made with swinging flashlight
• Seen in neurosyphilis, diabetes
• S hine light in Marcus Gunn pupil → pupils do not constrict fully • S hine light in normal eye → pupils constrict fully • S hine light immediately again in affected eye → apparent dilation of both pupils because stimulus carried through that CN II is weaker; seen in multiple sclerosis Horner syndrome
aused by a lesion of the oculosympathetic • C pathway; syndrome consists of miosis, ptosis, apparent enophthalmos, and hemianhidrosis
Adie pupil
• D ilated pupil that reacts sluggishly to light, but better to accommodation; often seen in women and often associated with loss of knee jerks. Ciliary ganglion lesion
Transtentorial (uncal) herniation
• Increased intracranial pressure → leads to uncal herniation → CN III compression → fixed and dilated pupil, “down-and-out” eye, ptosis
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To lateral geniculate body, pretectal nucleus
Pharmacology
Biochemistry
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
These axons will make up the optic nerve
Choroid
Site of detached retina
Light
Microbiology
Rod Cone Pigment epithelium
Outer nuclear layer
Inner nuclear layer
Nuclei of rods and cones
Bipolar cells
Ganglion layer
Vitreous humor
Figure III-8-2. RetinaRetina Figure III-8-2.
Note Photoreceptor Rods: 1 kind • Achromatic • Low-light sensitive • Night vision, motion Cones: 3 kinds • Red, green, blue • Chromatic
At the optic chiasm, 60% of the optic nerve fibers from the nasal half of each retina cross and project into the contralateral optic tract (Figure III-8-3). Fibers from the temporal retina do not cross at the chiasm and instead pass into the ipsilateral optic tract. The optic tract contains remixed optic nerve fibers from the temporal part of the ipsilateral retina and fibers from the nasal part of the contralateral retina. Because the eye inverts images like a camera, in reality each nasal retina receives information from a temporal hemifield, and each temporal retina receives information from a nasal hemifield. Most fibers in the optic tract project to the lateral geniculate nucleus. Optic tract fibers also project to the superior colliculi for reflex gaze, to the pretectal area for the light reflex, and to the suprachiasmatic nucleus of the hypothalamus for circadian rhythms.
• Bright light sensitive • Object recognition
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Visual Field Defects Visual Fields
Temporal
Nasal
Temporal
Defects
Ganglion cells of retina
Retinae
Anopia of left eye
Left nasal hemianopia
Bitemporal heteronymous hemianopia
1
3
Optic nerve
2
Optic chiasm Optic tract
Red nucleus
4
Substantia nigra Medial lemniscus
Crus cerebri
5
Right homonymous hemianopia
Meyer loop
LGNu MGNu
Right homonymous superior quadrantanopia
SC,Br
Right homonymous inferior quadrantanopia
SC,Br
PULNu
6
MGNu
Optic radiations (in retrolenticular limb of internal capsule)
Right homonymous hemianopia with macular sparing
PULNu
Superior colliculus Pretectal nucleus Edinger-Westphal preganglionic nucleus
Oculomotor nucleus Edinger-Westphal centrally projecting nucleus
Cuneus
Lingual gyrus
7 CalSul
Figure III-8-3. Visual Pathways
III-8-3. Visual Pathways 1, 2 Optic nerve, 3 Figure Chiasm, 4 Tract 1, 2 Optic nerve, 3 Chiasm, 4 Tract
Note Visual information from lower retina courses in lateral fibers forming Meyer’s loop, which projects to the lingual gyrus.
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Clinical Correlate Some Causes of Lesions
Pharmacology
Biochemistry
1. Optic neuritis, central retinal artery occlusion 2. Internal carotid artery aneurysm
Physiology
Medical Genetics
3. Pituitary adenoma (begins as superior quadrantanopia) Craniopharyngioma (begins as inferior quadrantanopia) 4. Vascular 5. Middle cerebral artery (MCA) occlusion
Pathology
Behavioral Science/Social Sciences
Note
Microbiology
Lesions to the visual radiations are more common than lesions to the optic tract.
Notes Like a camera, the lens inverts the image of the visual field, so the nasal retina receives information from the temporal visual field, and the temporal retina receives information from the nasal visual field. At the optic chiasm, optic nerve fibers from the nasal half of each retina cross and project to the contralateral optic tract.
Clinical Correlate Unilateral optic nerve lesions are seen in MS, where there is an immunerelated inflammatory demyelination of the nerve. The lesion typically presents with a central scotoma due to involvement of the deep fibers in the nerve from the macula.
6,7. Posterior cerebral artery occlusion Macula is spared in 7 due to collateral blood supply from MCA.
Most fibers from the optic tract project to the lateral geniculate body (LGB); some also project to the pretectal area (light reflex), the superior colliculi (reflex gaze), and the suprachiasmatic nuclei (circadian rhythm). The LGB projects to the primary visual cortex (striate cortex, Brodmann area 17) of the occipital lobe via the optic radiations. • Visual information from the lower retina (upper contralateral visual
field) → temporal lobe (Meyer loop) → lingual gyrus
• Visual information from the upper retina (lower contralateral visual
field) → parietal lobe → cuneus gyrus
The lateral geniculate body (LGB) is a laminated structure that receives input from the optic tract and gives rise to axons that terminate on cells in the primary visual cortex (striate cortex, Brodmann area 17) of the occipital lobe. The LGB laminae maintain a segregation of inputs from the ipsilateral and contralateral retina. The axons from the LGB that project to the striate cortex are known asoptic radiations, visual radiations, or the geniculocalcarine tract. The calcarine sulcus divides the striate cortex (primary visual cortex or Brodmann area 17) into the cuneus and the lingual gyri. The cuneus gyrus, which lies on the superior bank of the calcarine cortex, receives the medial fibers of the visual radiations. The lingual gyrus, which lies on the inferior bank of the calcarine cortex, receives the lateral fibers of the visual radiation. The medial fibers coursing in the visual radiations, which carry input from the upper retina (i.e., the lower contralateral visual field), pass from the LGB directly through the parietal lobe to reach the cuneus gyrus. Significantly, the lateral fibers coursing in the visual radiations, which carry input from the lower retina (i.e., the upper contralateral visual field), take a circuitous route from the LGB through Meyer loop anteriorly into the temporal lobe. The fibers of Meyer loop then turn posteriorly and course through the parietal lobe to reach the lingual gyrus in the striate cortex.
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LESIONS OF THE VISUAL PATHWAYS Lesions of the retina that include destruction of the macula produce a central scotoma. The macula is quite sensitive to intense light, trauma, aging, and neurotoxins. Lesions of an optic nerve produce blindness (anopsia) in that eye and a loss of the sensory limb of the light reflex. The pupil of the affected eye constricts when light is shined into the opposite eye (consensual light reflex) but not when light is shined into the blinded eye (absence of direct light reflex). Compression of the optic chiasm, often the result of a pituitary tumor or meningioma, results in a loss of peripheral vision in both temporal fields because the crossing fibers from each nasal retina are damaged. The resulting visual field defect is called a bitemporal heteronymous hemianopia. All lesions past the chiasm produce contralateral defects. Lesions of the optic tract result in a loss of visual input from the contralateral visual field. For example, a lesion of the right optic tract results in a loss of input from the left visual field. This is called a homonymous hemianopia; in this example, a left homonymous hemianopia. Lesions of the visual radiations are more common than lesions to the optic tract or lateral geniculate body and produce visual field defects (a contralateral homonymous hemianopia) similar to those of the optic tract if all fibers are involved. Lesions restricted to the lateral fibers in Meyer loop, usually in the temporal lobe, result in a loss of visual input from the contralateral upper quarter of the visual field. For example, a lesion of the temporal fibers in the right visual radiation results in loss of visual input from the upper left quarter of the field (a left superior quadrantanopia). Lesions restricted to the medial fibers in the visual radiation in the parietal lobe result in a loss of visual input from the contralateral lower quarter of the field (an inferior quadrantanopia). Lesions inside the primary visual cortex are equivalent to those of the visual radiations, resulting in a contralateral homonymous hemianopsia, except that macular (central) vision is spared. Lesions of the cuneus gyrus are equivalent to lesions restricted to the parietal fibers of the visual radiation, with macular sparing. Lesions of the lingula are similar to lesions of the Meyer’s loop fibers except for the presence of macular sparing. The pupillary light reflex is spared in lesions of the radiations or inside visual cortex because fibers of the pupillary light r eflex leave the optic tracts to terminate in the pretectal area. The combination of blindness with intact pupillary reflexes is termed cortical blindness.
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Diencephalon
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Learning Objectives ❏❏ Interpret scenarios on thalamus ❏❏ Demonstrate understanding of hypothalamus ❏❏ Use knowledge of epithalamus
DIENCEPHALON The diencephalon can be divided into 4 parts: the thalamus, the hypothalamus, the epithalamus, and the subthalamus. Table III-9-1. Thalamus Thalamus—serves as a major sensory relay for information that ultimately reaches the neocortex. Motor control areas (basal ganglia, cerebellum) also synapse in the thalamus before reaching the cortex. Other nuclei regulate states of consciousness.
Internal medullary lamina AN MD
VA VL
VPL VPM LGB
Pulvinar MGB
Thalamic Nuclei
Input
Output
VPL
Sensory from body and limbs
Somatosensory cortex
VPM
Sensory from face, taste
Somatosensory cortex
VA/VL
Motor info from BG, cerebellum
Motor cortices
LGB
Visual from optic tract
First-degree visual cortex
MGB
Auditory from inferior colliculus
First-degree auditory cortex
AN
Mamillary nucleus (via mammillothalamic tract)
Cingulate gyrus (part of Papez circuit)
MD
(Dorsomedial nucleus). Involved in memory Damaged in Wernicke-Korsakoff syndrome
Figure TB IV-9-1. Diencephalon Pulvinar
Helps integrate somesthetic, visual, and auditory input
Midline/intralaminar
Involved in arousal
Abbreviations: AN, anterior nuclear group; BG, basal ganglia; LGB, lateral geniculate body; MD, mediodorsal nucleus; MGB, medial geniculate body; VA, ventral anterior nucleus; VL, ventral lateral nucleus; VPL, ventroposterolateral nucleus; VPM, ventroposteromedial nucleus
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Clinical Correlate
Thiamine deficiency in alcoholics results in degeneration of the dorsomedial nucleusBehavioral of thalamus and Pathology Science/Social Sciences the mammillary bodies, hippocampus, and vermis of the cerebellum.
Microbiology
Thalamus The thalamus serves as the major sensory relay for the ascending tactile, visual, auditory, and gustatory information that ultimately reaches the neocortex. Motor control areas such as the basal ganglia and cerebellum also synapse in thalamic nuclei before they reach their cortical destinations. Other nuclei participate in the regulation of states of consciousness.
Major Thalamic Nuclei and Their Inputs and Outputs Anterior nuclear group (part of the Papez circuit of limbic system) Input is from the mammillary bodies via the mammillothalamic tract and from the cingulate gyrus; output is to the cingulate gyrus via the anterior limb of the internal capsule.
Medial nuclear group (part of limbic system) Input is from the amygdala, prefrontal cortex, and temporal lobe; output is to the prefrontal cortex and cingulate gyrus. The most important nucleus is the dorsomedial nucleus.
Clinical Correlate
Ventral nuclear group
Thalamic pain syndrome affects the ventral nuclear group. Patients present with burning, aching pain in contralateral limbs or body. Involvement of the dorsal columnmedial lemniscal part of VPL increases the sensitivity to pain and presents as contralateral loss of vibratory sense and gait ataxia. Thalamic pain syndrome is resistant to analgesic medications.
Motor Nuclei Ventral anterior nucleus (VA): Input to VA is from the globus pallidus, substantia nigra. Output is to the premotor and primary motor cortex. Ventral lateral nucleus (VL): Input to VL is mainly from the globus pallidus and the dentate nucleus of the cerebellum. Output is to the primary motor cortex (Brodmann area 4). Sensory Nuclei Ventral posterolateral (VPL) nucleus: Input to VPL conveying somatosensory and nociceptive information ascends in the medial lemniscus and spinothalamic tract. Output is to primary somatosensory cortex (Brodmann areas 3, 1, and 2) of the parietal lobe. Ventral posteromedial (VPM) nucleus: Input to VPM is from the ascending trigeminal and taste pathways. Output is to primary somatosensory cortex (Brodmann areas 3, 1, and 2) of the parietal lobe. Medial geniculate body (nucleus): Input is from auditory information that ascends from the inferior colliculus. Output is to primary auditory cortex. Lateral geniculate body (nucleus): Input is from the optic tract. Output is in the form of the geniculocalcarine or visual radiations that project to the primary visual (striate) cortex in the occipital lobe. Midline and Intralaminar Nuclei Midline and intralaminar nuclei receive input from the brain-stem reticular formation, and from the spinothalamic tract. Intralaminar nuclei send pain information to the cingulate gyrus. These nuclei appear to be important in mediating desynchronization of the EEG during behavioral arousal.
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Hypothalamus The hypothalamus is composed of numerous nuclei that have afferent and efferent connections with widespread regions of the nervous system, including the pituitary gland, the autonomic system, and the limbic system (Figure III-9-1).
Table III-9-2. Hypothalamus, Epithalamus, Subthalamus Hypothalamus— helps maintain homeostasis; has roles in the autonomic, endocrine, and limbic systems Hypothalamic Nuclei
Functions and Lesions
Lateral hypothalamic
Feeding center; lesion → starvation
Ventromedial
Satiety center; lesion → hyperphagia, obesity, savage behavior
Suprachiasmatic
Regulates circadian rhythms, receives direct retinal input
Supraoptic and paraventricular
Synthesizes ADH and oxytocin; regulates water balance
Mamillary body
Input from hippocampus; damaged in Wernicke encephalopathy
Arcuate
Produces hypothalamic releasing and inhibiting factors and gives rise to tuberohypophysial tract
Lesion → diabetes insipidus, characterized by polydipsia and polyuria
Has neurons that produce dopamine (prolactin-inhibiting factor) Anterior region
Temperature regulation; lesion → hyperthermia Stimulates the parasympathetic nervous system
Posterior region
Temperature regulation; lesion → poikilothermia (inability to thermoregulate) Stimulates sympathetic nervous system
Preoptic area
Regulates release of gonotrophic hormones; contains sexually dimorphic nucleus Lesion before puberty → arrested sexual development; lesion after puberty → amenorrhea or impotence
Dorsomedial
Stimulation → savage behavior
Epithalamus— Consists of pineal body and habenular nuclei. The pineal body secretes melatonin with a circadian rhythm. Subthalamus— The subthalamic nucleus is involved in basal ganglia circuitry. Lesion → hemiballismus (contralateral flinging movements of one or both extremities) Abbreviation: ADH, antidiuretic hormone
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Clinical Correlate Dopaminergic projections from the arcuate nuclei inhibit Pharmacology Biochemistry prolactin secretion from the anterior pituitary. Lesions result in galactorrhea (milk discharge) and Physiologyamenorrhea. Medical Genetics
Clinical Correlate Lesions of the mammillary Behavioral Science/Social Sciences bodies occur in Korsakoff syndrome and are usually associated with thiamine deficiency associated with Microbiology chronic alcoholism. Korsakoff syndrome results in both anterograde and retrograde amnesia with confabulations. Pathology
Major Hypothalamic Regions or Zones, and Their Nuclei Paraventricular nucleus
Lamina terminalis Anterior commissure
Dorsomedial nucleus
Preoptic nuclei
A
Anterior hypothalamus (parasympathetic)
M
P
Posterior hypothalamus (sympathetic) Descending hypothalamic fibers
Suprachiasmatic nucleus Supraoptic nucleus
Mammillary body
Optic tract/chiasm
Ventromedial nucleus
Anterior pituitary (adenohypophysis; derived from oral ectoderm of Rathke’s pouch)
Median eminence
Arcuate nucleus Posterior pituitary (neurohypophysis; ophysis; outgrowth of CNS)
Magnocellular neurons in paraventricular and supraoptic nuclei Parvocellular neuron in arcuate nuclei
Releasing and inhibiting hormones
Infundibulum Oxytocin and vasopressin (ADH)
Superior hypophyseal artery
Inferior hypophyseal artery
Hypothalamichypophyseal portal system
Anterior pituitary cells Hypophyseal veins
Drain into cavernous sinus FigureIII-9-1. III-9-1.(A) (A) Organization Organization of Figure of the the Hypothalamus Hypothalamus(Sagittal (SagittalSection) Section) (B) Secretory Mechanisms of the Adenoand Neuro-Hypophysis (B) Secretory Mechanisms of the Adeno- and Neuro-Hypophysis
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Anterior region The paraventricular and supraoptic nuclei synthesize the neuropeptides antidiuretic hormone (ADH) and oxytocin. Axons arising from these nuclei leave the hypothalamus and course in the supraopticohypophysial tract, which carries neurosecretory granules to the posterior pituitary gland, where they are released into capillaries. Lesions of the supraoptic nuclei lead to diabetes insipidus, which is characterized by polydipsia (excess water consumption) and polyuria (excess urination). Visual input from the retina by way of the optic tract terminates in the suprachiasmatic nucleus. This information helps set certain body rhythms to the 24-hour light-dark cycle (circadian rhythms).
Paraventricular nucleus
Posterior nucleus
Dorsomedial nucleus
Thalamus
Preoptic area Anterior nucleus Pineal gland
Suprachiasmatic nucleus Supraoptic nucleus
Midbrain
Optic chiasm
Cerebral aqueduct
Arcuate nucleus
Pons
Infundibulum Hypophysis
Ventromedial nucleus
Mammillary body
Figure III-9-2. The Hypothalamic Nuclei Figure III-9-2. The Hypothalamic Nuclei
Tuberal region Cells in the arcuate nucleus produce releasing hormones and inhibitory factors, which enter capillaries in the tuberoinfundibular tract and pass through the hypophyseal-portal veins to reach the secondary capillary plexus in the anterior pituitary gland. Releasing hormones and inhibitory factors influence the secretory activity of the acidophils and basophils in the anterior pituitary. (See Histology section.)
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The ventromedial hypothalamus is a satiety center and regulates food intake. Lesions of the ventromedial hypothalamus result in obesity.
Posterior region The mammillary nuclei are located in the mammillary bodies and are part of the limbic system. The mammillothalamic tract originates in the mammillary nuclei and terminates in the anterior nuclear group of the thalamus.
Physiology
Medical Genetics
Anterior hypothalamic zone Pathology
Behavioral Science/Social Sciences
The anterior hypothalamic zone senses an elevation of body temperature and mediates the response to dissipate heat. Lesions of the anterior hypothalamus lead to hyperthermia.
Posterior hypothalamic zone Microbiology
The posterior hypothalamic zone senses a decrease of body temperature and mediates the conservation of heat. Lesions of the posterior hypothalamus lead to poikilothermy (i.e., cold-blooded organisms). An individual with a lesion of the posterior hypothalamus has a body temperature that varies with the environmental temperature.
Lateral hypothalamic zone The lateral hypothalamic zone is a feeding center; lesions of the lateral hypothalamus produce severe aphagia.
Preoptic area The preoptic area is sensitive to androgens and estrogens, whereas other areas influence the production of sex hormones through their regulation of the anterior pituitary. Before puberty, hypothalamic lesions here may arrest sexual development. After puberty, hypothalamic lesions in this area may result in amenorrhea or impotence.
Clinical Correlate
EPITHALAMUS
• In young males, pineal lesions may cause precocious puberty.
The epithalamus is the part of the diencephalon located in the region of the posterior commissure which consists of the pineal body and the habenular nuclei.
• Pineal tumors may cause obstruction of CSF flow and increased intracranial pressure. Compression of the upper midbrain and pretectal area by a pineal tumor results in Parinaud syndrome, in which there is impairment of conjugate vertical gaze and pupillary reflex abnormalities.
• The pineal body is a small, highly vascularized structure situated above
the posterior commissure and attached by a stalk to the roof of the third ventricle. It contains pinealocytes and glial cells but no neurons. Pinealocytes synthesize melatonin, serotonin, and cholecystokinin.
• The pineal gland plays a role in growth, development, and the regula-
tion of circadian rhythms.
• Environmental light regulates the activity of the pineal gland through a
retinal–suprachiasmatic– pineal pathway.
• The subthalamus is reviewed with the basal ganglia.
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Cerebral Cortex
10
Learning Objectives ❏❏ Answer questions about general features ❏❏ Solve problems concerning language and the dominant hemisphere ❏❏ Solve problems concerning blood supply
GENERAL FEATURES The surface of the cerebral cortex is highly convoluted with the bulges or eminences, referred to as gyri; and the spaces separating the gyri, called sulci. Lobes of the cerebrum are divided according to prominent gyri and sulci that are fairly constant in humans. Two prominent sulci on the lateral surface are key to understanding the divisions of the hemispheres. The lateral fissure (of Sylvius) separates the frontal and temporal lobes rostrally; further posteriorly, it partially separates the parietal and the temporal lobes. The central sulcus (of Rolando) is situated roughly perpendicular to the lateral fissure. The central sulcus separates the frontal and the parietal lobes. The occipital lobe extends posteriorly from the temporal and parietal lobes, but its boundaries on the lateral aspect of the hemisphere are indistinct. On the medial aspect of the hemisphere, the frontal and parietal lobes are separated by a cingulate sulcus from the cingulate gyrus. The cingulate is part of an artificial limbic lobe. Posteriorly, the parieto-occipital sulcus separates the parietal lobe from the occipital lobe. The calcarine sulcus divides the occipital lobe horizontally into a superior cuneus and an inferior lingual gyrus.
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F: frontal lobe
Postcentral gyrus
P: parietal lobe Pharmacology
Superior parietal lobule
T: temporal lobe
Biochemistry
Supramarginal Medical Genetics gyrus
Physiology
Pathology
P
Inferior parietal lobule
O: occipital lobe
O
F
T
Behavioral Science/Social Sciences
Cerebellum
Central sulcus Precentral gyrus Superior frontal gyrus Middle frontal gyrus Inferior frontal gyrus Lateral sulcus Superior temporal gyrus Middle temporal gyrus Inferior temporal gyrus Pons Medulla oblongata
F: frontal lobe P: parietal lobe T: temporal lobe O: occipital lobe
Microbiology
FigureIII-10-1. III-10-1.Lateral Lateral View View of Figure of the the Right RightCerebral CerebralHemisphere Hemisphere Fornix Interthalamic adhesion
Cingulate sulcus
Precentral gyrus Central sulcus Cingulate gyrus
Septum pellucidum Interventricular foramen
Postcentral gyrus Corpus callosum
Anterior commissure
Thalamus
Third ventricle
Splenium
Lamina terminalis
Parieto-occipital sulcus
Hypothalamus
Cuneus gyrus
Optic chiasm Tuber cinereum Pituitary Mammillary body Pons
Calcarine sulcus Lingual gyrus Pineal body Cerebellum Cerebral aqueduct Fourth ventricle Figure III-10-2. Medial View of the Right Cerebral Hemisphere Figure III-10-2. Medial View of the Right Cerebral Hemisphere
About 90% of the cortex is composed of 6 layers, which form the neocortex (Figure III-10-5). The olfactory cortex and hippocampal formation are 3-layered structures and together comprise the allocortex. All of the neocortex contains
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a 6-layer cellular arrangement, but the actual structure varies considerably between different locations. On the basis of these variations in the cytoarchitecture, Brodmann divided the cortex into 47 areas, but only a few Brodmann numbers are used synonymously with functionally specific cortical areas.
MCA M E D I A L
L A T E R A L
ACA
Figure III-10-3. Motor Homunculus Precentral Gyrus (Area 4) Frontal Lobe Figure III-10-3. Motor in Homunculus in Precentral (Coronal Section) Gyrus (Area 4) Frontal Lobe (Coronal Section)
ACA
MCA
Figure III-10-4. Sensory Homunculus in Postcentral Gyrus (Areas 3, 1, 2) Figure III-10-4. Sensory Homunculus in Postcentral Parietal Lobe (Coronal Section) Gyrus (Areas 3, 1, 2) Parietal Lobe (Coronal Section)
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Efferent cortical fibers
Note The internal granular layer is the site of termination of the thalamocortical Pharmacology Biochemistry projections. In primary visual cortex, these fibers form a distinct Line of Gennari. The internal pyramidal layer gives rise to axons that form the tracts. Physiologycorticospinal and corticobulbar Medical Genetics
Pathology
Behavioral Science/Social Sciences
I. II. III.
IV.
Afferent cortical fibers
Molecular layer External granular layer External pyramidal layer
Internal granular layer
V. Internal pyramidal layer Microbiology
VI.
Multiform layer (layer of polymorphic cells)
Figure III-10-5. The Six-Layered Neocortex
Figure III-10-5. The 6-Layered Neocortex
LANGUAGE AND THE DOMINANT HEMISPHERE Most people (about 80%) are right-handed, which implies that the left side of the ajority brain has more highly developed hand-controlling circuits. In the vast m of right-handed people, speech and language functions are also predominantly organized in the left hemisphere. Most left-handed people show language functions bilaterally, although a few, with strong left-handed preferences, show right-sided speech and language functions.
BLOOD SUPPLY The cortex is supplied by the 2 internal carotid arteries and the 2 vertebral arteries (Figures III-10-6 and III-10-7). On the base (or inferior surface) of the brain, branches of the internal carotid arteries and the basilar artery anastomose to form the circle of Willis. The anterior part of the circle lies in front of the optic chiasm, whereas the posterior part is situated just below the mammillary bodies. The circle of Willis is formed by the terminal part of the internal carotid arteries; the proximal parts of the anterior and posterior cerebral arteries and the anterior and posterior communicating arteries. The middle, anterior, and posterior cerebral arteries, which arise from the circle of Willis, supply all of the cerebral cortex, basal ganglia, and diencephalon. The internal carotid artery arises from the bifurcation of the common carotid and enters the skull through the carotid canal. It enters the subarachnoid space and terminates by dividing into the anterior and middle cerebral arteries.
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Just before splitting into the middle and anterior cerebral arteries, the internal carotid artery gives rise to the ophthalmic artery. The ophthalmic artery enters the orbit through the optic canal and supplies the eye, including the retina and optic nerve. The middle cerebral artery is the larger terminal branch of the internal carotid artery. It supplies the bulk of the lateral surface of the hemisphere. Exceptions are the superior inch of the frontal and parietal lobes, which are supplied by the anterior cerebral artery, and the inferior part of the temporal lobe and the occipital pole, which are supplied by the posterior cerebral artery. The middle cerebral artery also supplies the genu and posterior limb of the internal capsule and the basal ganglia.
Superior parietal lobule
Posterior cerebral artery
Anterior cerebral artery Superior frontal gyrus Frontal pole Middle cerebral artery Temporal pole
Inferior temporal gyrus
Figure of the the Cerebral CerebralArteries: Arteries:Part Part1 1 FigureIII-10-6. III-10-6.The The Distributions Distributions of
The anterior cerebral artery is the smaller terminal branch of the internal c arotid artery. It is connected to the opposite anterior cerebral artery by the anterior communicating artery, completing the anterior part of the circle of Willis. The anterior cerebral artery supplies the medial surface of the frontal and parietal lobes, which include motor and sensory cortical areas for the pelvis and lower limbs. The anterior cerebral artery also supplies the anterior four-fifths of the corpus callosum and approximately 1 inch of the frontal and parietal cortex on the superior aspect of the lateral aspect of the hemisphere. Occlusion of the anterior cerebral artery results in spastic paresis of the contralateral lower limb and anesthesia of the contralateral lower limb. U rinary incontinence may be present, but this usually occurs only with bilateral d amage. A transcortical apraxia of the left limbs may result from involvement of the ecause anterior portion of the corpus callosum. A transcortical apraxia occurs b the left hemisphere (language dominant) has been disconnected from the motor cortex of the right hemisphere. The anterior cerebral artery also supplies the anterior limb of the internal capsule.
Clinical Correlate Occlusion of the middle cerebral artery results in spastic paresis of the contralateral lower face and upper limb and anesthesia of the contralateral face and upper limb. An aphasia (e.g., Broca, Wernicke, or conduction) may result when branches of the left middle cerebral artery are affected, and left-sided neglect may be seen with a blockage of branches of the right middle cerebral artery to the right parietal lobe. The middle cerebral artery also supplies the proximal parts of the visual radiations as they emerge from the lateral geniculate nucleus of the thalamus and course in Meyer’s loop. These fibers course into the temporal lobe before looping posteriorly to rejoin the rest of the visual radiation fibers. Occlusion of the branches that supply Meyer’s loop fibers in the temporal lobe results in a contralateral superior quadrantanopsia.
Note The middle cerebral artery (MCA) supplies: • t he lateral surface of the frontal, parietal, and upper temporal lobes • t he posterior limb and genu of the internal capsule • m ost of the basal ganglia
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Pericallosal artery
Note The anterior cerebral artery Pharmacology (ACA) supplies medial surface of frontal and parietal lobes; anterior 4/5 Physiologyof corpus callosum; anterior limb of internal capsule The posterior Pathologycerebral artery (PCA) supplies occipital lobe; lower temporal lobe; splenium; Microbiology midbrain
Splenium
Callosomarginal artery Corpus callosum
Biochemistry
Posterior cerebral artery
Frontal pole
Medical Genetics
Cuneus Superior cerebellar artery
Behavioral Science/Social Sciences
Anterior inferior cerebellar artery
The most common aneurysm site in the circle of Willis is where the anterior communicating artery joins an Middle cerebral anterior cerebral artery.
Anterior cerebral artery Inferior temporal gyrus Basilar artery
Posterior inferior cerebellar artery
Clinical Correlate
Orbital artery
Vertebral artery Internal carotid artery
Figure III-10-7. The The Distributions of theofCerebral Arteries: Part 2 Part 2 Figure III-10-7. Distributions the Cerebral Arteries:
Superior cerebellar (lateral pons)
Circle of Willis Anterior communicating Anterior cerebral Internal carotid Posterior communicating Posterior cerebral (medial midbrain)
Basilar Paramedian (medial pons)
Vertebral
Anterior inferior cerebellar (lateral pons) Anterior spinal (medial medulla)
Posterior inferior cerebellar (lateral medulla) III-10-8. Arterial Supply the Brain FigureFigure III-10-8. Arterial Supply of theof Brain
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Middle Cerebral Artery Internal Carotid Artery Figure III-10-9. Anteroposterior View of Left Internal Carotid Figure III-10-9. Anteroposterior View of Left Internal Carotid
Lateral view - Left Wernicke area Broca area
Lateral view - Right
Calculation finger recognition
Spatial perception
Angular gyrus
Medial view
Inferior view
Splenium of corpus callosum
Anterior cerebral artery
Posterior cerebral artery
Middle cerebral artery
FigureIII-10-10. III-10-10.Territories TerritoriesSupplied Supplied by by the Figure the Cerebral CerebralArteries Arteries
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The posterior cerebral artery is formed by the terminal bifurcation of the basilar artery. The posterior communicating artery arises near the termination of the internal carotid artery and passes posteriorly to join the posterior cerebral artery. The posterior communicating arteries complete the circle of Willis by joining the vertebrobasilar and carotid circulations. The posterior cerebral artery supplies the occipital and temporal cortex on the inferior and lateral surfaces of the hemisphere, the occipital lobe and posterior 2/3 of the temporal lobe on the medial surface of the hemisphere, and the thalamus and subthalamic nucleus. Occlusion of the posterior cerebral artery results in a homonymous hemianopia of the contralateral visual field with macular sparing.
Behavioral Science/Social Sciences
Table III-10-1. Cerebrovascular Disorders Disorder
Types
Key Concepts
Cerebral infarcts
Thrombotic
Anemic/pale infarct; usually atherosclerotic complication
Embolic
Hemorrhagic/red infarct; from heart or atherosclerotic plaques; middle cerebral artery most vulnerable to emboli
Hypotension
“Watershed” areas and deep cortical layers most affected
Hypertension
Lacunar infarcts; basal ganglia, internal capsule, and pons most affected
Epidural hematoma
Almost always traumatic
Hemorrhages
Rupture of middle meningeal artery after skull fracture Lucid interval before loss of consciousness (“talk and die” syndrome)
Subdural hematoma
Usually caused by trauma
Subarachnoid hemorrhage
Ruptured berry aneurysm is most frequent cause
Intracerebral hemorrhage
Common causes: hypertension, trauma, infarction
Rupture of bridging veins (drain brain to dural sinuses)
Predisposing factors: Marfan syndrome, Ehlers-Danlos type 4, adult polycystic kidney disease, hypertension, smoking
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Chapter 10 Voluntary contralateral horizontal gaze
Premotor Primary motor cortex cortex (area 4) Frontal eye field (area 6) (area 8)
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Central sulcus (Rolando) Primary somatosensory cortex (areas 3,1,2) Somatosensory association cortex Visual association cortex
Broca’s area (areas 44 & 45)
Primary visual cortex
Lateral sulcus (Sylvius)
Angular gyrus (area 39)
Primary auditory cortex (areas 41 & 42)
Wernicke’s area (area 22)
Figure III-10-11. Cerebral Cortex: Areas of Hemisphere Figure III-10-11. Cerebral Cortex: Functional AreasFunctional of Left (Dominant) Left (Dominant) Hemisphere
Frontal Lobe A large part of the frontal cortex rostral to the central sulcus is related to the control of movements, primarily on the opposite side of the body. These areas include primary motor cortex (Brodmann area 4), premotor cortex (area 6), the frontal eye field (area 8), and the motor speech areas of Broca (area 44 and 45). Traditionally, area 4 is considered the primary motor cortex. It is in the precentral gyrus, immediately anterior to the central sulcus, and contains an orderly skeletal motor map of the contralateral side of the body. The muscles of the head are represented most ventrally closest to the lateral fissure; then, proceeding dorsally, are the regions for the neck, upper limb, and trunk on the lateral aspect of the hemisphere. On the medial aspect of the hemisphere is the motor representation for the pelvis and lower limb.
Premotor cortex Just anterior to area 4 is the premotor cortex (area 6). Neurons here are particularly active prior to the activation of area 4 neurons, so it is thought that the premotor cortex is involved in the planning of motor activities. Damage here results in an apraxia, a disruption of the patterning and execution of learned motor movements. Individual movements are intact, and there is no weakness, but the patient is unable to perform movements in the correct sequence.
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Clinical Correlate Lesion of the Frontal Eye Field The frontal eye field lies in front of Biochemistry the motor cortex in Brodmann area 8. This cortical area is the center for contralateral horizontal gaze. A lesion here results in an inability to make Physiology Genetics voluntary eye movementsMedical toward the contralateral side. Because the activity of the intact frontal eye field in the opposite cortex would also be Pathologyunopposed after such Behavioral Science/Social Sciences a lesion, the result is conjugate slow deviation of the eyes toward the side of the lesion.
Pharmacology
If motor cortex is involved in the lesion, the patient may have a contralateral spastic paresis. The intact frontal eye field in the opposite hemisphere deviates the eyes away from the paralyzed limbs.
Microbiology
Prefrontal cortex The prefrontal cortex is located in front of the premotor area and represents about a quarter of the entire cerebral cortex in the human brain. This area is involved in organizing and planning the intellectual and emotional aspects of behavior, much as the adjacent premotor cortex is involved in planning its motor aspects.
Clinical Correlate Lesions in the Prefrontal Area Lesions in the prefrontal area produce what is called the frontal lobe syndrome. The patient cannot concentrate and is easily distracted; there is a general lack of initiative, foresight, and perspective. Another common aspect is apathy (i.e., severe emotional indifference). Apathy is usually associated with abulia, a slowing of intellectual faculties, slow speech, and decreased participation in social interactions. Prefrontal lesions also result in the emergence of infantile suckling or grasp reflexes that are suppressed in adults. In the suckling reflex, touching the cheek causes the head to turn toward the side of the stimulus as the mouth searches for a nipple to suckle. In the grasp reflex, touching the palm of the hand results in a reflex closing of the fingers, which allows an infant to grasp anything that touches the hand.
Clinical Correlate Expressive Aphasia Broca area is just anterior to the motor cortex region that provides upper motoneuron innervation of cranial nerve motor nuclei. This area in the left or dominant hemisphere is the center for motor speech and corresponds to Brodmann areas 44 and 45. Damage to Broca area produces a motor, nonfluent, or expressive aphasia that reflects a difficulty in piecing together words to produce expressive speech. Patients with this lesion can understand written and spoken language but normally say almost nothing. When pressed on a question such as “What did you do today?” they might reply “Went town.” The ability to write is usually also affected in a similar way (agraphia) in all aphasias, although the hand used for writing can be used normally in all other tasks. Patients are keenly aware of and frustrated by an expressive aphasia, because of their lack of the ability to verbalize their thoughts orally or in writing. Broca area damage often extends posteriorly into the primary motor cortex and might be combined with a contralateral paralysis of the muscles of the lower face, resulting in a drooping of the corner of the mouth. If the lesion is larger, the patient might have a spastic hemiparesis of the contralateral upper limb.
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Parietal Lobe Primary somatosensory cortex The parietal lobe begins just posterior to the central sulcus with the postcentral gyrus. The postcentral gyrus corresponds to Brodmann areas 3, 1, and 2 and contains primary somatosensory cortex. Like primary motor cortex, there is a similar somatotopic representation of the body here, with head, neck, u pper limb, and trunk represented on the lateral aspect of the hemisphere, and pelvis and lower limb represented medially. These areas are concerned with discriminative touch, vibration, position sense, pain, and temperature. Lesions in somatosensory cortex result in impairment of all somatic sensations on the opposite side of the body, including the face and scalp.
Posterior parietal association cortex Just posterior and ventral to the somatosensory areas is the posterior parietal association cortex, including Brodmann areas 5 and 7.
Clinical Correlate Lesions, usually in the dominant hemisphere and which include areas 5 and 7 of the posterior parietal association areas, often result in apraxia (also seen with lesions to the premotor cortex). Apraxia is a disruption of the patterning and execution of learned motor movements. This deficit seems to reflect a lack of understanding how to organize the performance of a pattern of movements (i.e., what should be done first, then next, etc.). The patient may be unable, for example, to draw a simple diagram (constructional apraxia) or describe how to get from his home to his work. Another deficit, with lesions of areas 5 and 7 is astereognosia (inability to recognize objects by touch). There is no loss of tactile or proprioceptive sensation; rather, it is the integration of visual and somatosensory information that is impaired. Both apraxia and astereognosia are more common after left hemisphere damage than in right hemisphere damage. The astereognosia is usually confined to the contralateral side of the body; in contrast, apraxia is usually bilateral. Apraxia is probably a result of the loss of input to the premotor cortex (area 6), which is involved in the actual organization of motor movements into a goal-directed pattern.
Wernicke area The inferior part of the parietal lobe and adjacent part of the temporal lobe in the dominant (left) hemisphere, known as Wernicke area, are cortical regions that function in language comprehension. At a minimum, Wernicke area consists of area 22 in the temporal lobe but may also include areas 39 and 40 in the parietal lobe. Areas 39 (the angular gyrus) and 40 (the supramarginal gyrus) are regions of convergence of visual, auditory, and somatosensory information.
Note Any blockage of the left middle cerebral artery that results in an aphasia (Broca Wernicke, conduction) or Gerstmann syndrome will also result in agraphia.
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Clinical Correlate Receptive Aphasia Pharmacology
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Physiology
Medical Genetics
Lesions in area 22 in the temporal lobe and area 39 or 40 in the parietal lobe produce a fluent, receptive, or Wernicke aphasia. The patient with Wernicke aphasia cannot comprehend spoken language and may or may not be able to read (alexia) depending on the extent of the lesion. The deficit is characterized by fluent verbalization but lacks meaning. Patients are paraphasic, often misusing words as if speaking using a “word salad.” Patients with Wernicke aphasia are generally unaware of their deficit and show no distress as a result of their condition.
Pathology
Microbiology
Behavioral Science/Social Sciences
Gerstmann Syndrome If the lesion is confined to just the angular gyrus (area 39), the result is a loss of ability to comprehend written language (alexia) and to write it (agraphia), but spoken language may be understood. Alexia with agraphia in pure angular gyrus lesions is often seen with 3 other unique symptoms: acalculia (loss of the ability to perform simple arithmetic problems), finger agnosia (inability to recognize one’s fingers), and right– left disorientation. This constellation of deficits constitutes Gerstmann syndrome and underscores the role of this cortical area in the integration of how children begin to count, add, and subtract using their fingers.
Conduction Aphasia There is a large fiber bundle connecting areas 22, 39, and 40 with Broca area in the frontal lobe, known as the superior longitudinal fasciculus (or the arcuate fasciculus). A lesion affecting this fiber bundle results in a conduction aphasia. In this patient, verbal output is fluent, but there are many paraphrases and word-finding pauses. Both verbal and visual language comprehension are also normal, but if asked to, the patient cannot repeat words or execute verbal commands by an examiner (such as “Count backwards beginning at 100”) and also demonstrates poor object naming. This is an example of a disconnect syndrome in which the deficit represents an inability to send information from one cortical area to another. As with an expressive aphasia, these patients are aware of the deficit and are frustrated by their inability to execute a verbal command that they fully understand.
Transcortical Apraxia Lesions to the corpus callosum caused by an infarct of the anterior cerebral artery may result in another type of disconnect syndrome known as a transcortical apraxia. As in other cases of apraxia, there is no motor weakness, but the patient cannot execute a command to move the left arm. They understand the command, which is perceived in the Wernicke area of the left hemisphere, but the callosal lesion disconnects the Wernicke area from the right primary motor cortex so that the command cannot be executed. The patient is still able to execute a command to move the right arm because Wernicke area in the left hemisphere is able to communicate with the left primary motor cortex without using the corpus callosum.
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Asomatognosia The integration of visual and somatosensory information is important for the formation of the “body image” and awareness of the body and its position in space. Widespread lesions in areas 7, 39, and 40 in the nondominant right parietal lobe may result in unawareness or neglect of the contralateral half of the body, known as asomatognosia. Although somatic sensation is intact, the patients ignore half of their body and may fail to dress, undress, or wash the affected (left) side. Patients will have no visual field deficits, so they can see, but deny the existence of things in the left visual field. Asking them to bisect a horizontal line produces a point well to the right of true center. If asked to draw a clock face from memory, they will draw only the numbers on the right side, ignoring those on the left. Patients may deny that the left arm or leg belongs to them when the affected limb is passively brought into their field of vision. Patients may also deny their deficit, an anosognosia.
Occipital Lobe The occipital lobe is essential for the reception and recognition of visual stimuli and contains primary visual and visual association cortex.
Visual cortex The visual cortex is divided into striate (area 17) and extrastriate (areas 18 and 19). Area 17, also referred to as the primary visual cortex, lies on the medial portion of the occipital lobe on either side of the calcarine sulcus. Its major thalamic input is from the lateral geniculate nucleus. Some input fibers are gathered in a thick bundle that can be visible on the cut surface of the gross brain, called the line of Gennari. The retinal surface (and therefore the visual field) is represented in an orderly manner on the surface of area 17, such that damage to a discrete part of area 17 will produce a scotoma (i.e., a blind spot) in the corresponding portion of the visual field. A unilateral lesion inside area 17 results in a contralateral homonymous hemianopsia with macular sparing, usually caused by an infarct of a branch of the posterior cerebral artery. The area of the macula of the retina containing the fovea is spared because of a dual blood supply from both the posterior and middle cerebral arteries. The actual cortical area serving the macula is represented in the most posterior part of the occipital lobe. Blows to the back of the head or a blockage in occipital branches of the middle cerebral artery that supply this area may produce loss of macular representation of the visual fields. Bilateral visual cortex lesions result in cortical blindness; the patient cannot see, but pupillary reflexes are intact.
Visual association cortex Anterior to the primary visual or striate cortex are extensive areas of visual association cortex. Visual association cortex is distributed throughout the entire occipital lobe and in the posterior parts of the parietal and temporal lobes. These regions receive fibers from the striate cortex and integrate complex visual input from both hemispheres. From the retina to the visual association cortex, information about form and color, versus motion, depth and spatial information are processed separately. Form and color information is processed by the parvocellular-blob system. This “cone stream” originates mainly in the central part of the retina, relays through separate layers of the lateral geniculate, and projects to blob zones of primary visual cortex.
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Blob zones project to the inferior part of the temporal lobe in areas 20 and 21. Unilateral lesions here result in achromatopsia, a complete loss of color vision in the contralateral hemifields. Patients see everything in shades of gray. Additionally, these patients may also present with prosopagnosia, an inability to recognize faces. Motion and depth are processed by the magnocellular system. This “rod stream” originates in the peripheral part of the retina, relays through separate layers of the lateral geniculate, and projects to thick stripe zones of primary visual cortex. Striped areas project through the middle temporal lobe to the parietal lobe in areas 18 and 19. Lesions here result in a deficit in perceiving visual motion; visual fields, color vision, and reading are unaffected.
Clinical Correlate Microbiology
Visual Agnosia Damage to parts of the temporal lobes involving the cone stream produces a visual agnosia. Visual agnosia is the inability to recognize visual patterns (including objects) in the absence of a visual field deficit. For example, you might show a patient with an object agnosia a pair of glasses, and the patient would describe them as 2 circles and a bar. Lesions in areas 20 and 21 of the temporal lobe that also include some destruction of adjacent occipital lobe in either hemisphere result in prosopagnosia, a specific inability to recognize faces. The patient can usually read and name objects. The deficiency is an inability to form associations between faces and identities. On hearing the voice of the same person, the patient can immediately identify the person.
Alexia Without Agraphia A principal “higher-order” deficit associated with occipital lobe damage is alexia without agraphia (or pure word blindness). The patients are unable to read at all and, curiously, often have a color anomia (inability to name colors). However, they are able to write. This is another example of a disconnect syndrome in which information from the occipital lobe is not available to the parietal or frontal lobes to either understand or express what has been seen. (Recall that alexia with agraphia—inability to read or write—occurs with lesions encompassing the angular gyrus in the dominant parietal lobe.) The cause of the syndrome is usually an infarction of the left posterior cerebral artery that affects not only the anterior part of the occipital lobe but the splenium of the corpus callosum. Involvement of the left occipital cortex results in a right homonymous hemianopsia with macular sparing. Involvement of the splenium of the corpus callosum prevents visual information from the intact right occipital cortex from reaching language comprehension centers in the left hemisphere. Patients can see words in the left visual field but do not understand what the words mean.
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Temporal Lobe Primary auditory cortex On its superior and lateral aspect, the temporal lobe contains the primary auditory cortex. Auditory cortex (areas 41 and 42) is located on the 2 transverse gyri of Heschl, which cross the superior temporal lobe deep within the lateral sulcus. Much of the remaining superior temporal gyrus is occupied by area 22 (auditory association cortex), which receives a considerable projection from both areas 41 and 42 and projects widely to both parietal and occipital cortices. Patients with unilateral damage to the primary auditory cortex show little loss of auditory sensitivity but have some difficulty in localizing sounds in the contralateral sound field. Area 22 is a component of Wernicke area in the dominant hemisphere, and lesions here produce a Wernicke aphasia.
Corpus callosum Lateral ventricle
Anterior limb
Internal capsule
Genu
Third ventricle
Posterior limb Optic radiations
Figure III-10-12. Internal Capsule: Capsule: Arterial ArterialSupply Supply Figure III-10-12. Internal
Table III-10-2. Internal Capsule: Arterial Supply Internal Capsule
Arterial Supply
Tracts
Anterior limb
Medial striate br. of ACA
Thalamocortical
Genu
Lenticulostriate br. of MCA
Corticobulbar
Posterior limb
Lenticulostriate br. of MCA
Corticospinal, all somatosensory thalamocortical projections
Note: The posterior cerebral artery also supplies the optic radiations. Abbreviations: ACA, anterior cerebral artery; MCA, middle cerebral artery
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Alexia Without Agraphia
Resulting from occlusion of the anterior cerebral artery
Resulting from occlusion of the left posterior cerebral artery Language area in communication with the motor cortex (both sides)
3. Left arm cannot be moved in response to the verbal command
Microbiology
Left motor cortex Wernicke area and angular gyrus
Right motor cortex
1. Verbal command to move the left arm interpreted here
Corpus callosum
Left visual cortex (lesion)—cannot process any visual information
2. Right motor cortex is disconnected from the left cortex by the lesion in the corpus callosum Anterior cerebral artery
Right visual cortex Visual information from right visual cortex blocked by lesion—cannot get to language area Result: Alexia
Posterior cerebral artery
Figure III-10-13.Disconnect DisconnectSyndromes Syndromes Figure III-10-13.
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Table III-10-3. CNS Blood Supply and Stroke-related Deficits System
Primary Arteries
Branches
Supplies
Deficits after Stroke
Vertebrobasilar (posterior circulation)
Vertebral arteries
Anterior spinal artery
Anterior two-thirds of spinal cord
Dorsal columns spared; all else bilateral
Posterior inferior cerebellar (PICA)
Dorsolateral medulla
See Brain-Stem Lesions in Chapter IV-5.
Pontine arteries
Base of pons
Anterior inferior cerebellar artery (AICA)
Inferior cerebellum, cerebellar nuclei
Superior cerebellar artery
Dorsal cerebellar hemispheres; superior cerebellar peduncle
Labyrinthine artery (sometimes arises from AICA)
Inner ear
Posterior cerebral arteries
—
Midbrain, thalamus, occipital lobe
Ophthalmic artery
Central artery of retina
Retina
Blindness
Posterior communicating artery
—
—
Second most common aneurysm site (often with CN III palsy)
Anterior cerebral artery
—
Primary motor and sensory cortex (leg/foot)
Contralateral spastic paralysis and anesthesia of lower limb
Basilar artery
Internal carotid (anterior circulation)
Contralateral hemianopia with macular sparing Alexia without agraphia*
Frontal lobe abnormalities Anterior communicating artery
—
—
Most common site of aneurysm
Middle cerebral artery
Outer cortical
Lateral convexity of hemispheres
Lenticulostriate
Internal capsule, caudate, putamen, globus pallidus
Contralateral spastic paralysis and anesthesia of upper limb/face Gaze palsy Aphasia* Gerstmann syndrome* Hemi inattention and neglect of contralateral body†
*If dominant hemisphere is affected (usually the left) †Right parietal lobe lesion
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Table III-10-4. Key Features of Lobes Lobes
Important Regions
Deficit After Lesion
Frontal
Primary motor and Biochemistry premotor cortex
Contralateral spastic paresis (region depends on area of homunculus affected), premotor: apraxia
Frontal eye fields
Eyes deviate to ipsilateral side
Broca speech area*
Broca aphasia (expressive, nonfluent aphasia): patient can understand written and spoken language, but speech and writing are slow and effortful; patients are aware of their problem; often associated with right arm weakness and right lower face weakness.
Pharmacology
(Areas 44, 45)
Physiology
Medical Genetics
Prefrontal cortex Pathology
Behavioral Science/Social Sciences
Parietal
Microbiology
Primary somatosensory cortex
Contralateral hemihypesthesia (region depends on area of homunculus affected)
Superior parietal lobule
Contralateral astereognosis/apraxia
Inferior parietal lobule
Gerstmann syndrome (if dominant hemisphere): right/left confusion, alexia, dyscalculia and dysgraphia, finger agnosia, contralateral hemianopia or lower quadrantanopia; unilateral neglect (nondominant)
(Angular gyrus; Area 39) Temporal
Occipital
Frontal lobe syndrome: symptoms can include poor judgment, difficulty concentrating and problem solving, apathy, inappropriate social behavior
Primary auditory cortex
Bilateral damage → deafness
Wernicke area* (Area 22)
Wernicke aphasia (receptive, fluent aphasia): patient cannot understand any form of language; speech is fast and fluent, but not comprehensible
Hippocampus
Bilateral lesions lead to inability to consolidate short-term to long-term memory
Amygdala
Klüver-Bucy syndrome: hyperphagia, hypersexuality, visual agnosia
Olfactory bulb, tract, primary cortex
Ipsilateral anosmia
Meyer loop (visual radiations)
Contralateral upper quadrantanopia (“pie in the sky”)
Primary visual cortex
Cortical blindness if bilateral; macular sparing hemianopia
Unilateral leads to slight hearing loss
*In the dominant hemisphere. Eighty percent of people are left-hemisphere dominant.
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Limbic System
11
Learning Objectives ❏❏ Solve problems concerning general features ❏❏ Solve problems concerning olfactory system ❏❏ Demonstrate understanding of limbic system
FUNCTIONS OF THE LIMBIC SYSTEM The limbic system is involved in emotion, memory, attention, feeding, and mating behaviors. It consists of a core of cortical and diencephalic structures found on the medial aspect of the hemisphere. A prominent structure in the limbic system is the hippocampal formation on the medial aspect of the temporal lobe. The hippocampal formation extends along the floor of the inferior horn of the lateral ventricle in the temporal lobe and includes the hippocampus, the dentate gyrus, the subiculum, and adjacent entorhinal cortex. The hippocampus is characterized by a 3-layered cerebral cortex. Other limbic-related structures include the amygdala, which is located deep in the medial part of the anterior temporal lobe rostral to the hippocampus, and the septal nuclei, located medially between the anterior horns of the lateral ventricle. The limbic system is interconnected with thalamic and hypothalamic structures, including the anterior and dorsomedial nuclei of the thalamus and the mammillary bodies of the hypothalamus. The cingulate gyrus is the main limbic cortical area. The cingulate gyrus is located on the medial surface of each hemisphere above the corpus callosum. Limbic-related structures also project to wide areas of the prefrontal cortex.
Olfactory System Central projections of olfactory structures reach parts of the temporal lobe without a thalamic relay and the amygdala. The olfactory nerve consists of numerous fascicles of the central processes of bipolar neurons, which reach the anterior cranial fossa from the nasal cavity through openings in the cribriform plate of the ethmoid bone. These primary olfactory neurons differ from other primary sensory neurons in 2 ways. First, the cell bodies of these neurons, which lie scattered in the olfactory mucosa, are not collected together in a sensory ganglion, and second, primary olfactory neurons are continuously replaced. The life span of these cells ranges from 30 to 120 days in mammals. Within the mucosa of the nasal cavity, the peripheral process of the primary olfactory neuron ramifies to reach the surface of the mucous membrane. The central processes of primary olfactory neurons terminate by synapsing with neurons found in the olfactory bulb. The bulb is a 6-layered outgrowth of the brain that rests on the cribriform plate. Olfactory information entering the
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olfactory bulb undergoes a great deal of convergence before the olfactory tract carries axons from the bulb to parts of the temporal lobe and amygdala.
Biochemistry
Alzheimer disease results from neurons, beginning in the hippocampus, that exhibit Physiology Medical Genetics neurofibrillary tangles and amyloid plaques. Other nuclei affected are the cholinergic neurons in the nucleus basalis of Meynert, noradrenergic Pathology Behavioral Science/Social Sciences neurons in the locus coeruleus, and serotonergic neurons in the raphe nuclei. Patients with Down syndrome commonly present with Alzheimer in Microbiology middle age because chromosome 21 is one site of a defective gene.
Clinical Correlate Olfactory deficits may be incomplete (hyposmia), distorted (dysosmia), or complete (anosmia). Olfactory deficits are caused by transport problems or by damage to the primary olfactory neurons or to neurons in the olfactory pathway to the central nervous system (CNS). Head injuries that fracture the cribriform plate can tear the central processes of olfactory nerve fibers as they pass through the plate to terminate in the olfactory bulb, or they may injure the bulb itself. Because the olfactory bulb is an outgrowth of the CNS covered by meninges, separation of the bulb from the plate may tear the meninges, resulting in cerebrospinal fluid (CSF) leaking through the cribriform plate into the nasal cavity.
The limbic system is involved in emotion, memory, attention, feeding, and mating behaviors. It consists of a core of cortical and diencephalic structures found on the medial aspect of the hemisphere. The limbic system modulates feelings, such as fear, anxiety, sadness, happiness, sexual pleasure, and familiarity.
The Papez Circuit A summary of the simplified connections of the limbic system is expressed by the Papez circuit (Figure III-11-1). The Papez circuit oversimplifies the role of the limbic system in modulating feelings, such as fear, anxiety, sadness, happiness, sexual pleasure, and familiarity; yet, it provides a useful starting point for understanding the system. Arbitrarily, the Papez circuit begins and ends in the hippocampus. Axons of hippocampal pyramidal cells converge to form the fimbria and, finally, the fornix. The fornix projects mainly to the mammillary bodies in the hypothalamus. The mammillary bodies, in turn, project to the anterior nucleus of the thalamus by way of the mammillothalamic tract. The anterior nuclei project to the cingulate gyrus through the anterior limb of the internal capsule, and the cingulate gyrus communicates with the hippocampus through the cingulum and entorhinal cortex. The amygdala functions to attach an emotional significance to a stimulus and helps imprint the emotional response in memory.
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Corpus callosum Cingulate gyrus
Thalamus
Fornix Olfactory bulb Mammillary body Hippocampus
Amygdala (deep to uncus) Cingulate gyrus Thalamus (anterior nucleus)
Hippocampus via fornix
Mammillary body
Papez Circuit
Figure III-11-1. Limbic and Papez CircuitCircuit Figure The III-11-1. TheSystem Limbic System and Papez
Limbic Structures and Function • Hippocampal formation (hippocampus, dentate gyrus, the subiculum,
and entorhinal cortex)
• Amygdala • Septal nuclei • The hippocampus is important in learning and memory. The amygdala
attaches an emotional significance to a stimulus and helps imprint the emotional response in memory.
Limbic Connections • The limbic system is interconnected with anterior and dorsomedial
nuclei of the thalamus and the mammillary bodies.
• The cingulate gyrus is the main limbic cortical area. • Limbic-related structures also project to wide areas of the prefrontal
cortex.
• Central projections of olfactory structures reach parts of the temporal
lobe and the amygdala.
Papez Circuit Axons of hippocampal pyramidal cells converge to form the fimbria and, finally, the fornix. The fornix projects mainly to the mammillary bodies in
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the hypothalamus. The mammillary bodies project to the anterior nucleus of the thalamus (mammillothalamic tract). The anterior nuclei project to the cingulate gyrus, and the cingulate gyrus projects to the entorhinal cortex (via the cingulum). The entorhinal cortex projects to the hippocampus (via the perforant pathway).
Clinical Correlate Anterograde Amnesia
Pathology
Behavioral Science/Social Sciences
Bilateral damage to the medial temporal lobes including the hippocampus results in a profound loss of the ability to acquire new information, known as anterograde amnesia. Korsakoff Syndrome
Microbiology
Anterograde amnesia is also observed in patients with Korsakoff syndrome. Korsakoff syndrome is seen mainly in alcoholics who have a thiamine deficiency and often follows an acute presentation of Wernicke encephalopathy. Wernicke encephalopathy presents with ocular palsies, confusion, and gait ataxia and is also related to a thiamine deficiency. In Wernicke-Korsakoff syndrome, lesions are always found in the mammillary bodies and the dorsomedial nuclei of the thalamus. In addition to exhibiting an anterograde amnesia, Korsakoff patients also present with retrograde amnesia. These patients confabulate, making up stories to replace past memories they can no longer retrieve. Klüver-Bucy Syndrome Klüver-Bucy syndrome results from bilateral lesions of the amygdala and hippocampus. These lesions result in: • P lacidity—there is marked decrease in aggressive behavior; the subjects become passive, exhibiting little emotional reaction to external stimuli. • P sychic blindness—objects in the visual field are treated inappropriately. For example, monkeys may approach a snake or a human with inappropriate docility. • H ypermetamorphosis—visual stimuli (even old ones) are repeatedly approached as though they were completely new. • Increased oral exploratory behavior—monkeys put everything in their mouths, eating only appropriate objects. • Hypersexuality and loss of sexual preference • Anterograde amnesia
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Alzheimer Disease • Alzheimer disease accounts for 60% of all cases of dementia. The inci-
dence increases with age.
• Clinical: insidious onset, progressive memory impairment, mood
alterations, disorientation, aphasia, apraxia, and progression to a bedridden state with eventual death
• Five to 10% of Alzheimer cases are hereditary, early onset, and trans-
mitted as an autosomal dominant trait.
Lesions involve the neocortex, hippocampus, and subcortical nuclei, including forebrain cholinergic nuclei (i.e., basal nucleus of Meynert). These areas show atrophy, as well as characteristic microscopic changes. The earliest and most severely affected areas are the hippocampus and temporal lobe, which are involved in learning and memory.
Figure III-11-2. MRI of Medial View of the Central Nervous System (a) Corpus callosum (splenium) (b) Lingual gyrus (c) Cuneus gyrus (d) Primary motor cortex (e) Primary somatosensory cortex (f) Midbrain (g) Pons (h) Medulla (i) Hypothalamus in wall of third ventricle (j) Posterior vermis of cerebellum with intracerebral hemorrhage (k) Pituitary (l) Mammillary body (m) Pineal
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Index
A Abdomen aneurysm, 126 anterior wall, 85–90 fluid accumulation, 165 innervation, 90 layers, 87, 89 male urine extravasation, 154, 165 planes and regions, 85–86 arterial supply, 126–130 diaphragm boundary, 38 inguinal region hernias, 92–94 inguinal canal, 90–91 testes descent, 91–92 posterior wall bony landmarks, 137 muscles, 137 radiology, 173–177 barium enema, 173 venous drainage, 130–133 Abdominal ectopic pregnancy, 8 Abdominal reflex, 260 Abducens nerves (CN VI) brain stem, 275, 276, 277, 279, 287 cavernous sinus, 219, 220, 247 thrombosis, 220 embryology, 211 functions, 281 horizontal conjugate gaze, 297, 298, 299 lesions, 281, 298, 299, 304, 305 nuclei, 285 orbital muscles, 221, 297, 298 vestibular fibers, 293, 294 Abortions and hCG levels, 9 Acalculia, 352 Accessory duct of Santorini, 122 Accessory nerves (CN XI) cervical spinal cord, 275, 276, 277, 284 corticobulbar fibers, 288 functions, 281 lesions, 281 nuclei, 284 Accommodation-convergence reaction, 327, 328 Acetabulum, 202 Acetylcholine (ACh) basal ganglia indirect path, 319 parietal cell secretion, 113 peripheral nervous system, 230 Acid–base balance by kidneys, 140
Acini hepatic, 124 pancreas, exocrine, 121, 122 salivary glands, 120, 121 Acoustic neuroma (schwannoma), 244, 306 Acromion (radiology), 192 Acrosome, 8, 159 Actin proteins, 14–15, 16, 17 Addiction and blood–brain barrier, 242 Adductor longus muscles, 201 Adenohypophysis, 338 Adie pupil, 329 Adrenal glands (radiology), 175 Adrenal hyperplasia, congenital, 147 Aganglionic megacolon (Hirschsprung disease), 103, 109, 231 Agraphia, 350, 351, 352 alexia without, 354, 356 Alar plate, 225, 226 Alcohol abuse gait ataxia, 315 thiamine deficiency, 336, 338, 362 Alexia, 352 without agraphia, 354, 356 Allantois, 134, 135, 136, 137 Allergies and air intake, 45 Alpha motoneurons, 254–256, 271 lesions, 260–261 reflexes, 258–260 Alpha-fetoprotein (AFP) levels, 225 anencephaly, 226, 228 spina bifida, 226, 228 5α-reductase 2 deficiency, 148 Alveoli (lungs) alveolar ducts, 50 alveolar sacs, 50 alveolar wall, 52 capillary diseases, 45 histology, 50–53 hyaline membrane disease, 39 macrophages, 51, 53 respiratory bronchioles, 50 surfactant, 51, 52 Alveoli (mammary glands), 172 Alzheimer disease, 363 amyloid plaques, 360 Down syndrome and, 360 intermediate filaments, 15 neurofibrillary tangles, 238, 360 raphe and locus caeruleus, 308 Ambiguus nucleus. See Nucleus ambiguus
Amenorrhea, 337, 338, 340 Amnesia, 362 Amniotic cavity from epiblast, 8–9 Ampulla of uterine tube anatomy, 165 fertilization, 7, 168, 169 histology, 170 tubal ectopic pregnancy, 8 Ampulla of Vater, 105, 107, 122, 125 Amygdala lesions, 358 Klüver-Bucy syndrome, 362 limbic system, 359, 360, 361 Amyloid plaques, 360 Amyotrophic lateral sclerosis, 272, 273 neurofibrillary tangles, 238 Anal canal, 107, 108 anal triangle, 152 fecal material, 118 female perineum, 155 Anal sphincters, 107–108, 119 Anal triangle, 152 female, 155 Anastomoses pancreas head, 105, 127, 129 portacaval, 132, 133 Anchoring junctions, 16 Androgen insensitivity, 148 Androstenedione, 169 Anencephaly, 226, 228 Anesthesia epidural, 27, 29 intercostal, 38 pudendal, 152 Aneurysms abdominal, 126 circle of Willis, 221, 346, 357 superior mesenteric artery, 130 Angiotensin conversion, 45 Angular gyrus, 347, 349 lesions, 352, 358 Ankle joints, 205 deep tendon reflex, 258 Anopia, 331, 333 Anorectal canal, 135, 136 Anosmia, 280, 358, 360 Anterior cardiac veins, 77 Anterior cerebral arteries, 345, 346, 347 aneurysm, 346 occlusion, 345, 352, 356, 357 radiology, 347
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Anatomy Anatomy
Immunology
Anterior communicating arteries aneurysm, 221, 346, 357 circle of Willis, 301, 346 Anterior cruciate ligaments (ACL), 203, 204 anterior drawer sign, 204 Pharmacology Biochemistry common injury, 205 Anterior scalene muscles, 208 Anterior spinal artery, 346 occlusion, 272, 274, 302, 303 Anterior superior iliac spine,Medical 86, Genetics 88 Physiology Anterior talofibular ligament injury, 205 Anterior tibial arteries and fractures, 201 Anterograde amnesia, 362 Anterograde axonal degeneration, 243, 244 Anterolateral sensory system, 262, 263, Pathology Behavioral Science/Social Sciences 265–267, 269 brain stem, 277, 282 lesions, 265, 266, 267, 282 Antidiurectic hormone (ADH), 337, 339 Antrum of follicle, 166, 168 Microbiology Anulus fibrosus, 23, 24 Anus, 107 embryology, 135 sphincters defecation, 107–108, 119 innervation, 152, 155 Aorta abdominal aneurysm, 126 abdominal branches, 126 atherosclerotic plaque site, 126 coarctation of, 67–68 descending aorta, 64 radiology, 83, 84 radiology abdomen, 174–176 thorax, 83, 84 Aortic arch radiological landmark, 66, 81, 82 superior mediastinum, 66 Aortic hiatus, 64, 65, 80 Aortic semilunar valve aortic insufficiency, 74, 75 aortic stenosis, 74, 75 auscultation, 74, 75 blood flow, 73 murmurs, 74–76 Aortic vestibule, 54, 73 Aorticopulmonary septum, 60, 61 Apathy, 350 “Ape hand,” 185, 186, 187, 190 Apex of lung, 42 Aphasias, 345, 350, 351, 352, 358 Appendix, 107 Apraxia, 345, 349, 351, 358 transcortical, 352, 356 APUD cells (Amino-Precursor-UptakeDecarboxylase) gastrointestinal, 114 respiratory, 48, 49 Aqueous humor, 326 ciliary body epithelium, 328 glaucoma, 326
Arachnoid granulations, 217, 218, 245, 246, 247, 249 Arachnoid mater cranial, 217, 247 spinal, 26, 252 Arcuate nuclei, 337, 338, 339 Argyll Robertson pupils, 274, 327, 329 Arnold-Chiari malformation, 228 Arousal and thalamus, 335, 336 Ascending colon, 107 radiology, 175–176 Asomatognosia, 353 Aspiration of foreign body, 43 Astereognosia, 264, 351, 358 Asthma, 50 Astrocytes, 239, 242 Ataxia of gait, 268, 315 Atherosclerotic plaque in aorta, 126 Athetosis, 323 Atlas, 22 Atonic bladder, 138, 272 Atria anatomy of heart, 70 blood flow, 72 borders, 69, 70 surfaces, 70 embryology atrial septal defects, 58–59, 63 atrial septation, 56–58, 72 fetal circulation, 54–56 heart tube, 53, 54 radiology, 81, 84 esophagus and, 64 Atrioventricular nodal artery, 76, 77 Atrioventricular (AV) node, 78, 79 Atrioventricular valves auscultation, 74, 75 blood flow, 72, 73 murmurs, 74–76 Auditory system, 291–293 auditory tests, 293 cerebral cortex, 349, 355, 358 hearing loss, 291, 292 pitch of sound, 290, 291 thalamus, 335, 336 Auerbach’s plexus, 109, 110 Auricle of heart, 72 Auscultation breath sounds, 43 heart valves, 74, 75 Autonomic nervous system, 30–33, 225, 230–233. See also Parasympathetic nervous system; Sympathetic nervous system Avascular necrosis, 193, 202 Axillary arteries, 188, 189 Axillary lymph nodes, 36 Axillary nerves brachial plexus, 179, 180, 181 injury, 183, 184 lesions, 186, 187
humeral head dislocation, 187, 191 humeral surgical neck fracture, 186, 187, 192 Axis of vertebral column, 22 Axonal polyneuropathies, 227, 239 Axons axonal transport, 238–239 axonal polyneuropathies, 227, 239 microtubules, 237 neurological disorders and, 239 axotomy, 243, 244 histology, 241–242 initial segment, 236, 238 regeneration of neuron, 243, 244 spinal tracts or fasciculi, 251, 252 structure of neuron, 236, 238–239 Axotomy, 243, 244 Azygos system of veins, 65
B Babinski sign, 260, 261 Barium enema radiology, 173 Bartholin glands, 153 Basal cells, 48 Basal ganglia anatomy, 317 sections, 318, 320, 321 subthalamus, 337 thalamus, 335, 336 direct pathway, 317, 319 lesions, 323 diseases of, 322–323 indirect pathway, 318–319 lesions, 323 Basal lamina, 16, 17 Basal plate, 225, 226 Basement membrane, 15, 16 bullous pemphigoid, 16 Basilar arteries, 301, 344, 346, 348 occlusion, 357 medial pontine syndrome, 304 Basis pontis, 278 Basket cells, 311, 312, 313 Bell palsy, 289, 291 Bicuspid valve auscultation, 74, 75 blood flow, 72, 73 murmurs, 74–76 Bilaminar embryonic disk, 8–9 Bile, 125 Bile canaliculi, 123 Bile duct, 105, 123 Bladder anatomy, 137, 138 atonic, 138 embryology, 136 exstrophy of, 148 female pelvis, 151 herniation into vagina, 152 male pelvis, 150 spastic, 138 trigone, 136, 138 Blastocyst, 7, 8
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Index Blastomeres, 7, 8 Blastula, 7, 8 Blepharospasm, 323 Blindness cortical blindness, 353, 358 night blindness, 325 psychic blindness, 362 Blood pressure control by kidneys, 140 Blood–brain barrier about, 242, 247, 249 astrocytes, 239, 242 choroid plexus, 247, 249 drugs of addiction crossing, 242 pericytes, 240, 242 Bowel ischemia at splenic flexure, 130 Bowman’s capsule, 141 renal corpuscle, 141, 142–144, 146 Brachial arteries, 188, 189 Brachial plexus, 179–181 cervical spinal nerves, 251, 253 collateral nerves, 182 injuries, 183–184 branches, 185–187 scalene triangle, 207, 208 Brachiocephalic veins, 66 radiology, 82 Brain anatomy, 276, 342, 361 arterial supply, 300–301 anterior cerebral infarcts, 345, 352, 356, 357 cerebral cortex, 344–348 cerebral infarcts, 348, 357 hemorrhages, 348, 357 posterior cerebral infarcts, 332, 348, 353, 354, 356, 357 blood–brain barrier, 242, 247, 249 astrocytes, 239, 242 choroid plexus, 247, 249 drugs of addiction crossing, 242 pericytes, 240, 242 central nervous system definition, 225 cranial meninges, 217–218 embryology, 225, 226 lesion diagnosis, 307 radiology, 320, 347, 363 schwannoma, 244, 306 ventricles anatomy, 245, 246 cerebrospinal fluid, 245, 246. See also Cerebrospinal fluid embryology, 227 ependymal cells, 242 hydrocephalus, 228, 248 vesicle embryology, 225, 227 Brain stem anatomy, 275, 276, 277 medulla, 282–284 midbrain, 287–289 pons, 284–287 sections, 278–280 arterial supply, 300–301 caloric test of function, 295, 296
corticospinal tract, 277, 282 cranial nerves, 275–281. See also Cranial nerves hypothalamic fibers, 277, 278, 279, 280, 282 lesions, 303, 304, 305 midbrain, 287 pons, 284 lesions, 282, 302–308 diagnosis of, 307 medial lemniscus, 263, 264, 265, 277, 282 medial longitudinal fasciculus, 278, 279, 282 reticular formation, 308 spinothalamic tract, 265, 266, 267, 282 upper motoneurons, 256 corticospinal tract, 257 Breasts anatomy, 35–36 cancer, 172 mastectomy nerve lesion, 35 metastasis, 36 orange-peel appearance, 35 histology, 172 Bridging veins, 217, 218 subdural hematoma, 221, 348 Broad ligament, 152 Broca’s motor speech area anatomy, 320 lesions, 350, 352, 358 Brodmann numbers, 343 cerebral cortex functional areas, 349 motor pathways, 256, 336, 343, 349 Broca area, 350 sensory pathways, 262, 336, 343 auditory system, 292, 355 parietal lobe, 351–353 visual system, 297, 332, 349, 350, 353–354 Wernicke area, 351 Bronchi aspiration of foreign body, 43 cancer from K cells, 49 embryology, 36–38 histology, 46, 49 Bronchiole histology, 46, 49–50 Bronchomediastinal lymph nodes, 44 Bronchopulmonary lymph nodes, 44 Brown-Séquard syndrome, 271, 272, 273 Brunner glands, 110, 116 Brush cells, 48, 49 Buck fascia, 153 Bulb of penis, 150, 154 injury and urine extravasation, 154, 165 superficial perineal pouch, 153 Bulbospongiosus muscle, 153 ejaculation, 164 Bulbourethral glands, 150, 154, 156 deep perineal pouch, 153 ejaculation, 164 Bullous pemphigoid, 16 Bundle of His, 78, 79
C Cadherins, 15, 16 Calcium adhesion molecules, 15 gap junction movement, 16 Calculus, biliary, 125 Caloric test, 295, 296 Camper fascia, 87 Canal of Schlemm, 326 narrow-angle glaucoma, 326 Cancers breast, 172 mastectomy nerve lesion, 35 metastasis, 36 orange-peel appearance, 35 bronchial from K cells, 49 epithelial cadherins and malignancy, 15, 16 lung, 45 apex of lung, 42 metastasis, 44 lymphatic system metastasis breast, 36 internal vertebral venous plexus, 27 lung, 44 penis and scrotum, 91 testes, 91 mesothelioma, 45 mitotic spindle inhibition, 15 nervous system cerebrospinal tumors, 249 craniopharyngioma, 244 glioma, 239 metastastatic tumors, 244 Schwannoma, 244, 306 pancreas, 105 parotid salivary glands, 121 penis, metastasis, 91 pineal body, 306, 308, 340 scrotum, metastasis, 91 testes, metastasis, 91 thymoma, 64 Capacitation, 8 Capillaries alveolus, 51 lung diseases, 45 kidneys blood circulation, 140 renal corpuscle, 141, 142–144 Capitate, 193 Capitulum of humerus (radiology), 192 Caput medusae, 132, 133 Cardiac conduction system, 78–79 intercalated discs, 74 Purkinje fibers, 74, 78, 79 septomarginal trabecula, 73, 79 Cardiac impression, 42 Cardiac muscle histology, 73–74 Cardiac tamponade, 69 Cardinal veins, 54 Carina, 67 Carotid arteries (radiology), 82
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Immunology
Carpal tunnel, 190 median nerve lesions, 186, 187 syndrome, 190, 193 sensory loss, 183, 190 Cauda equina, 27, 251, 253 Pharmacology Biochemistry Caudate nucleus, 318, 320, 321 Caval hiatus, 80 Cavernous sinuses, 219, 220, 247 thrombosis, 220 Cecum, 107 Physiology Medical Genetics embryology, 98 fecal material, 118 Celiac artery, 126–127, 128 Cell adhesion, 15, 16 Cell junctions, 16–17, 18 Pathology Behavioral Science/Social Sciences Cellular transport systems epithelial, 13–14 gap junctions, 16–17 ovarian follicles, 167 microtubules, 15 Microbiology Central nervous system autonomic nervous system, 30–33, 225, 230–233. See also Parasympathetic nervous system; Sympathetic nervous system cancers cerebrospinal tumor cells, 249 craniopharyngioma, 244 glioma, 239 metastastatic tumors, 244 Schwannoma, 244, 306 definition, 225 diseases, 237 embryology, 225–229 congenital malformations, 228 ectoderm origins, 10, 12, 225 vesicles, 225, 227 glial and supporting cells, 239–240 histology of neurons, 235–240 immune system and microglia, 240 radiology brain, 320, 347, 363 spinal cord, 83, 84 ventricles anatomy, 245, 246 cerebrospinal fluid, 245, 246. See also Cerebrospinal fluid embryology, 227 ependymal cells, 242 hydrocephalus, 228, 248 Central retinal artery occlusion, 332 Central sulcus (of Rolando), 341, 342, 349 Centroacinar cells, 122 Centromeres in meiosis, 4, 5 Cerebellar peduncles anatomy, 277, 278, 279, 309 input and outflow, 310, 314, 315 lesions, 305 pons, 284 Cerebellum anatomy, 309–310 cerebral hemispheres, 342 circuitry, 313–315
cytoarchitecture, 310–315 thalamus, 335, 336 embryology, 227, 309 lesions, 264, 313, 315 Cerebral aqueduct anatomy, 276, 278, 342 cerebrospinal fluid circulation, 245, 246 hydrocephalus, 228, 248 embryology, 227 lesions, 306, 308 midbrain, 287 Cerebral cortex anatomy, 341–344 frontal lobe, 349–350, 358 functional areas, 349 neocortex, 342–344 occipital lobe, 353–354, 358 parietal lobe, 351–353, 358 temporal lobe, 355, 358 arterial supply, 344–348 cerebral infarcts, 348 hemorrhages, 348 dominant hemisphere, 344 embryology, 227 language, 344 lesions, 348 sensory systems, 262, 263, 264, 266 upper motoneurons, 256 corticospinal tract, 256, 257 Cerebral peduncles, 276, 278 lesions, 306 midbrain, 287 Cerebrospinal fluid (CSF), 249 arachnoid granulations, 217, 218, 245, 246, 247 chemistry of, 249 choroid plexus as source, 242, 245, 246, 247, 249 circulation, 245, 246, 247, 249 cribriform plate fractures, 215, 360 hydrocephalus, 228, 248 lumbar puncture, 27, 29 pineal body tumors, 340 polymorphonuclear leukocytes in, 249 subarachnoid space, 27, 218 Cervical enlargement, 253 Cervical parietal pleura, 40 Cervical vertebrae, 22 Cervix, 151, 170 Chain motor ganglia, 30 Chief cells of stomach, 114 Chorda tympani, 213 Chordae tendineae, 72, 73 Chordoma, 11 Chorea, 322, 323 Chorion, 9 Chorionic cavity, 9 Choroid (eye), 326, 330 Choroid plexus, 242, 245, 246, 247, 249 blood–brain barrier, 247, 249 Chromaffin cells, 225 Chromatolysis, 243 Chromosomes, 3, 4, 5
Chronic obstructive pulmonary disease (COPD), 50 Cilia, 18 ductuli efferentes, 161 ependymal cells, 242 Kartagener syndrome, 18, 48 ovum transport and, 170 microtubules, 15, 18 respiratory system, 48 ciliated columnar cells, 18, 46, 49 Ciliary body epithelium, 328 Ciliary muscles, 326, 328 Cingulate gyrus brain anatomy, 276 limbic system, 359, 361, 362 Papez circuit, 360, 361 Circadian rhythms, 337, 339, 340 Circle of Willis, 301, 344, 345, 346, 348 aneurysm site, 221, 346, 357 Circumflex artery, 76, 77 Circumvallate papillae, 213 Cirrhotic liver diseases, 15 Clara cells, 49–50 cystic fibrosis and, 49 Clarke’s nucleus, 252, 255, 271 dorsal spinocerebellar tract cell bodies, 267, 268 Clasp knife reflex, 259, 261 Clavicle (radiology), 192 “Claw hand,” 184, 186, 187 Cleavage of zygote, 7, 8 Cleft lip, 213 Cleft palate, 214 Climbing fibers, 310, 312 circuitry, 312, 313–314 Clitoris embryology, 136, 147 female genitalia, 151, 155 Cloaca embryology, 96 Cloacal membrane, 10, 136 Coarctation of the aorta, 67–68 Coccyx, 22, 88 Cochlear ducts, 290, 291 Cochlear nuclei, 285, 291, 292 lesions, 292, 305 Colchicine, 15 Collateral circulation macula, 332, 348, 353, 357 marginal artery, 129 pancreas head, 105, 127, 129 upper limbs, 189, 190 Collateral ligament of ankle, 205 Collateral motor ganglia, 30 Collecting ducts, 139, 141, 145 Colles’ fascia, 153 Colon, 107–108 colonic aganglionosis, 103, 109 embryology midgut boundary, 107 midgut rotation, 98 fecal material, 118 histology, 110, 111
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Index peritoneal membranes, 100 radiology, 173–176 Colonic aganglionosis (Hirschsprung disease), 103, 109, 231 Common bile duct, 104–105, 125 hepatopancreatic ampulla, 105, 107, 122, 125 Common carotid arteries, 209 embryology, 211 Common fibular nerves, 195, 196 injury, 198 Common hepatic artery, 127, 128 Common hepatic duct, 105, 125 Common iliac arteries, 126 Communicating junctions. See Gap junctions Compartment syndrome, 201 Complete androgen insensitivity, 148 Conduction aphasia, 352 Cones, 325, 330 cone stream, 353–354 visual agnosia, 354 fovea, 326 Confluence of sinuses, 218, 219, 247 Congenital abnormalities adrenal hyperplasia, 147 annular pancreas, 102 diaphragmatic hernia, 38, 80 gut tube abnormalities, 102–103 heart and circulatory atrial septal defects, 58–59, 63 coarctation of the aorta, 67–68 patent ductus arteriosus, 60, 63, 68 persistent truncus arteriosus, 62, 63 tetralogy of Fallot, 61, 63 transposition of the great vessels, 62, 63 ventricular septal defects, 59, 63 indirect inguinal hernia, 92 nervous system, 228 anencephaly, 226 spina bifida, 226 pharyngeal apparatus, 215 cleft lip, 214 cleft palate, 214 renal system, 136–137 renal agenesis, 38, 136 reproductive system, 147–148 Conjoint tendon, 88, 89, 91 Conjugate gaze, 296–300 Connexons, 17 Constrictor pupillae, 326 Conus arteriosus, 54 Conus medullaris, 27, 251, 253 Convergence-accommodation reaction, 327, 328 Cooper ligaments, 35, 36 Coracoid (radiology), 192 Cornea, 326 Corona radiata acrosome enzymes, 159 fertilization, 7 graafian follicle, 166, 168
Coronary arteries, 76–77, 78 Coronary sinus, 72, 77, 78 heart embryology, 54, 58 Coronoid process of ulna, 192 Corpus albicans, 166, 169 Corpus callosum anatomy, 276, 318, 320, 342 lesions, 345, 352, 354 radiology, 363 Corpus cavernosum clitoris, 155 penis, 150, 154, 156 erection, 164 Corpus luteum, 166, 168–169 Corpus spongiosum, 150, 154, 156 erection, 164 Cortical blindness, 353, 358 Corticobulbar fibers, 288–289 cerebellar efferents, 315 lesions, 306, 307 neocortex, 344 Corticospinal tracts anatomy, 256, 257, 269, 271 brain stem, 277, 278, 279, 282 medulla, 282 pons, 284 cerebellar efferents, 314, 315 lesions, 257, 260, 261, 282, 302, 304, 305, 307 neocortex, 344 Costal groove, 38 Costal notching, 67 Costal parietal pleura, 39, 40 Costal surface of lung, 42 Costodiaphragmatic recesses, 40, 41 Costomedial recess, 41 Cowper glands. See Bulbourethral glands Cranial nerves I olfactory anatomy, 276, 277 functions, 280 lesions, 280, 358, 360 II optic brain anatomy, 276, 277 eye anatomy, 222 functions, 280 lesions, 280, 332, 333 pupillary light reflex, 326, 327 visual field defects, 331–332 visual pathway, 325, 326 III oculomotor brain stem, 275, 276, 277, 278, 287 cavernous sinus, 219, 220, 247 cavernous sinus thrombosis, 220 embryology, 211 functions, 280 horizontal conjugate gaze, 297, 298 lesions, 280, 306, 307, 329 nuclei, 287 orbital muscles, 221, 297, 298, 326 pupillary light reflex, 326, 327 vestibular fibers, 293, 294
IV trochlear brain stem, 275, 276, 277, 278, 287 cavernous sinus, 219, 220, 247 cavernous sinus thrombosis, 220 embryology, 211 functions, 280 lesions, 280 nuclei, 287 orbital muscles, 221 vestibular fibers, 293, 294 V trigeminal brain stem, 275, 276, 277, 278, 279, 280, 287 cavernous sinus, 219, 220, 247 corticobulbar fibers, 288, 289 embryology, 211 functions, 280 lesions, 280, 303, 304, 305 medulla, 283 nuclei, 285–286 VI abducens brain stem, 275, 276, 277, 279, 287 cavernous sinus, 219, 220, 247 cavernous sinus thrombosis, 220 embryology, 211 functions, 281 horizontal conjugate gaze, 297, 298, 299 lesions, 281, 298, 299, 304, 305 nuclei, 285 orbital muscles, 221, 297, 298 vestibular fibers, 293, 294 VII facial brain stem, 275, 276, 277, 279, 287 corticobulbar fibers, 288, 289 embryology, 211 functions, 281 lesions, 281, 289, 291, 299, 304, 305 nuclei, 283, 285 tongue innervation, 213 VIII vestibulocochlear brain stem, 275, 276, 277, 279, 287 cochlear division, 290, 291 functions, 281 lesions, 281, 292, 294, 303, 304 schwannomas, 244, 306 vestibular system, 293, 294 IX glossopharyngeal brain stem, 275, 276, 277, 279 dorsal motor nucleus, 283 embryology, 211 functions, 281 lesions, 281, 303 nuclei, 283 tongue innervation, 213 X vagus brain stem, 275, 276, 277, 279 corticobulbar fibers, 288 dorsal motor nucleus, 283 embryology, 211 heart innervation, 79 lesions, 303 nuclei, 283 superior mediastinum, 66, 67
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Immunology
XI accessory cervical spinal cord, 275, 276, 277, 284 corticobulbar fibers, 288 functions, 281 Pharmacology Biochemistry lesions, 281 nuclei, 284 XII hypoglossal brain stem, 275, 276, 277, 279 corticobulbar fibers, 288 Physiology Medical Genetics embryology, 211 functions, 281 lesions, 281, 302, 303 nuclei, 284 tongue innervation, 213 Pathology Behavioral Science/Social Sciences brain stem, 275, 276, 277 lesions, 302–308 embryology, 211 jugular foramen syndrome, 217 nuclei Microbiology medulla, 283–284 midbrain, 287–289 pons, 285–286 parasympathetic nervous system, 32, 33 as peripheral nervous system, 27, 225 Craniopharyngioma, 244 Cranium, 215–216 arterial supply, 209 dural venous sinuses, 218–219 hemorrhages, 220–221 meninges, 217–218 orbital muscles, 221–222 respiratory pathways, 46 Cremasteric muscle and fascia, 88, 89, 91 cremasteric reflex, 91, 260 Cribriform plate cranium, 215 fractures, 215, 360 olfactory system, 359, 360 Crista terminalis, 72 Crossover in meiosis, 4, 5 Cryptorchidism, 91, 148 Crypts of Lieberkühn, 110, 115, 117, 118 Cumulus oophorus, 166, 168 Cuneocerebellar tract, 267, 268 Cuneus gyrus, 331, 332 lesions, 333 radiology, 363 Cyanotic conditions persistent truncus arteriosus, 62, 63 pulmonary hypertension causing, 59 right-to-left shunts, 58, 59, 61, 62, 63 tetralogy of Fallot, 61, 63 transposition of the great vessels, 62, 63 Cystic artery, 127, 128 Cystic duct, 105, 125 Cystic fibrosis, 48 Clara cells, 49 epithelial transport, 14 Cytokinesis, 15 Cytoskeletal elements, 14–15 Cytotrophoblast, 7, 8, 9
D Dandy-Walker malformation, 228 Decerebrate rigidity, 260 Decorticate rigidity, 260 Decussation of the pyramids, 256, 257, 271, 280 Deep cerebellar nuclei, 311–312 Deep face veins, 218, 219 Deep fibular nerves, 195, 196, 199 injury, 198–199 Deep inguinal ring, 89, 90 Deep perineal pouch, 152, 153 pudendal innervation, 155 Deep tendon reflex, 258–259 Defecation, 119 anal sphincters, 107–108, 119 innervation, 152, 155 meconium and Hirschsprung disease, 231 Deltoid ligament of ankle, 205 Deltoid muscles, 208 Dendrites, 236, 238 Dentate nucleus, 279, 312, 314 Denticulate ligaments, 26 Descending aorta, 64 radiology, 83, 84 Descending colon, 107 radiology, 173–176 barium enema, 173 Descending hypothalamic fibers, 282 brain anatomy, 277, 278, 279, 280 lesions, 303, 304, 305 midbrain, 287 pons, 284 Desmosomes, 16, 17, 18 pemphigus vulgaris, 16 Detrusor muscle, 138 atonic bladder, 138 male pelvis, 150 spastic bladder, 138 Diabetes insipidus, 337, 339 Diabetes mellitus infants of diabetic mothers, 39, 52 neuropathies, 227, 239 Diaphragm, 79–80 apertures, 80 aortic hiatus, 64, 65 diaphragmatic hernia, 80 pulmonary hypoplasia and, 38 diaphragmatic parietal pleura, 39, 40 embryology, 80 innervation, 79, 80 pain referral, 80 radiology, 81, 174–175 sliding hiatal hernia, 106 thoracic outlet, 38 Diaphragmatic surface of lung, 42 Diastole in valvular defects, 74, 75, 76 Diencephalon anatomy, 335–340 embryology, 227 DiGeorge sequence, 212, 215
Digestion bile functions, 125 kidney reabsorptive functions, 140 large intestine, 119 salivary glands, 120–121 small intestine, 115, 116, 117 stomach, 112 Dihydrotestosterone (DHT), 3 Dilator pupillae, 326 Diploic veins, 218, 247 Diploid cells in meiosis, 4, 5 Diplopia, 296 Direct inguinal hernias, 92–93 Disjunction in meiosis, 4, 5 Distal convoluted tubule, 141, 145 Diuretics, 145 DNES cells (Diffuse Neuro Endocrine System), 48 Dominant hemisphere, 344 Dopamine, 319 Dorsal column–medial lemniscal system, 262, 263–265 brain stem, 263, 264, 265, 277 brain stem medial lemniscus, 277, 278, 279, 280, 282 lesions in brain stem, 282 lesions of dorsal columns, 264, 265 medial lemniscus, 263, 264, 265, 271 Dorsal embryonic mesentery, 95, 97, 98 Dorsal horn, 254 anterolateral system, 265 as sensory, 252, 253, 254 spinal cord sections, 269, 270 Dorsal rami, 28, 32, 233, 252 Dorsal root of spinal nerve denticulate ligaments, 26 dorsal column–medial lemniscal system, 263 dorsal root ganglion anatomy, 28 dorsal horn, 254 reflexes, 259 sensory receptors, 262, 263, 264, 265, 266 reflexes, 259 as sensory, 28, 252, 253, 262 Dorsal spinocerebellar tract, 267, 268, 271 Down syndrome alpha-fetoprotein levels, 225 Alzheimer disease and, 360 neurofibrillary tangles, 238 Drawer signs, 204 Duct of Gartner embryology, 147 Ductuli efferentes, 161 Ductus arteriosus fetal circulation, 55, 56 patent ductus arteriosus, 60 pharyngeal arches, 211 Ductus deferens ejaculation, 164 embryology, 134 histology, 162, 163
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Index male anatomy, 150, 154, 156 spermatic cord, 91 vasectomy, 162 Ductus venosus, 54, 55, 56 Duodenum, 106–107 bile delivery, 125 digestion, 116 duodenal atresia, 103 foregut boundary, 107 histology, 110, 111, 114–118 peritoneal membranes, 100 radiology, 173, 176 ulcer and gastroduodenal artery, 127 Dura mater cranial, 217, 247 arachnoid granulations, 217, 247 dural venous sinuses, 218–219, 247 spinal, 26, 252 Dural sac, 26, 27 Dural venous sinuses, 218–219, 247–248 Dust cells, 53 Dynein cilia, 18 Kartagener syndrome, 18, 48 retrograde axonal transport, 15, 239 spermatozoa flagella, 159 Dysdiadochokinesia, 315 Dyskinesias, 323 Dysmetria, 315 Dystonia, 323
E Ears anatomy, 290–292 inner ear stereocilia, 17 auditory system, 291–293 auditory tests, 293 hearing loss, 291, 292 embryology, 211, 212 middle ear diseases, 291 vestibular system, 293–296 Ectoderm derivatives, 10, 12, 229 pharyngeal arch derivatives, 211 epiblast origins, 10 gastrulation, 10 nervous system, 10, 12, 225 pectinate line, 108 pharyngeal grooves, 210 primitive gut tube, 96 Ectopic pregnancy, 8, 170 hCG levels, 9 Edinger-Westphal nuclei, 287 accommodation, 327, 328 pupillary light reflex, 326, 327 Eisenmenger complex, 59 Ejaculate, 163, 164 Ejaculation, 164 Ejaculatory ducts, 150, 156, 163 ejaculation, 164 embryology, 134, 136, 147
Elbow deep tendon reflex, 258 median nerve lesion, 185 musculocutaneous nerve lesion, 186 radial nerve lesion, 185 radiology, 192 ulnar nerve lesion, 186 Electrolyte balance by kidneys, 140 Emboliform nucleus, 312, 314 Embryoblast, 7, 8–9 Embryology first week, 7–8 second week, 8–9 third to eighth weeks, 10–12 heart, 53, 57, 59, 60 kidney, 134 neurulation, 225 respiratory system, 36 urorectal septum, 135 diaphragm, 80 embryonic mesentery derivatives, 95 fetal circulation, 54–56 gastrointestinal system foregut rotation, 95, 96 midgut rotation, 99 organ development, 95, 96, 97, 101–102 peritoneum, 98–99 primitive gut tube, 94, 95 gastrulation, 10 gonads, 3, 4, 91, 147 extraperitoneal connective tissue, 89 mesonephric tubules, 134, 136 vagina, 136, 147 head and neck, 210–215 heart atrial septation, 56–59 fetal circulation, 54–56 heart tube, 53 heart tube derivatives, 54, 72 heart tube septation, 56–63 truncus arteriosus septation, 60–63 ventricular septation, 59 nervous system, 225–226 ectoderm origins, 10, 12, 225 respiratory system, 36–38 corticosteroids and surfactant, 52 urinary system, 134–136 kidneys, 97, 134–135 vertebral column, 21 Embryonic disk, 8–9 Emissary veins, 218, 219, 247 Emphysema, 50 Endocardial cushions, 57, 59 Endocardium, 74 Endocrine functions of kidney, 139, 145, 146 Endoderm derivatives, 12, 229 gastrulation, 10 liver, 101, 122 pancreas, 101 pectinate line, 108
pharyngeal pouches, 210 primitive gut tube, 96 derivatives, 95 epithelia, 94 respiratory system, 36 urogenital sinus, 136 bladder, 136 Endolymph, 290, 291, 294 Endometrium, 165, 170, 171 Enterocytes, 115, 117, 119 Enteroendocrine cells gastrointestinal, 114, 117 respiratory, 48, 49 Ependymal cells, 242 Epiblast, 8–9 ectoderm, 10 extraembryonic mesoderm, 9 gastrulation, 10 Epicardium, 74 Epididymis, 156, 162 ejaculation, 164 microvilli, 17 vasectomy, 162 Epidural anesthesia, 27, 29 Epidural hematoma, 220–221, 348 epidural space, 218 middle meningeal artery laceration, 209 Epidural space cranial, 218 spinal, 26, 27 epidural anesthesia, 27, 29 lumbar puncture, 27, 29 Epigastrium, 86 foregut referred pain, 95 Epiploic foramen (of Winslow), 97, 99, 100, 101 Epispadias, 148 Epithalamus, 337, 340 Epithelia basement membrane, 16 embryology gastrulation, 10 germ layer derivatives, 10, 12, 229 respiratory, 36 yolk sac derivatives, 12 histology, 13–14 cell adhesion molecules, 15 cell surface specializations, 16–18 connective tissue alongside, 14 cytoskeletal elements, 14–15 heart, 74 polarity, 13–14 hepatocytes, 123 tight junctions, 13, 16 as tissue type, 13, 14 Erb-Duchenne palsy, 183–184 Erection of penis, 164 hypothalamic lesions, 337, 340 Erythrocytes and vitamin B12, 113 Erythropoietin, 139, 145 Esophageal atresia, 37
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Immunology
Esophageal hiatus, 80 esophageal hiatal hernia, 80 sliding hiatal hernia, 106 Esophageal varices, 132, 133 Esophageal vein anastomoses, 132, 133 Pharmacology Biochemistry Esophagus embryology, 36–38 primitive gut tube, 96 histology, 110, 111, 112 portacaval anastomoses, 132, 133 Physiology Medical Genetics radiology, 82, 84 left atrium and, 64 superior mediastinum, 66, 67 tracheoesophageal fistula, 37, 38 Estradiol from granulosa cells, 167 Pathology Behavioral Science/Social Sciences Estrogen granulosa lutein cells, 169 ovary embryology, 3 Eustachian tube, 290, 291 Eversion loss in foot, 198, 199 Microbiology Expressive aphasia, 350 External abdominal oblique muscle, 87, 89, 91 External cuneate nucleus, 267, 268 External iliac arteries, 126, 200, 201 External spermatic fascia, 87, 89, 91 Extraembryonic mesoderm, 9 Extrahepatic biliary atresia, 102 Extraperitoneal connective tissue, 89 Extremeties. See Lower limbs; Upper limbs Eyes movement control, 296–300 nystagmus, 296 caloric test, 295 vestibular, 294, 296 orbital muscles, 221–222 vestibulo-ocular reflex, 282, 293, 294 brain stem integrity, 295, 296 visual field defects, 331–333 visual pathways, 325, 326, 330 visual reflexes, 326–329
F Face embryology, 214 prechordal plate, 8, 9 facial paralysis, 289, 299 corticobulbar fibers, 288 oral cavity histology, 112 salivary glands, 120–121 Facial colliculus, 279 Facial nerves (CN VII) brain stem, 275, 276, 277, 279, 287 corticobulbar fibers, 288, 289 embryology, 211 functions, 281 lesions, 281, 289, 291, 299, 304, 305 nuclei, 283, 285 tongue innervation, 213 Falciform ligament, 101, 103 Fallopian tubes. See Oviducts Falx cerebri, 217, 247 dural venous sinuses, 218–219
Falx inguinalis, 88, 89, 91 Fasciculus cuneatus, 263, 264, 265, 269 Fasciculus gracilis, 263, 264, 265, 269, 271 Fastigial nucleus, 312, 314 Fat-soluble vitamins in liver, 125 Feet, 198, 199, 201, 205 Female pelvic anatomy, 151, 155 Female pseudointersexuality, 147 Femoral arteries, 200, 201 Femoral hernias, 94, 201 Femoral nerves femoral triangle, 201 injuries, 198 lumbosacral plexus, 195, 196 Femoral sheath, 89, 201 Femoral triangle, 201 Femurs avascular necrosis of head, 202 hip joint, 202 knee joints, 203–205 deep tendon reflex, 258–259 injuries, 203, 204, 205 radiology, 206 neck fractures, 202 Fertilization, 168 ectopic pregnancy, 8, 170 embryology, 7, 8 second meiotic division, 168 Fetal circulation, 54–56 Fetal development. See Embryology Fibrous pericardium, 68–69 Fibula, 203, 205 radiology, 206 Fibular collateral ligaments, 203 Filiform papillae, 213 Filum terminale, 27, 253 Fimbriae, 165, 169 Finger agnosia, 352 First arch syndrome, 215 First jejunal artery, 129 Flaccid paralysis, 260, 261, 269, 272, 273, 274, 303 Flaccid weakness, 257, 271, 273 Flagella Kartagener syndrome, 18, 48 microtubules, 15, 18 spermatozoa, 159 Flexor digitorum profundus, 190 Flexor digitorum superficialis, 190 Flexor pollicis longus, 190 Flexor withdrawal reflex, 260 Flocculonodular lobe, 309, 310, 312 vestibular system, 294 Fluid balance by kidneys, 140 Foliate papillae, 213 Follicular development, 166, 167–168 progesterone preventing, 169 “Foot drop,” 198, 199 Foramen cecum, 212, 213 Foramen magnum, 216, 217 Foramen ovale atrial septation, 54, 56, 57, 58 fetal circulation, 54, 55, 56
Foramen primum, 57 Foramen secundum, 57 Forearm arterial supply, 187–190 collateral circulation, 189, 190 deep tendon reflex, 258 innervation, 181 sensory, 182, 183 Forebrain, 227 Foregut, 94, 95 celiac artery, 126 derivatives, 95 duodenum boundary, 107 respiratory system origins, 36–38 rotation, 95, 96, 97 splenic vein, 131, 132 Fornix brain anatomy, 276, 342 basal ganglia section, 321 Papez circuit, 360, 361 posterior, 151 Fossa ovalis, 55, 56, 58, 72 Fovea, 326 Frequency of sound and hearing, 290, 291 Friedreich ataxia, 268 Frontal eye field, 296, 297, 298 cerebral cortex, 349 lesions, 350, 358 Frontal lobe, 349–350, 358 anatomy, 342, 349 lesions, 349, 350 frontal lobe syndrome, 350, 358 motor homunculus, 343, 349 Fundus (gallbladder), 105, 125 Fundus (stomach), 106, 111 Fundus (uterus), 151, 152 Fungiform papillae, 213 Fusion fascia, 97
G Gait abnormalities ataxia, 268, 315 lumbar plexus injuries, 198–199 tabes dorsalis, 274 Galea aponeurotica, 217, 247 Gallbladder, 104–105 embryology, 101, 102 histology, 125 peritoneal membranes, 100 Gametogenesis, 4, 5 Gamma motoneurons, 254–255, 256, 271 lesions, 260–261 muscle tone and reflex activity, 254–255, 259 reflexes, 258–260 γ-aminobutyric acid (GABA), 317–319 Gap junctions, 16–17 ovarian follicles, 167 Gastric glands, 110, 113 Gastric pits, 110, 113 Gastroduodenal artery, 127, 128 Gastroepiploic artery, 128
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Index Gastrointestinal system embryology foregut rotation, 95, 96 midgut rotation, 99 organ development, 95, 96, 97, 101–102 peritoneum, 98–99 primitive gut tube, 94, 95 glands liver, 122–125 pancreas, exocrine, 121–122 salivary, 120–121 histology, 108–109 regional differences, 110–111 immune functions, 110 bile transport of IgA, 125 gut-associated lymphatic tissue, 109, 110, 116, 118 ileum, 116 Langerhans cells, 112 Peyer’s patches, 110, 116, 118 innervation, 109–110 mucous production Brunner glands, 110, 116 goblet cells, 115, 116, 117, 119 stomach, 111, 113 peritoneal cavity, 99 peritoneum, 98 intra- vs. retroperitoneal organs, 99 Gastroschisis, 103 Gastrosplenic ligament, 95, 97, 101, 102 Gastrulation, 10 Gaze dysfunction cerebellar lesions, 315 conjugate gaze, 296–300 Genes determining sex, 3 Genitalia embryology, 3, 4, 91, 136, 147 extraperitoneal connective tissue, 89 mesonephric tubules, 134, 136 female pelvis, 151, 152, 155 male pelvis, 150, 153, 154 urogenital triangle, 152–153, 155 Gerstmann syndrome, 351, 352, 358 Gestational trophoblastic disease, 9 Glaucoma, 326 Glenoid fossa (radiology), 192 Glial cells, 239–240 Glial fibrillary acidic protein (GFAP), 239 Globose nucleus, 312, 314 Globus pallidus, 317, 318, 319, 321 Glomeruli blood circulation, 140 embryology, 134 kidney anatomy, 139, 140 renal corpuscle, 141, 142–144, 146 Glossopharyngeal nerves (CN IX) brain stem, 275, 276, 277, 279 dorsal motor nucleus, 283 embryology, 211 functions, 281 lesions, 281, 303
nuclei, 283 tongue innervation, 213 “Glove-and-stocking” weakness, 227, 239 Goblet cells brush cells, 48 large intestine, 116, 119 respiratory system, 48 small intestine, 115, 116, 117 Golgi cells, 311, 312, 313 Golgi tendon organs (GTOs), 259 Gonadal arteries, 126, 130 Gout and colchicine, 15 Graafian follicles, 166, 168 Granule cells (cerebellum), 311, 312, 313 circuitry, 311, 312, 313–314 Granulosa cells, 166, 167, 168 lutein cells, 168–169 Grasp reflex, 350 Gray rami, 32, 233 Great cardiac vein, 77, 78 Greater tubercle (radiology), 192 Greater vestibular glands, 153 Gubernaculum, 91, 92 Guillain-Barré syndrome, 241 Gut tube. See Primitive gut tube Gut-associated lymphatic tissue (GALT), 109, 110, 116, 118 Peyer’s patches, 110, 116, 118 Gyri of cerebral cortex, 341–342
H Habenular nuclei, 340 Hair cells auditory system, 291, 292 endolymph, 290 vestibular system, 293 Hand arterial supply, 187–190 collateral circulation, 189, 190 innervation, 181 sensory, 182, 183 radiology, 193 “Hand of benediction,” 185, 187 Haploid cells in meiosis, 4, 5, 158 Haustra, 118 Head. See also Cranium arterial supply, 209 embryology, 210–215 congenital abnormalities, 214, 215 Hearing. See Auditory system Hearing loss auditory tests, 293 conductive, 291, 292 lesions causing, 292 sensorineural, 291, 292 Heart anatomy, 70 arterial supply, 76–77 blood flow, 72–73 blood flow, fetal, 54–56 borders, 69, 70, 71 chambers, 72–73 innervation, 79
surface projections, 71, 75 surfaces, 70 venous drainage, 77–78 auscultation, 74, 75 conduction system, 78–79 intercalated discs, 74 Purkinje fibers, 74, 78, 79 septomarginal trabecula, 73, 79 embryology atrial septation, 56–59 fetal circulation, 54–56 heart tube, 53 heart tube derivatives, 54, 72 heart tube septation, 56–63 truncus arteriosus septation, 60–63 ventricular septation, 59 histology, 73–74 middle mediastinum, 69 murmurs, 74–76 auscultation, 74, 75 Heart failure cells, 53 Helicobacter pylori infection, 114 Hematopoiesis, 9, 12 Hemianopia, 331 Hemiballismus, 322, 323, 337 Hemidesmosomes, 16, 17 Hemorrhoids, 108 rectal anastomoses, 132, 133 Hepatic arteries, 100, 101, 104, 123, 127 liver blood flow value, 122 Hepatic ducts, 105 Hepatic flexure (radiology), 173 Hepatic lobules, 123, 124 Hepatic portal system, 131–133 Hepatic portal vein epiploic foramen, 100 fetal circulation, 55 hepatic portal system, 131, 132, 133 liver blood flow, 122, 123 liver central hilus, 104 peritoneal cavity, 101 radiology, 174–175 Hepatocytes, 122–123 zones, 124 Hepatoduodenal ligament, 100, 103, 104 Hepatogastric ligament, 100, 103 Hepatopancreatic ampulla of Vater, 105, 107, 122, 125 Hernias bladder or rectum into vagina, 152 diaphragmatic, 80 pulmonary hypoplasia and, 38 esophageal hiatal hernia, 80 femoral, 94 inguinal, 92–93 sliding hiatal hernia, 106 Herniated disk, 24, 25 Herpes virus, 239 Hesselbach’s triangle, 92, 93 Hilar lymph nodes, 44 Hillock of axon, 238 Hilum, hepatic, 104, 123 Hindbrain, 227
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Immunology
Hindgut colon boundary, 107 derivatives, 95 inferior mesenteric artery, 129 inferior mesenteric vein, 131, 132 Pharmacology Biochemistry primitive gut tube, 94, 95 rectum, 107 septation, 96 urorectal septum, 135–136 Hip joints, 202 Physiology Medical Genetics avascular necrosis of head of femur, 202 dislocation and sciatic nerve injury, 199 innervation, 195–197 Hippocampus lesions, 358 Pathology Behavioral Science/Social Sciences anterograde amnesia, 362 Klüver-Bucy syndrome, 362 limbic hippocampal formation, 359, 361 Negri bodies, 237 Microbiology Papez circuit, 360, 361, 362 thiamine deficiency, 336 Hirschsprung disease, 103, 109, 231 Histology definition, 13 epithelia, 13–14 cell adhesion molecules, 15 cell surface specializations, 16–18 cytoskeletal elements, 14–15 gastrointestinal system, 108–109 esophagus, 110, 111, 112 gallbladder, 125 large intestine, 118–119 liver, 122–125 oral cavity, 112 pancreas, exocrine, 121–122 regional differences, 110–111 salivary glands, 120–121 small intestine, 114–118 stomach, 110, 111, 112–114 heart, 73–74 nervous system axons, 241–242 neurons, 235–236, 237, 238–239 Nissl substance, 235, 236, 237 Schwann cells, 241, 242 reproductive systems ovaries, 167–170 penis, 154 testes and accessory glands, 156–165 uterus, 170, 171 vagina, 171 respiratory system alveoli, 50–53 bronchi, 46, 49 bronchioles, 46, 49–50 overview, 45–46 trachea, 46–49 tissue types, 13 urinary system, 139–146 HIV-1 virus, 240 Holoprosencephaly, 228
Homeostasis hypothalamus, 337–340 kidneys, 140 Hook of Hamate, 193 Horner syndrome, 31, 232, 269, 274, 282, 304, 305 pupillary abnormalities, 329 thoracic outlet syndrome, 207 Horseshoe kidney, 137 Human chorionic gonadotropin (hCG) levels and pregnancy, 9, 11 placenta, 169 Humerus head dislocation, 186, 187, 191 mid-shaft fracture, 185, 187, 192 radiology, 192 surgical neck fracture, 186, 187, 192 Huntington disease, 322, 323 Hyaline cartilage rings of trachea, 47 Hyaline membrane disease, 39 Hydatidiform mole, 11 hCG levels, 9, 11 Hydrocele, 92, 148 Hydrocephalus, 228, 248 Parinaud syndrome, 306, 308 Hyperacusis, 291 Hypermetamorphosis, 362 Hyperplasia of the prostate, 150 Hypertrophic pyloric stenosis, 102 Hypoblast, 8–9, 10 Hypogastrium, 86 hindgut referred pain, 95 Hypoglossal nerves (CN XII) brain stem, 275, 276, 277, 279 corticobulbar fibers, 288 embryology, 211 functions, 281 lesions, 281, 302, 303 nuclei, 284 tongue innervation, 213 Hypospadias, 148 Hypothalamus anatomy, 276 cerebral hemispheres, 342 nuclei, 337–340 descending fibers, 277, 278, 279, 280, 282 lesions, 303, 304, 305 midbrain, 287 pons, 284 endocrine functions, 338–340 lesions, 337, 338, 339, 340 brain stem lesions, 282 limbic system, 359, 362 radiology, 363 Hypotonia, 315
I Ileal diverticulum, 103 Ileocolic artery, 128, 129 Ileum, 107 embryology, 98 histology, 110, 111, 114–118
ileal diverticulum, 103 immune activity, 116, 118 radiology, 173 Iliac crest and lumbar puncture, 29 Iliacus muscle, 137 Iliofemoral ligament, 202 Ilioinguinal nerve, 90 Imaging. See Radiology Immune system gastrointestinal system, 110 bile transport of IgA, 125 gut-associated lymphatic tissue, 109, 110, 116, 118 ileum, 116, 118 Langerhans cells, 112 Peyer’s patches, 110, 116, 118 infant passive immunity, 116, 172 mammary glands, 172 microglia link with CNS, 240 Implantation of zygote, 7, 8 ectopic pregnancy, 8, 170 hCG levels, 9 Impotence, 337, 340 Incisive foramen, 214 Incus, 290, 291 embryology, 211 Indifferent gonads, 3, 4, 6 Indirect inguinal hernias, 92, 93 Infants passive immunity, 116, 172 premature lung development, 37 patent ductus arteriosus, 60 respiratory distress syndrome, 39 respiratory distress syndrome, 39, 52 tracheoesophageal fistula, 37 Inferior cerebellar peduncle lesions, 303 Inferior colliculi, 276, 277, 278 auditory system, 292 midbrain, 287 Inferior epigastric vessels, 89, 91 Inferior gluteal nerves, 197 injuries, 198 lumbosacral plexus, 195, 196 Inferior mesenteric artery, 126, 129, 130 Inferior mesenteric vein, 131, 132 Inferior olivary nuclei, 279 Inferior pancreaticoduodenal arteries, 128, 129 Inferior phrenic arteries, 126 Inferior sagittal sinus, 217, 219, 247 Inferior vena cava, 130–131, 132 radiology, 174–177 Infraspinatus muscles, 191 Infundibulum, 73, 165, 168, 169 Inguinal canal, 90 boundaries, 91 deep inguinal ring, 89, 90 female contents, 90 inguinal triangle, 92, 93 male contents, 90–91 superficial inguinal ring, 87, 89, 90 Inguinal hernias, 92–93, 94
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Index Inguinal ligament, 86, 87, 88, 91 femoral triangle, 201 inguinal vs. femoral hernias, 94 Insufficiency of heart valves, 74, 75 Insulin and corticosteroids, 52 Integrins, 15 Intercalated discs, 74 Intercalated ducts pancreas, exocrine, 122 salivary glands, 120 Intercostal spaces, 38 Interlaminar spaces, 22 ligamenta flava, 27, 29 lumbar puncture, 27, 29 Intermediate filaments, 15, 17 Intermediate mesoderm, 3, 10 Intermediate zone of spinal cord, 252, 255 Internal abdominal oblique muscle, 88, 89, 91 Internal arcuate fibers, 280 Internal capsule arterial supply, 355 basal ganglia, 318, 320, 321 corticospinal tract, 257 Internal carotid arteries cavernous sinuses, 219, 220 thrombosis, 220 cerebral cortex, 344–345, 346 radiology, 347 visual field defects, 332 Internal iliac arteries, 126 Internal jugular veins, 66 dural venous sinus drainage, 218, 219, 247 lymphatic drainage, 43, 45, 65, 67 Internal mammary artery, 35 Internal pudendal artery, 152 Internal spermatic fascia, 89, 91 Internal thoracic artery, 35 Internal urethral sphincter, 138 Internal vertebral venous plexus, 26, 27 Internuclear ophthalmoplegia, 282 Interposed nucleus, 312, 314 Interventricular arteries, 76, 77 Interventricular septum, 59 Intervertebral disks, 22, 23, 24 Intervertebral foramina, 22, 23, 24, 25, 26 Intestinal arteries, 128, 129 Intracerebral hemorrhage, 348 radiology, 363 Intrafusal muscle fibers, 256, 258 gamma motoneurons, 254–255, 256 reflexes, 258–260 Intraocular pressure, 326 Intraperitoneal organs duodenum, 106 pancreas tail, 105 retroperitoneal organs versus, 99 visceral peritoneum, 98, 99 Intrinsic factor, 113 Inverse muscle stretch reflex, 259 Iris, 326, 328 Ischial spine, 88 Ischioanal fossa, 152
Ischiocavernosus muscle, 153 ejaculation, 164 Ischiofemoral ligament, 202 Ischiopubic ramus, 155 Islets of Langerhans, 121, 122 Isthmus of uterus, 165, 169 Ito cells, 125
J Jaundice, obstructive, 105 Jejunum, 107 digestion, 116 embryology, 98 histology, 110, 111, 114–118 radiology, 173, 176 Jugular foramen, 216 jugular vein, 218 sigmoid sinuses, 219, 247 syndrome, 217 Juxtaglomerular complex, 146
K K (Kulchitsky) cells, 48 bronchial metastatic tumors, 49 Kartagener syndrome, 18, 48 ovum transport and, 170 Kayser-Fleischer ring, 322, 323 Keratins as intermediate filaments, 15, 17 Kidneys anatomy, 137, 139, 140 blood circulation, 140 congenital abnormalities, 136–137 renal agenesis, 38, 136 embryology, 134–135 dorsal embryonic mesentery, 97 endocrine functions, 139, 145, 146 histology, 139–146 homeostasis by, 140 radiology, 175–176 ureters, 176, 177 renal calculi, 137 Kinesin, 15 fast anterograde transport, 238 Klumpke’s paralysis, 184 Klüver-Bucy syndrome, 358, 362 Knee joints, 203–205 deep tendon reflex, 258–259 injuries anterior cruciate ligament, 205 drawer signs, 204 medial meniscus, 204, 205 tibial collateral ligament, 203, 205 radiology, 206 Korsakoff syndrome, 336, 338, 362 Kulchitsky (K) cells, 48 bronchial metastatic tumors, 49 Kupffer cells, 122
L Labia majora embryology, 147 Labia minora, 155 embryology, 147
Lactation, 172 Lacunar ligament, 87 Lamina propria of GI mucosa, 109, 110 duodenum, 116 esophagus, 112 gut-associated lymphatic tissue, 109, 118 small intestine, 115 Laminae of vertebrae, 23 Langerhans cells, 112 Language aphasias, 345, 350, 351, 352, 358 dominant hemisphere and, 344 Large intestine, 118–119 Laryngotracheal diverticulum, 36 Larynx, 46 embryology, 211 Lateral cervical cysts, 212 Lateral epicondyle, 192 Lateral geniculate body, 332, 353, 354 Lateral horn gray matter, 28, 30, 32, 269 Lateral lemniscus auditory system, 291, 292 pons, 284 Lateral ligament of ankle, 205 Lateral medullary syndrome, 303 Lateral menisci, 203, 204 Lateral mesoderm, 10 Lateral plantar nerves, 199 Lateral pontine syndrome, 304–305 Lateral sulcus, 342, 349 Lateral thoracic artery, 35 Left anterior descending (LAD) artery, 76, 77, 79 Left colic artery, 129, 130 Left common iliac artery (radiology), 177 Left gastric artery, 126–127, 128 Left gastric vein, 132 Left gastroepiploic artery, 128 Left renal vein compression, 130 Left-to-right shunts atrial septal defects, 58, 63 as noncyanotic, 58, 59, 63 patent ductus arteriosus, 60, 63, 68 pulmonary hypertension, 59 ventricular septal defects, 59, 63 Lens of eye, 326 accommodation-convergence reaction, 327, 328 Leukodystrophies, 240–241 Levator ani muscle, 149 Lewy bodies, 237 Parkinson disease, 322 Leydig cells testis interstitial tissues, 157, 160, 161 testosterone secretion, 3, 160 Ligamenta flava, 27, 29 Ligamentum arteriosum coarctaction of the aorta, 68 fetal circulation, 55, 56 patent ductus arteriosus, 60 heart anatomy, 66, 70 Ligamentum capitis femorum, 202
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Immunology
Ligamentum teres of liver, 55, 56, 104 Ligamentum venosum, 55, 56 Light reflex, 277 Limbic system anatomy, 359, 361 Pharmacology Biochemistry functions, 359, 360, 361 olfactory system, 359–360, 361 Papez circuit, 360, 361 Limbs. See Lower limbs; Upper limbs Line of Gennari, 344, 353 Physiology Medical Genetics Linea alba, 85 Linea semilunaris, 85 Lingual gyrus lesions, 333 Meyer’s loop, 331, 332 Pathology Behavioral Science/Social Sciences radiology, 363 Lingula of left lung, 43 Lithiasis, biliary, 125 Liver, 103–104 embryology, 97, 101 Microbiology ventral embryonic mesentery, 95, 97, 101 hepatocytes, 122–123 zones, 124 histology, 122–125 lobules, 123, 124 peritoneal membranes, 100 radiology, 174–175 vitamin storage, 125 Locus caeruleus, 308 Long thoracic nerve, 35, 182 lesions, 186–187 Loop of Henle, 141, 145 Lower limbs ankle joints, 205 arterial supply, 200–201 embryology, 210 feet, 198, 199, 201, 205 femoral triangle, 201 hip joints, 202 innervation injuries and gait, 198–199 lumbosacral plexus, 195–197 segmental, 197 sensory, 199 knee joints, 203–205 radiology, 206 Lumbar arteries, 126 Lumbar plexus, 251, 253 ilioinguinal nerve, 90 parietal peritoneum, 98 Lumbar puncture, 27, 29 Lumbar splanchnic nerves, 138 ejaculation, 164 Lumbar vertebrae, 22 iliac crest and lumbar puncture, 29 Lumbosacral plexus, 195–196 collateral nerves, 197 injuries, 198–199 Lunate, 193 Lungs. See also Surfactant anatomy, 42–43 aspiration of foreign body, 43
auscultation, 43 cancer, 45 apex of lung, 42 metastasis, 44 capillary diseases, 45 embryology, 36–38 primitive gut tube, 95, 96 pulmonary hypoplasia, 38 histology, 45–53 lymphatic drainage, 43–45 pleura, 39–41 tracheoesophageal fistula, 37, 38 Luteinizing hormone, 168 Lymphatic system abdominal wall, 90 bladder, 138 breast, 36 cancer metastasis breast, 36 internal vertebral venous plexus, 27 lung, 44 penis and scrotum, 91 testes, 91 drainage, 43–45 duodenum, 116 ileum, 116 lungs, 44–45 pectinate line, 108 testes, 91 thoracic duct, 43–45 posterior mediastinum, 65 superior mediastinum, 67
M Macrophages, alveolar, 51, 53 Macula (eye), 326 collateral circulation, 332, 348, 353, 357 hemianopia with macular sparing, 331, 353 lesions, 333 Macula (vestibular system), 293 Macula adherens, 16 Major duodenal papilla, 105, 107 Male pelvic anatomy, 150, 153, 154 Male pseudointersexuality, 147 Malignancies. See Cancers Malleus, 290, 291 embryology, 211 Mammary glands, 172. See also Breasts Mammillary bodies, 337, 340 anatomy, 276, 338, 342 lesions, 338 Papez circuit, 360, 361–362 radiology, 363 Mandible embryology, 210, 211 Mandibular nerves embryology, 211 functions, 280 lesions, 280 nuclei, 286 tongue, 213 Marcus Gunn pupil, 329 Marginal artery, 129, 130
Mastectomy nerve lesion, 35, 186–187 Maxilla embryology, 210, 211 Maxillary nerves cavernous sinus, 219, 220 thrombosis, 220 functions, 280 lesions, 280 nuclei, 286 Meckel diverticulum, 103 Meconium and Hirschsprung disease, 231 Medial collateral ligaments, 203 Medial geniculate body, 292 Medial lemniscus, 263, 264, 265, 271 brain stem, 277, 278, 279, 282 internal arcuate fibers, 280 medulla, 282 pons, 284 lesions, 282, 302, 303, 304, 305 midbrain, 287 Medial ligament of ankle, 205 Medial longitudinal fasciculus (MLF) anatomy, 278, 279, 282 horizontal conjugate gaze, 296, 297 lesions, 282, 297, 298, 300 midbrain, 287 pons, 284 vestibular fibers, 293, 294 Medial medullary syndrome, 302–303 Medial menisci, 203, 204 Medial midbrain syndrome, 306–307 Medial plantar nerves, 199 Medial pontine syndrome, 304, 305 Medial umbilical ligaments, 55, 56 Median nerves brachial plexus, 179, 180, 181 carpal tunnel, 183, 190 syndrome, 183, 190, 193 lesions, 185–186, 187 radiology, 192, 193 sensory, 182, 183 Median sacral artery, 126 Median umbilical ligament, 136 Mediastinal surface of lung, 42 Mediastinum, 63–69 adult thoracic cavity, 38 anterior, 64 inferior, 63 mediastinal parietal pleura, 40 middle, 66, 68–69. See also Heart pneumothorax, 40 posterior, 64–65 sternal angle, 63, 64, 66 superior, 63, 65–67 Medulla, 282–283 anatomy, 276, 277, 279, 280 cerebral hemispheres, 342 cranial nerves, 275, 277, 279, 280 embryology, 227 medial medullary syndrome, 302–303 radiology, 363 Meiosis, 4, 5 microfilaments in cytokinesis, 15 microtubules of mitotic spindle, 15
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Index ovarian follicle, 167, 168 seminiferous tubule, 158 Meissner’s plexus, 109, 110 Membranous ventricular septal defect, 59 Memory. See also Alzheimer disease amnesias, 362 emotional imprint, 360 limbic system, 359 thalamus, 335, 336 Ménière disease, 295 Meningeal dural layer, 217 dural venous sinuses, 218–219 Meninges cranial, 217–218 spaces of, 218, 247 spinal, 25–27, 217 epidural anesthesia, 27, 29 lumbar puncture, 27, 29 Meniscus of knees, 203 Menstrual cycle amenorrhea, 337, 338, 340 first missed in pregnancy, 10 progestational phase, 8 Mesangial cells, 145, 146 Mesencephalic nuclei, 286, 287 Mesencephalon, 227 Mesenteries colon, 107 embryonic, 95, 97, 98, 101 histology, 108 intra- vs. retroperitoneal organs, 99 mesoappendix, 107 peritoneum, 98–99, 100 Mesocolon, 98 Mesoderm derivatives, 10, 12, 229 pharyngeal arch derivatives, 211 extraembryonic, 9 face, 214 gastrulation, 10 heart, 53 endocardial cushions, 57 hematopoiesis, 9 kidneys, 134 nervous system, 12 pharyngeal arches, 210 pleura, 39 primitive gut tube, 94, 96 respiratory system, 36 spleen, 102 vertebral column, 21, 210 Mesometrium, 152 Mesonephric ducts (Wolffian), 3, 4, 136 embryology, 134, 135, 136 duct of Gartner, 147 Mesonephros, 134, 135, 136 Mesosalpinx, 152 Mesothelioma, 45 Mesothelium of GI serosa, 109 gallbladder covered by, 125 Mesovarium, 152 Metanephric mass, 134, 135 Metanephros, 134
Metencephalon, 309 Meyer’s loop, 331, 332 lesions, 333, 345 Microfilaments, 14–15, 237 Microglia, 240 Microtubules, 15 axonal transport, 237, 238, 239 neuropathies and, 227, 239 cilia, 15, 18 colchicine and, 15 neuron cytoskeleton, 237 tau protein, 238 spermatozoa, 159 Microvilli, 17, 18 Micturition, 138 autonomic nervous system, 138 hyperplasia of the prostate, 150 urethral sphincters, 138, 149, 150 Midaxillary line, 41 Midbrain anatomy, 276, 277, 278, 287–289 cranial nerves, 275, 277, 287–289 embryology, 227 medial midbrain syndrome, 306–307 radiology, 363 substantia nigra, 278, 287 Midclavicular lines, 86 pleural reflections, 41 Middle cardiac vein, 77, 78 Middle cerebral arteries, 345, 346, 347 occlusion, 332, 345, 351, 357 radiology, 347 Middle colic artery, 128, 129 Middle meningeal arteries, 209 epidural hematoma, 348 Middle scalene muscles, 208 Middle suprarenal arteries, 126, 130 Midgut, 94, 95 colon boundary, 107 derivatives, 95 duodenum, 107 malrotation, 103 rotation, 96, 98 superior mesenteric artery, 128 superior mesenteric vein, 131, 132 Miosis, 327, 328 Mitochondria in spermatozoa, 159 Mitosis microfilaments in cytokinesis, 15 microtubules of mitotic spindle, 15 none in syncytiotrophoblast, 9 zygotes, 7, 8 Mitotic spindle microtubules, 15 Mitral valve auscultation, 74, 75 blood flow, 72, 73 murmurs, 74–76 Moderator band, 73, 79 Molar pregnancies, 11 hCG levels, 9, 11 Morula, 7, 8 Mossy fibers, 310, 312–313
Motor cortex basal ganglia pathways, 317–319 cerebral cortex frontal lobe, 349, 358 functional areas, 349 motor homunculus, 343, 349 precentral gyrus, 256, 257 radiology, 363 Motor system 2 motor neurons, 255, 256, 271 alpha motoneurons, 254–256, 271 lesions, 260–261 reflexes, 258–260 autonomic nervous system, 30, 230 corticospinal tracts anatomy, 256, 257, 269, 271 brain stem, 277, 278, 279, 282, 284 lesions, 257, 260, 261, 282, 302, 304, 305, 307 neocortex, 344 embryology, 225, 226 gamma motoneurons, 254–255, 256, 271 lesions, 260–261 muscle tone and reflex activity, 254–255, 259 reflexes, 258–260 motor homunculus, 343, 349. See also Motor cortex reflexes, 258–260 thalamus, 335, 336 upper and lower, 255–256, 257 corticobulbar fibers, 288–289 lesions, 259, 260, 261, 271 ventral horn, 252, 253, 254–255 ventral root, 28, 252, 254, 255 Mucociliary escalator system, 48 Mucosa of GI tract, 108, 109, 110, 111 gastric and H. pylori infection, 114 large intestine, 119 Mucous-secreting cells of stomach, 111, 113 Müllerian ducts, 3, 4 Müllerian-inhibiting factor (MIF), 3, 4, 160 Multiple sclerosis (MS), 241 relative afferent pupil, 329 unilateral optic nerve lesions, 332 Mumps and parotid salivary glands, 121 Murmurs of heart, 74–76 auscultation, 74, 75 Muscle stretch reflex, 258–259 Muscularis externa, 108, 109, 110, 112 Muscularis mucosa, 109, 110, 115 Musculocutaneous nerves brachial plexus, 179, 180, 181 injury, 183, 184 lesions, 186, 187 sensory, 183 Mydriasis, 328 Myelencephalon, 227
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Immunology
Myelin sheath axon initial segment, 238 disorders of myelination, 240–241 subacute combined degeneration, 273, 274 Pharmacology Biochemistry neuron structure, 236, 238 oligodendrocytes forming, 240 optic nerves, 325 Schwann cells forming, 240 vitamin B12 deficiency, 113 Physiology Myocardial infarction, 76 Medical Genetics Myocardium histology, 73–74 Myometrium, 165, 170, 171 Myotatic reflex, 258–259
N
Pathology
Behavioral Science/Social Sciences
Narrow-angle glaucoma, 326 NAVEL contents of femoral canal, 201 Neck arterial supply, 209 Microbiology cervical parietal pleura, 40 embryology, 210–215 congenital abnormalities, 215 scalene triangle, 207, 208 thoracic outlet, 38, 207 syndrome, 207 Negri bodies, 237 Neocortex, 342–344 Nephrons embryology, 135 histology, 141–146 Nerve blocks epidural, 27, 29 intercostal, 38 pudendal, 152 Nervous system. See Central nervous system; Peripheral nervous system Neural crest cells colonic aganglionosis, 103, 109 derivatives, 12, 229 endocardial cushion development, 57, 59 face, 214 gastrulation, 10, 12 heart tube formation, 53 nervous system, 225–226 postganglionic neurons, 30, 225 Schwann cells, 240 pharyngeal arches, 210, 211 truncus arteriosus septation, 60, 61 Neural fold, 225, 226 Neural plate, 225, 226 Neural tube, 225, 226, 229 Neuroectoderm, 10, 12, 225, 229 Neuroendocrine cells gastrointestinal, 114 pulmonary, 48, 49 Neurofibrillary tangles, 238, 360 Neurofibromatosis (type 2), 244 Neurofilaments, 15, 237 Neurohypophysis, 338 Neurons action potential, 238, 240 degenerative diseases
astroglial scars, 239 inclusions seen in, 237 microglia cytokines, 240 microglia free-radical production, 240 neurofibrillary tangles, 238 tau protein, 238 histology, 235–236, 237, 238–239 axons, 241–242 Nissl substance, 235, 236, 237 inclusions, 237 myelination disorders, 240–241 subacute combined degeneration, 273, 274 neurofilaments, 15 regeneration of, 243, 244 structure of, 236, 238 cytoskeleton, 236, 237 tau protein, 238 Neuropathies, 227, 239 Neurosyphilis and Argyll Robertson pupils, 274, 327, 329 Neurulation, 225–226 Night blindness, 325 Nissl substance, 235, 236, 237 axon hillock, 238 chromatolysis, 243 Nitric oxide for erection, 164 Nodes of Ranvier, 236, 240 Noncyanotic conditions atrial septic defects, 58, 63 left-to-right shunts, 58, 59, 63 patent ductus arteriosus, 60, 63, 68 pulmonary hypertension, 59 ventricular septal defects, 59, 63 Notochord chordoma, 11 germ layer derivatives, 12 nervous system embryology, 10, 225–226 neural plate, 225, 226 nucleus pulposus, 12, 23 vertebral column embryology, 21 Nuclear envelope, 15 Nucleus ambiguus, 279, 283 lesions, 303 Nucleus cuneatus, 263, 280, 282 Nucleus gracilis, 263, 271, 280, 282 Nucleus pulposus, 23, 24 herniation, 24, 25 Nystagmus, 296 caloric test, 295, 296 cerebellar lesions, 315 vestibular, 294, 295, 296
O Obturator nerves, 195, 196 injuries, 198 Occipital lobe, 353–354, 358 anatomy, 342 lesions, 354 Occipital sinus, 219 Oculomotor nerves (CN III) brain stem, 275, 276, 277, 278, 287 cavernous sinus, 219, 220, 247
thrombosis, 220 embryology, 211 functions, 280 horizontal conjugate gaze, 297, 298 lesions, 280, 306, 307, 329 nuclei, 287 orbital muscles, 221, 297, 298, 326 pupillary light reflex, 326, 327 vestibular fibers, 293, 294 Olfactory system, 359–360, 361 deficits, 280, 358, 360 olfactory bulb, 276, 359–360 brain anatomy, 361 Olfactory tract (CN I) anatomy, 276, 277 functions, 280 lesions, 280, 358, 360 Oligodendrocytes, 240 Oligohydramnios and renal agenesis, 38, 136 Olive, 276 Omental bursa, 99, 101 Omentum, 98 greater, 100 dorsal embryonic mesentery, 95 lesser, 100, 101 hepatoduodenal ligament, 100, 103 hepatogastric ligament, 100, 103 ventral embryonic mesentery, 95, 97, 101 Omphalocele, 103 Omphalomesenteric veins, 54 Oocytes fertilization, 7 follicular development, 166, 168 meiosis, 5, 168 oogenesis, 6 ovulation, 166, 167, 168 Oogenesis, 4, 6 meiosis, 4, 5 Oogonia follicular development, 166, 167 meiosis, 5, 167 oogenesis, 6 Open pneumothorax, 40 Open-angle glaucoma, 326 Ophthalmic arteries, 345 occlusion, 357 Ophthalmic nerves cavernous sinus, 219, 220 thrombosis, 220 functions, 280 lesions, 280 nuclei, 286 Ophthalmic veins, 218, 219 Optic chiasm anatomy, 276, 277, 321 cerebral hemispheres, 342 hypothalamus, 338, 339 lesions, 333 visual field defects, 331–332 visual pathway, 330, 332 Optic disc, 325, 326
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Index Optic nerves (CN II) brain anatomy, 276, 277 eye anatomy, 222 functions, 280 lesions, 280, 332, 333 visual field defects, 331–332 pupillary light reflex, 326, 327 visual pathway, 325, 326 Optic neuritis, 332 Optic tract lesions, 333 visual field defects, 331–332 optic chiasm, 330 thalamus, 335, 336 Oral cavity embryology, 8, 9, 214 histology, 112 salivary glands, 120–121 Orbit veins, 218, 219 Orbital muscles, 221–222 embryology, 211 Organ of Corti, 290, 291 Oval window, 290, 291 Ovaries anatomy, 165 female anatomy, 151, 152 embryology, 3, 4, 147 fertilization, 7 follicular development, 166, 167–168 histology, 167–170 oogenesis, 4, 6 meiosis, 4, 5 Oviducts ampulla, 7 tubal ectopic pregnancy, 8 anatomy, 165, 169 fertilization, 7, 8, 168, 169, 170 histology, 169–170 ovulation, 169 Ovulation, 166, 167, 168, 169 progesterone preventing, 169 Ovum fertilization, 7, 8, 170 infundibulum, 169 ovulation, 166, 168 Oxyntic cells, 113 Oxytocin, 337, 339
P Pacemaker of heart. See Sinoatrial (SA) node Pain anterolateral sensory system, 265 medial meniscus tear, 205 peritonitis, 98 referred pain diaphragmatic in shoulder, 80 primitive gut tube structures, 95 spinal lesion, 265, 266, 269 thalamic pain syndrome, 336 Palate embryology, 214 Pampiniform venous plexus, 91
Pancreas, 105–106 anastomoses, 105, 127, 129 annular, 102 embryology, 97, 101, 102 foregut, 95, 96 exocrine gland, 121–122 radiology, 175 Pancreatic duct of Wirsung, 105, 106, 122 hepatopancreatic ampulla, 105, 107, 122, 125 Paneth cells, 110, 111, 115, 117 Papez circuit, 360, 361–362 anterior thalamic nuclei, 335, 336 Papillae of tongue, 213 Papillary muscles, 72, 73 Paramesonephric ducts, 3, 4 Parasternal lymph nodes, 36 Parasympathetic nervous system, 32–33, 231–232 autonomic nervous system, 30, 230, 231 bladder innervation, 138 craniosacral outflow, 32, 33, 231, 232 eye innervation, 326, 328 gastrointestinal system, 110 peristalsis, 111, 116 salivary glands, 120 heart innervation, 79 hypothalamus, 338 internal anal sphincter, 107 micturition, 138 spastic bladder, 138 penile erection, 164 Parathyroid gland ectopic, 215 embryology, 212 Paraventricular nuclei, 337, 338, 339 Paravertebral line, 41 Paravertebral motor ganglia, 30 Paraxial mesoderm, 10 Parietal cells of stomach, 113, 114 Parietal layer, 39 pericardium, 68–69 peritoneum, 89, 98 embryology, 98 female pelvis, 151 male pelvis, 150 peritonitis, 98 retroperitoneal organs, 98, 99 secondary retroperitonealization, 97, 99 pleura, 39–40 pleural reflections, 41 pleurisy, 40 Parietal lobe, 351–353, 358 anatomy, 342 corticospinal tract, 257 lesions, 351, 354 postcentral gyrus, 262, 263, 264 sensory homunculus, 343, 351 Parinaud syndrome, 306, 308, 340 Parkinson disease, 322, 323 Parotid salivary glands, 120, 121 Passive immunity of infants, 116, 172 Patau syndrome holoprosencephaly, 228
Patella, 203 deep tendon reflex, 258–259 radiology, 206 Patent ductus arteriosus (PDA), 60, 63, 68 Pectinate line, 108 Pectinate muscles, 72 Pectoral lymph node group, 36 Pedicles of vertebrae, 23, 24 Pelvic brim, 149 Pelvic diaphragm, 149, 152 Pelvic kidney, 137 Pelvic splanchnic nerves, 32, 33 bladder innervation, 138 penile erection, 164 Pelvis female, 151–152, 155 hip joint, 202 innervation, 155 lumbosacral plexus, 195–197 male, 150, 153, 154 Pemphigus vulgaris, 16 Penis anatomy, 150, 154, 156 cancer, 91 ejaculation, 164 embryology, 136, 147 congenital abnormalities, 148 erection, 164 hypothalamic lesions, 337, 340 fluid accumulation, 165 histology, 154 urine extravasation, 154, 165 urogenital triangle, 152–154 Peptic cells, 114 Periaqueductal gray, 308 Pericardium, 68–69 cardiac tamponade, 69 heart wall, 74 mesodermal origins, 39 Pericranium, 217 Pericytes, 240, 242 Perilymph, 290, 291 Perimetrium, 165 Perineal membrane, 153 Perineum, 152 anal triangle, 152 female, 155 pudendal innervation, 155 trauma to, 165 Periosteal dural layer, 217 dural venous sinuses, 218–219 Peripheral nervous system autonomic nervous system, 30, 230–231 parasympathetic nervous system, 32–33 sympathetic nervous system, 30–32 axonal regeneration, 243, 244 definition, 225 embryology, 225–229 glial and supporting cells, 239–240 histology of neurons, 235–240 postganglionic neurons, 30 somatic, 230–231 spinal and cranial nerves as, 27
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Anatomy Anatomy
Immunology
Peristalsis of GI tract Hirschsprung disease, 103, 109, 231 innervation, 109–110, 116 muscularis externa, 109 Peritoneal cavity, 99, 101 Pharmacology Biochemistry embryology, 97, 98 Peritoneum, 89, 98 embryology descent of testes, 92 mesodermal origins, 39 Physiology primitive gut tube, 97 Medical Genetics female pelvis, 151 intra- vs. retroperitoneal organs, 99 male pelvis, 150 membranes, 100 Pathology Behavioral Science/Social Sciences peritonitis, 98 serosa of GI tract, 108 Peritonitis, 98 Pernicious anemia, 113 Persistent truncus arteriosus, 62, 63 Microbiology Peyer’s patches, 110, 116, 118 Pharyngeal apparatus, 210–212 congenital abnormalities, 215 cleft lip, 214 cleft palate, 214 Pharyngeal arches, 210, 211 face, 214 first arch syndrome, 215 tongue, 213 Pharyngeal cyst, 215 Pharyngeal fistula, 215 Pharyngeal grooves, 210 pharyngeal cyst, 215 pharyngeal fistula, 215 Pharyngeal pouches, 210, 212 DiGeorge sequence, 212, 215 pharyngeal fistula, 215 Pharynx embryology, 210–211 congenital abnormalities, 214, 215 thyroid diverticulum, 213 Philtrum, 214 Phrenic nerves diaphragm, 79 scalene triangle and, 207, 208 superior mediastinum, 66, 67 Pia mater cranial, 217, 247 spinal, 26–27, 252 PICA (posterior inferior cerebellar artery) occlusion, 303 Pineal body, 337, 340 anatomy, 276, 277, 342 circadian rhythms, 337, 339, 340 lesions, 340 radiology, 363 tumors, 306, 308, 340 Piriformis syndrome, 198 Pisiform, 193 Pitch of sound and hearing, 290, 291 Pituitary anatomy, 276, 342 cavernous sinuses, 220 hypothalamus, 338, 339
ovulation, 168 radiology, 363 visual field defects, 332 Placenta embryology, 7, 8 human chorionic gonadotropin, 169 Pleura, 39–40 mesothelioma, 45 pleural recesses, 41 pleural reflections, 41 Pleural cavity, 39, 40 pleural reflections, 41 pneumothorax, 40 Pleurisy, 40 Plicae circulares, 115, 116 Pneumocytes, 51, 52 Pneumothorax, 40 Podocytes, 142, 143, 144 Polar body, 6, 168 Polio virus poliomyelitis, 272, 273 retrograde axonal transport, 239 Polkissen cells, 145, 146 Polyhydramnios anencephaly, 226 annular pancreas, 102 duodenal atresia, 103 hypertrophic pyloric stenosis, 102 tracheoesophageal fistula and, 37 Pons anatomy, 276, 277, 278, 279, 284–287 cerebral hemispheres, 342 cranial nerves, 275, 277, 285–287 embryology, 227 lateral pontine syndrome, 304–305 medial pontine syndrome, 304, 305 radiology, 363 Pontocerebellar angle syndrome, 306 Popliteal arteries, 200, 201 Pores of Kohn, 52 Portacaval anastomoses, 132, 133 Portal hypertension, 132 Portal lobules, 123, 124 Portal triad, 104, 123 Portal vein. See Hepatic portal vein Postcentral gyrus anterolateral system, 262, 265, 266 dorsal column–medial lemniscal system, 262, 263, 264 Posterior cerebral arteries, 345, 346, 347, 348 occlusion, 332, 348, 353, 354, 356, 357 Posterior chamber (eye), 326 Posterior communicating arteries aneurysm, 221, 357 circle of Willis, 301, 344, 346, 348 occlusion, 357 Posterior cruciate ligaments, 203, 204 posterior drawer sign, 204 Posterior tibial arteries and fractures, 201
Postganglionic neurons, 30, 225, 230, 231 parasympathetic nervous system, 32, 33, 231, 232 sympathetic nervous system, 30, 31, 225, 231, 232 Potter sequence, 38, 136 Pouch of Douglas, 8, 151 PPRF (paramedian pontine reticular formation), 296, 297, 298, 299 Precentral gyrus cerebellum, 314 cerebral cortex, 342 primary motor cortex, 256, 257 upper motor neurons, 261, 288, 314 Prechordal plate, 8, 9, 10 Prefrontal cortex, 350, 358 limbic system, 361 Preganglionic neurons, 30, 230, 231 parasympathetic nervous system, 32, 33, 230, 231 sympathetic nervous system, 30, 31, 230, 231, 232 Pregnancy alpha-fetoprotein levels, 225 anencephaly, 226, 228 spina bifida, 226, 228 corpus luteum and, 169 ectopic, 8, 170 hCG levels, 9 human chorionic gonadotropin levels, 9, 11 menstrual cycle first missed, 10 molar, 11 myometrium growth, 170 Premature infants lung development, 37 patent ductus arteriosus, 60 respiratory distress syndrome, 39 Presbycusis, 291 Pretectal nuclei, 277 Prevertebral motor ganglia, 30, 31 Primary palate, 214 Primary sex cords, 3 Primitive gut tube, 94, 96 congenital abnormalities, 102–103 derivatives, 95 foregut rotation, 95, 96 hindgut, 94, 95 derivatives, 95 septation, 96 midgut, 94, 95 derivatives, 95 malrotation, 103 rotation, 96, 98 organ development, 95, 97 secondary retroperitonealization, 97, 99 Primitive node, 10 Primitive pit, 10 Primitive streak, 10 Primordial germ cells, 3 Primum atrial septal defect, 58, 59 Process vaginalis, 92, 148 Progestational phase of menstrual cycle, 8
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Index Progesterone, 169 Prolactin and arcuate nuclei, 338 Prolapse of the uterus, 152 Pronephros, 134 Proper hepatic artery, 100, 101, 104, 127, 128 Proprioception Clarke nucleus, 255 dorsal column–medial lemniscal system, 263, 264 spinocerebellar tracts, 267–268 Prosopagnosia, 354 Prostaglandins, 139 Prostate gland ejaculation, 164 embryology, 136 histology, 164 hyperplasia, 150 male anatomy, 150, 154, 156 perineal pouches, 153 Proximal convoluted tubule, 141, 145 renal corpuscle, 142, 143 Pseudointersexuality, 147 Psoas major muscle (radiology), 176, 177 ureters on anterior surface, 137 Psychic blindness, 362 Puberty 5α-reductase 2 deficiency virilization, 148 hypothalamic lesions, 337, 340 oogenesis, 6 pineal lesions, 340 Sertoli cells in seminiferous tubules, 160 spermatogenesis, 6 Pubic symphysis, 88, 155 Pubic tubercle, 86, 88 Pubofemoral ligament, 202 Puborectalis muscle, 149 Pudendal nerve course of, 137 ejaculation, 164 external anal sphincter, 108, 119, 152 external urethral sphincter, 138 pelvis, 150, 155 perineum, 152 Pudendal vessels, 137 Pulmonary arteries alveolar capillaries, 52 coarctation of the aorta, 68 embryology, 211 fetal circulation, 55 patent ductus arteriosus, 60 persistent truncus arteriosus, 63 heart anatomy, 70 radiology, 81, 83, 84 Pulmonary hypertension, 59 Pulmonary hypoplasia, 38, 136 Pulmonary lymph nodes, 44 Pulmonary neuroendocrine (PNE) cells, 48, 49 Pulmonary semilunar valve auscultation, 74, 75 blood flow, 72 murmurs, 74–76
Pulmonary veins heart anatomy, 70 blood flow, 72 heart embryology, 54 Pupil abnormalities, 329 constriction, 327, 328 light reflex, 326, 327 Purkinje cells (cerebellum), 310–311, 312, 313 circuitry, 311, 312, 313–314 Purkinje fibers (heart), 74, 78, 79 Putamen, 318, 320, 321 Pylorus of stomach, 106, 111 pyloric stenosis, hypertrophic, 102 Pyramids, 276, 279 decussation, 256, 257, 271, 280 lesions, 303
Q Quadrantanopia, 331, 358 Quadratus lumborum muscle, 137
R Rabies virus parotid salivary glands, 121 retrograde axonal transport, 239 Radial arteries, 188, 189 Radial dilator muscles, 328 Radial glia, 240 Radial nerves brachial plexus, 179, 180, 181 lesions, 185, 187 humeral head dislocation, 187, 191 humeral mid-shaft fracture, 185, 187, 192 radiology, 192 sensory, 182, 183 Radical mastectomy nerve lesion, 35, 186–187 Radiology abdomen, 173–177 aortic arch, 66 central nervous system brain, 320, 347, 363 spinal cord, 83, 84 costal notching, 67 esophagus and left atrium, 64 knee joint, 206 left internal carotid artery, 347 thorax, 81–84 transpyloric plane, 85 upper limbs, 192–193 Radius (radiology), 192 Raphe nuclei, 308 Receptive aphasia, 352 Rectal vein anastomoses, 132, 133 Rectouterine pouch, 8, 151 Rectum, 107 colonic aganglionosis, 103, 109, 231 embryology, 135 fecal material, 118
herniation into vagina, 152 portacaval anastomoses, 133 Rectus sheath, 87, 88, 89 Recurrent laryngeal nerves, 66, 67 Red nucleus, 278, 314, 315 Referred pain diaphragmatic in shoulder, 80 primitive gut tube structures, 95 Reflexes accommodation-convergence reaction, 327 light reflex, 277 motor system, 258–260, 271 motoneuron lesions and, 260 prefronal lesions, 350 pupillary light reflex, 326, 327 vestibulo-ocular, 282, 293, 294 brain stem integrity, 295, 296 Relative afferent pupil, 329 Renal agenesis, 136 pulmonary hypoplasia and, 38 Renal arteries, 126, 130, 140 Renal corpuscle, 141, 142–144, 146 Renal pelvis (radiology), 176 Renal system. See Kidneys; Urinary system Renin, 139, 146 Reproductive systems. See also Ovaries; Penis; Testes; Uterus embryology, 147 congenital abnormalities, 147–148 extraperitoneal connective tissue, 89 gonads, 3, 4, 91 mesonephric tubules, 134, 136 Müllerian-inhibiting factor, 160 vagina, 136, 147 female pelvis, 151–152, 155 histology ovaries, 167–170 penis, 154 testes and accessory glands, 156–165 uterus, 170, 171 vagina, 171 male pelvis, 150, 153, 154 Müllerian-inhibiting factor, 3, 4, 160 Respiratory bronchioles, 50 Respiratory distress syndrome, 39 infants of diabetic mothers, 39, 52 Respiratory system. See also Lungs embryology, 36–38, 95 histology, 45–53 Rete testes, 156, 161 embryology, 147 Reticular formation, 308 cerebellar efferents, 314, 315 Reticular lamina, 16 Retina circadian rhythms, 340 histology, 330 lesions, 333 visual field defects, 331–332 visual pathway, 325, 326, 330 Retrograde amnesia, 362
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Anatomy Anatomy
Immunology
Retroperitoneal organs duodenum, 106 intraperitoneal versus, 99 parietal peritoneum, 98 secondary retroperitonealization, 97, 99 Pharmacology Biochemistry Ribs intercostal spaces, 38 radiology, 82, 83 spleen laceration, 106 Right colic artery, 128, 129 Physiology Medical Genetics Right common iliac artery (radiology), 177 Right gastroepiploic artery, 127, 128 Right lymphatic duct, 43–45 Right-to-left shunts Pathology as cyanotic, 58, 59, 61, Behavioral 62, 63Science/Social Sciences fetal foramen ovale, 54, 55 fetal foramen secundum, 57 persistent truncus arteriosus, 62, 63 pulmonary hypertension causing, 59 Microbiology tetralogy of Fallot, 61, 63 transposition of the great vessels, 62, 63 Rinne test, 293 Robin sequence, 215 Rods, 325, 330 rod stream, 354 Romberg sign, 264, 315 Rotator cuff, 191 Round ligaments of the hip, 202 Round ligaments of the uterus, 90, 151, 152 Round window, 290, 291 Rubrospinal tract, 314
S Saccule, 290, 291 vestibular system, 293, 294 Sacral hiatus, 22 Sacral plexus, 251, 253 Sacrococcygeal teratoma, 11 Sacrum, 22, 88 Salivary glands, 120–121 Saltatory conduction, 240 Saphenous nerve, 199 Sartorius muscles, 201 Scala media, 290, 291 Scala tympani, 290, 291 Scala vestibuli, 290, 291 Scalene triangle, 207, 208 thoracic outlet syndrome, 207 Scalp venous drainage, 217 Scanning dysarthria, 315 Scaphoid, 193 Scapula (radiology), 82, 83 “winged scapula,” 35, 187 Scarpa fascia, 87 urine extravasation, 154, 165 Schwann cells axonal regeneration, 243, 244 histology, 241, 242 myelin formation, 240 neuron structure, 236 Schwannomas, 244, 306
Sciatic nerves, 195, 196 injuries, 198–199 sciatica, 25 Sclera, 326 Sclerotomes, 21 Scrotum cancer, 91 embryology, 147 fluid accumulation, 165 hydrocele, 92 Secondary palate, 214 Secondary retroperitonealization, 97, 99 Secundum atrial septal defect, 58, 59 Selectins, 15 Semicircular canals, 290, 291 Semicircular ducts, 290, 291 caloric test, 295 vestibular system, 293, 294 Semilunar valves. See Aortic semilunar valve; Pulmonary semilunar valve Seminal vesicles ejaculation, 164 histology, 163 male anatomy, 150, 156 Seminiferous tubules embryology, 147 histology, 157–158, 160, 161 male anatomy, 156 spermatogenesis, 157–158 Sensory systems 3 sensory neurons, 262, 263 anterolateral sensory system, 262, 263, 265–267, 269 brain stem, 277, 282 lesions, 265, 266, 267, 282 auditory system, 291–293 cerebral cortex, 343, 349 parietal lobe, 351–353, 358 sensory homunculus, 343, 351 deficits auditory, 291, 292 axonal polyneuropathies, 227, 239 olfactory lesions, 280, 358, 360 spinal cord lesions, 264, 265, 266, 267, 268, 269 vestibular dysfunction, 295 visual, 325, 353, 354, 358, 362 dorsal column–medial lemniscal system, 262, 263–265 brain stem, 263, 264, 265, 277 brain stem medial lemniscus, 277, 278, 279, 280, 282 lesions in brain stem, 282 lesions in dorsal columns, 264, 265 medial lemniscus, 263, 264, 265, 271 dorsal horn, 252, 253, 254 embryology, 225, 226 lesions, 264, 265, 266, 267, 268, 269, 271 lower limbs, 199 olfactory system, 359–360 proprioception Clarke nucleus, 255
dorsal column–medial lemniscal system, 263, 264 spinocerebellar tracts, 267–268 radiology, 363 reflex initiation, 258 spinocerebellar tracts, 267–268 thalamus, 335, 336 tongue, 213 upper limbs, 182–183 carpal tunnel syndrome and, 183, 190 vestibular system, 293–296 vibratory dorsal column–medial lemniscal system, 263, 264 spinal cord lesion, 269 Septal nuclei, 359, 361 Septomarginal trabecula, 73, 79 Septum pellucidum, 276 Septum primum, 57, 58 Septum secundum, 57, 58 Serosa of GI tract, 108, 109, 110 Serous pericardium, 68–69 Sertoli cells, 160 androgen-binding protein, 160 blood–testis barrier, 157, 158, 160 inhibin, 160 Müllerian-inhibiting factor, 3, 4, 160 seminiferous tubule, 157, 158, 160 Shoulder collateral circulation, 190 diaphragmatic referred pain, 80 rotator cuff, 191 Sigmoid arteries, 129, 130 Sigmoid colon, 107 radiology, 173 Sigmoid sinuses, 219, 247 Sinoatrial nodal artery, 76, 77, 78 Sinoatrial (SA) node, 72, 78, 79 Sinus venarum, 54, 72 Sinus venosus, 53, 54, 56, 72 SITS muscles of rotator cuff, 191 Skeletal muscle innervation. See also Motor system basal ganglia, 317, 322–323 cerebellar functions, 309, 312, 315 corticobulbar fibers, 288–289 corticospinal tract, 256, 257 lesions, 257, 259, 260, 261, 315, 322–323 reflexes, 258–260 upper and lower motoneurons, 255–256 Skull, 215–216 arterial supply, 209 dural venous sinuses, 218–219 hemorrhages, 220–221 meninges, 217–218 orbital muscles, 221–222 respiratory pathways, 46 Sliding hiatal hernia, 106 Small intestine, 114–115 histology, 115–118 Smoking tobacco lung cancer, 45 squamous metaplasia, 49
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Index Solitary nucleus, 279, 283 lesions, 303 Somatosensory cortex, 262, 263, 264, 265, 266, 267 Space of Disse, 122, 123, 125 Spasmodic torticollis, 323 Spastic bladder, 138, 272 Spastic paresis, 260, 261, 345 Spastic weakness, 257, 261, 269, 271, 273, 307 Spermatic cord, 90–91 Spermatic fascia external, 87, 89, 91 internal, 89, 91 Spermatids meiosis, 5 seminiferous tubule, 157, 158 spermatogenesis, 6, 158 spermiogenesis, 6, 159 Spermatocytes meiosis, 5, 158 seminiferous tubule, 157, 158 spermatogenesis, 6, 158 Spermatogenesis, 4, 6, 8 meiosis, 4, 5 seminiferous tubule, 157–158 Spermatogonia pre-meiosis, 5, 158 seminiferous tubule, 157–158 spermatogenesis, 6, 157–158 Spermatozoa capacitation, 8 ductuli efferentes, 161 ejaculate, 163, 164 ejaculation, 164 epididymis, 162 fertilization, 8 flagella, 18 Kartagener syndrome, 18, 48 seminiferous tubule, 157 spermiogenesis, 6, 159 vasectomy, 162 Spermiogenesis, 6, 159 Sphincter of Oddi, 105, 107, 122, 125 Sphincter urethrae muscle, 149 Spina bifida, 226, 228 Spinal cord accessory nerve origin, 275, 276 anatomy, 251–255, 269, 271 gray/white matter, 251, 252, 257, 269 bladder atonic/spastic, 138 cancers, 244, 249 central nervous system definition, 225 embryology, 225, 226 inferior limit in adults, 27 lesions, 271–274 diagnosis of, 307 motor system, 257, 259, 260, 261, 269 sensory systems, 264, 265, 266, 267, 268, 269 meninges, 25–27 cranial versus, 217 motor system
2 motor neurons, 255, 256, 271 alpha motoneurons, 254–255, 255–256 corticospinal tract, 256, 257, 277 gamma motoneurons, 254–255, 256 lesions, 257, 259, 260, 261, 269, 271 reflexes, 258–260 radiology, 83, 84 sections, 269–270 sensory systems 3 neurons, 262, 263 anterolateral, 262, 263, 265–267, 269, 277 dorsal column–medial lemniscal system, 262, 263–265, 277 lesions, 264, 265, 266, 267, 268, 269, 271 spinocerebellar tracts, 267–268 sympathetic outflow, 32, 233 vertebrae protecting, 21 vertebral canal, 23, 251 Spinal meninges, 25–27, 217 epidural anesthesia, 27, 29 lumbar puncture, 27, 29 Spinal nerves anatomy, 28, 251–255 transition point, 29 cauda equina, 27 denticulate ligaments, 26 parasympathetic nervous system, 32, 33 as peripheral nervous system, 27, 225 sympathetic nervous system, 30, 31, 32 vertebral column, 22, 24 exiting, 29 herniated disk, 25 intervertebral foramina, 25, 26, 29 Spinocerebellar tracts, 267–268 lesions, 268 Spinothalamic tracts, 265, 266, 271 anterolateral sensory system, 262, 263, 265–267, 269 brain stem, 277, 278, 279, 280, 282 pons, 284 hypothalamic fibers, 277, 278, 279, 282 midbrain, 287 pons, 284 lesions, 265, 266, 267, 282, 303, 304, 305 unilateral, 265 midbrain, 287 Spinous processes of vertebrae, 23 Spiral ganglion, 290, 291, 292 Spleen, 106 embryology, 97, 102 dorsal embryonic mesentery, 95, 102 peritoneal membranes, 100 radiology, 174 ribs lacerating, 106 Splenic artery, 106, 127, 128 Splenic flexure bowel ischemia and, 130 radiology, 173 Splenic vein, 131, 132 radiology, 175 Splenium, 342, 354
Splenorenal ligament, 95, 97, 101, 102, 106 pancreas tail, 105 Spontaneous abortion and hCG levels, 9 Sry gene, 3 Stapedius, 290 Stapes, 290, 291 embryology, 211 Stellate cells (cerebellum), 311, 313 Stellate cells (liver), 125 Stenosis of heart valves, 74, 75 Stensen’s ducts, 121 Stereocilia, 17, 162 Sternal angle (of Louis), 63, 64, 66 Sternocleidomastoid muscles, 208 Sternum (radiology), 83 Stomach, 106 embryology, 95 H. pylori infection, 114 histology, 110, 111, 112–114 peritoneal membranes, 100 radiology, 173–175 sliding hiatal hernia, 106 ulcers and artery erosion, 127 Straight sinus, 219 Stria vascularis, 290 Striatum, 317, 318, 319 Styloid process embryology, 211 Subacute combined degeneration, 273, 274 Subarachnoid hemorrhage, 221, 348 subarachnoid space, 218 Subarachnoid space, 217, 218 cerebrospinal fluid circulation, 246, 247, 249 inferior limit, 27 lumbar puncture, 27, 29 spinal, 26, 27 Subclavian arteries, 188, 189 embryology, 211 head and neck, 209 radiology, 82 scalene triangle, 207, 208 Subclavian veins, 66 lymphatic drainage, 43, 45, 65, 67 scalene triangle and, 207, 208 Subcostal plane, 85, 86 Subdural hematoma, 221, 348 Subdural space, 218 Sublingual salivary glands, 120, 121 Submandibular salivary glands, 120, 121 Submucosa of GI tract, 108, 109, 110 Subscapularis muscles, 191 Substantia nigra basal ganglia, 317, 319 midbrain, 278, 287 Parkinson disease, 322, 323 Subthalamus, 337 subthalamic nucleus, 317, 337 lesions, 322, 323, 337 Suckling reflex, 350 Sulci of cerebral cortex, 341–342 Sulci of heart, 70 Superficial fibular nerves, 195, 196, 199 injury, 199
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Anatomy Anatomy
Immunology
Superficial inguinal ring, 87, 89, 90 Superficial perineal fascia, 153 Superficial perineal pouch, 152, 153 pudendal innervation, 155 Superior colliculi, 276, 277, 278 Pharmacology Biochemistry lesion, 306, 308 midbrain, 287 Superior gluteal nerves, 197 injuries, 198 lumbosacral plexus, 195, 196 Physiology Medical Genetics Superior mesenteric artery, 126, 128, 129 radiology, 175, 176 Superior mesenteric vein, 131, 132 radiology, 176 Superior olivary nuclei, 279, 285, 291, 292 Pathology Behavioral Science/Social Sciences Superior pancreaticoduodenal arteries, 127, 128 Superior rectal artery, 129, 130 Superior sagittal sinus, 217, 219 cerebrospinal fluid circulation, 246, 249 Microbiology dural venous sinus drainage, 247 Superior temporal gyrus, 292 Superior vena cava, 66 radiology, 81, 83 Suprachiasmatic nucleus, 337, 338, 339 circadian rhythms, 340 Supraoptic nuclei, 337, 338, 339 lesions, 337, 339 Suprascapular nerves, 182 injury, 183, 184, 187 Supraspinatus muscles, 191 Sural nerve, 199 Surfactant alveolar, 51, 52 Clara cells, 50 cystic fibrosis, 49 corticosteroids for fetal synthesis, 52 hyaline membrane disease, 39 lung embryology, 37 respiratory distress syndrome, 39, 52 Suspensory ligament of ovary, 152 female pelvis, 151, 152 Sympathetic nervous system, 30–32, 232–233 autonomic nervous system, 30, 230, 231 ejaculation, 164 eye innervation, 221, 326 gastrointestinal system, 110 salivary glands, 120 heart innervation, 79 hypothalamus, 338 internal anal sphincter, 107, 152 micturition, 138 postganglionic neurons, 30 preganglionic neurons, 30 sympathetic trunks, 63 thoracolumbar outflow, 30, 31, 32, 232, 233 Synapsis, 4, 5 Syncytiotrophoblast, 7, 8, 9 Syringomyelia, 228, 273, 274 Systole in valvular defects, 74, 75, 76
T Tabes dorsalis, 272, 274 “Talk and die” syndrome, 348 Tanycytes, 242 Tau protein, 238 Telencephalon, 227 Temperature regulation, 337, 340 Temporal lobe, 355, 358 anatomy, 342 visual association cortex, 353–354 lesions, 354 Wernicke area, 351 lesions, 351–352, 355, 358 Teniae coli, 118 Tension pneumothorax, 40 Tensor tympani, 290 Tentorium cerebelli, 218, 219 Teres minor muscles, 191 Terminal bronchiole, 50 Terminal ganglia, 32, 33 Testes cancer, 91 descent, 91–92 cryptorchidism, 91, 148 embryology, 3, 4, 91, 147 congenital abnormalities, 148 mesonephric tubules, 134, 136 histology, 156–165 blood–testis barrier, 157, 158, 160 male anatomy, 150, 154, 156 spermatic cord, 90–91 spermatogenesis, 4, 6, 8 meiosis, 4, 5 Testicular artery, 90 Testicular feminization syndrome, 148 Testis-determining factor (TDF), 3, 4 Testosterone Leydig cells synthesizing, 3, 160 testis embryology, 3 Tetralogy of Fallot, 61, 63 Thalamus anatomy, 276, 277, 320, 342 thalamic nuclei, 335, 336 basal ganglia, 317, 318, 319 cerebellar efferents, 314, 315 embryology, 227 functions, 335, 336 limbic system, 359, 361 thalamic pain syndrome, 336 thalamocortical projections, 344 ventropostero-lateral nucleus, 335, 336 anterolateral system, 262, 265, 266, 267 dorsal column–medial lemniscal system, 262, 263, 264 Thebesian veins, 77 Theca externa, 166, 167 Theca folliculi, 166, 167 Theca interna, 166, 167 lutein cells, 168–169 Thoracic (descending) aorta, 64 radiology, 83, 84 Thoracic cavity boundaries, 38, 39
intercostal spaces, 38, 39 lymphatic system, 43–45 pleura, 39–41 radiology, 81–84 transverse section, 39 Thoracic diaphragm. See Diaphragm Thoracic duct, 43–45 posterior mediastinum, 65 superior mediastinum, 67 Thoracic inlet, 38, 63, 64 Thoracic outlet, 207 syndrome, 207 Thoracic vertebrae, 22 Thoracodorsal nerve, 35 Thoracoepigastric vein anastomoses, 132 Thorax radiology, 81–84 Thymoma, 64 Thymus gland anterior mediastinum, 64 ectopic, 215 embryology, 212 superior mediastinum, 66 tumors, 64 Thyroglossal duct, 212, 213 cyst, 215 Thyroid cartilage embryology, 211 Thyroid gland ectopic, 215 embryology, 212, 213 laryngeal nerve lesion, 67 Tibial collateral ligaments, 203 Tibial nerves injuries, 198 lumbosacral plexus, 195, 196 sensory, 199 Tibias ankle joints, 205 knee joints, 203–205 radiology, 206 shaft fractures, 201 Tight junctions, 16, 17, 18 blood–brain barrier, 242, 249 choroid plexus, 247, 249 epithelial polarity, 13, 16 microfilaments, 15 paracellular pathway, 13 Sertoli cells, 157, 160 Tissue types, 13 Tongue embryology, 211, 213 lingual cyst, 215 jugular foramen syndrome, 217 Tourette syndrome, 322, 323 Trabeculae carneae, 72, 73 Trachea carina, 67 embryology, 36–38 histology, 46–49 radiology, 82, 83 as respiratory pathway, 46 superior mediastinum, 66, 67 tracheoesophageal fistula, 37, 38 Tracheobronchial lymph nodes, 44
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Index Tracheoesophageal fistula, 37, 38 Tracheoesophageal septum, 37 Transcortical apraxia, 352, 356 Transition point of spinal nerves, 29 Transport systems. See Cellular transport systems Transposition of the great vessels, 62, 63 Transpyloric plane, 85 Transtentorial herniation, 329 Transversalis fascia, 88, 89, 91 Transverse cervical ligament, 152 Transverse colon, 107 radiology, 173 Transverse processes of vertebrae, 23 Transverse sinuses, 219, 247 Transversus abdominis muscle, 88, 89 Trapezium, 193 Trapezius muscles, 208 Trapezoid, 193 Treacher Collins syndrome, 215 Tremors, 315 “Trendelenburg gait,” 198 Tricuspid valve auscultation, 74, 75 blood flow, 72, 73 murmurs, 74–76 Trigeminal nerves (CN V) brain stem, 275, 276, 277, 278, 279, 280, 287 cavernous sinus, 219, 220, 247 corticobulbar fibers, 288, 289 embryology, 211 functions, 280 lesions, 280, 303, 304, 305 medulla, 283 nuclei, 285–286 Trigone of the bladder, 138 embryology, 136 Triquetrum, 193 Trisomy 13 holoprosencephaly, 228 Trochlear nerves (CN IV) brain stem, 275, 276, 277, 278, 287 cavernous sinus, 219, 220, 247 thrombosis, 220 embryology, 211 functions, 280 lesions, 280 nuclei, 287 orbital muscles, 221 vestibular fibers, 293, 294 Trophoblast, 7, 8 Truncus arteriosus septation, 60–63 Tubal ectopic pregnancy, 8 Tuber cinereum, 342 Tumors. See Cancers Tunica albuginea, 156 Tympanic membrane, 290, 291 embryology, 212
U Ulna (radiology), 192 Ulnar arteries, 188, 189
Ulnar nerves, 182, 183 brachial plexus, 179, 180, 181 lesions, 186, 187 radiology, 192, 193 Umbilical arteries, 55, 56 Umbilical region, 86 midgut referred pain, 95 Umbilical vein, 54, 55, 56 Umbilicus patent urachus, 137 portacaval anastomoses, 133 Uncinate process, 105 ventral pancreatic bud, 101, 102 Uncus, 276 uncal herniation, 329 Undescended testes, 91, 148 Upper limbs arterial supply, 187–190 collateral circulation, 189, 190 carpal tunnel, 190 median nerve lesions, 186, 187 syndrome, 183, 190, 193 embryology, 210 innervation brachial plexus, 179–182 brachial plexus injuries, 183–187 segmental, 182 sensory, 182–183 radiology, 192–193 rotator cuff, 191 Urachus, 136 fistulas or sinuses, 137 patent, 137 Ureteric bud, 134–135, 136 Ureters anatomy, 137 double, 137 embryology, 135 female pelvis, 151, 152 “water under bridge,” 152 radiology, 177 Urethra compression by prostate, 150 embryology, 136 female, 139, 151, 155 laceration of, 165 male, 138–139 corpus spongiosus, 150, 154 ejaculation, 164 prostate, 164 neck of bladder, 138 spermatozoa, 162 sphincters, 138, 149, 150 innervation, 138 Urinary bladder. See Bladder Urinary system anatomy, 137–139 embryology, 134–136 congenital abnormalities, 136–137 renal agenesis, 38, 136 histology, 139–146 renal calculi, 137 Urination. See Micturition
Urogenital diaphragm, 149 deep perineal pouch, 153 female pelvis, 151, 152 male pelvis, 150, 154 pudendal innervation, 155 Urogenital ridge, 3, 4, 91 extraperitoneal connective tissue, 89 Urogenital sinus, 135–136 Urogenital triangle, 152–153, 155 Urorectal septum, 135, 136 Uterine artery, 152 “water under bridge,” 152 Uterine tube, 151, 152 Uterosacral ligament, 152 Uterus anatomy, 151, 152, 165, 170 embryology, 147 fertilization, 7, 8 histology, 170, 171 implantation, 7, 8 pelvis, 151, 152 prolapse, 152 Utricle, 290, 291 vestibular system, 293, 294
V Vagina embryology, 136, 147 herniation into, 152 histology, 171 pelvis, 151, 152 perineum, 155 Vagus nerves (CN X) brain stem, 275, 276, 277, 279 corticobulbar fibers, 288 dorsal motor nucleus, 283 embryology, 211 heart innervation, 79 lesions, 303 nuclei, 283 superior mediastinum, 66, 67 Valsalva maneuver in defecation, 119 Valvular insufficiency, 74 Valvular regurgitation, 74 Vas deferens. See Ductus deferens Vasectomy, 162 Venae cordis minimae, 77 Ventral embryonic mesentery, 95, 97 Ventral horn, 254–255 lower motoneurons, 255–256, 257 as motor, 252, 253, 254 spinal cord sections, 269, 270 Ventral rami, 28, 32, 233, 252 Ventral root of spinal nerve denticulate ligaments, 26 as motor, 28, 252, 254, 255 Ventricles (brain) anatomy, 245, 246 cerebrospinal fluid, 245, 246. See also Cerebrospinal fluid embryology, 227 ependymal cells, 242 hydrocephalus, 228, 248
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Anatomy Anatomy
Immunology
Ventricles (heart) anatomy of heart, 70 blood flow, 72–73 borders, 69, 70 surfaces, 70 Pharmacology Biochemistry embryology fetal circulation, 54–56 heart tube, 53, 54 ventricular septal defects, 59, 63 ventricular septation, 59 Physiology Medical Genetics radiology, 81, 84 Vermis anatomy, 278, 279, 309 function, 309, 310, 314 lesions, 313, 315 Pathology Behavioral Science/Social Sciences congenital malformations, 228 radiology, 363 Vertebral arteries, 300–301 cerebral cortex, 344, 346 occlusion, 357 Microbiology Vertebral column curvatures, 22 dural sac inferior limit, 27 embryology, 21, 210 intervertebral disks, 22, 23, 24 intervertebral foramina, 22, 23, 24, 25, 26 ligaments, 24 radiology, 82, 83, 84 spinal cord inferior limit, 27 vertebrae, 21–23 vertebral arch, 23 vertebral canal, 23 vertebral notches, 23 Vertigo, 295 Vesicourterine pouch, 151 Vestibular fibers, 293 Vestibular nuclei, 285, 293, 294 cerebellar efferents, 314, 315 lesions, 294, 303, 304, 305 Vestibular system, 293–296 caloric test, 295, 296 dysfunction, 295 vestibulo-ocular reflex, 282, 293, 294 brain stem integrity, 295, 296 Vestibule, 151, 155 Vestibulocochlear nerves (CN VIII) brain stem, 275, 276, 277, 279, 287 cochlear division, 290, 291 functions, 281 lesions, 281, 292, 294, 303, 304 schwannomas, 244, 306 vestibular system, 293, 294 Vestibulo-ocular reflex, 282, 293, 294 brain stem integrity, 295, 296
Vibratory sense dorsal column–medial lemniscal system, 263, 264 spinal cord lesion, 269 Visceral layer, 39 pericardium, 68–69 peritoneum, 98 embryology, 98 intraperitoneal organs, 98, 99 secondary retroperitonealization, 97, 99 pleura, 39, 40 pleural reflections, 41 serosa of GI tract, 108 Visual agnosia, 354 Visual association cortex, 349, 353–354 Visual cortex, 349, 353 frontal eye field, 296, 297, 298 lesions, 350, 358 lateral geniculate body, 332 lesions, 333, 353 line of Gennari, 344, 353 pupillary light reflex, 327 Visual pathways circadian rhythms, 340 eyeball, 325, 326 optic chiasm, 330 retina, 330 suprachiasmatic nucleus, 338, 339 thalamus, 335, 336 visual field defects, 331–333 visual reflexes, 326–329 Vitamin A deficiency and night blindness, 325 liver storage, 125 Vitamin B1 and neural degeneration, 336, 338, 362 Vitamin B12 bacteria of GI tract, 110 intrinsic factor, 113 pernicious anemia, 113 subacute combined degeneration, 273, 274 Vitamin K, 110 Vitamins stored in liver, 125 Vitelline duct ileal diverticulum, 103 primitive gut tube, 96 vitelline fistula, 103 Vitelline fistula, 103 Vitelline veins, 54 Vitreous humor, 326 Volvulus, 103 VPM (ventroposteromedial nucleus), 286
W Waiter’s tip syndrome, 183–184 Wallenberg syndrome, 303 Wallerian degeneration, 243, 244 Weber syndrome, 307 Weber test, 293 Wernicke-Korsakoff syndrome, 335, 362 Wernicke’s oral comprehension area anatomy, 320 cerebral cortex, 349, 351 auditory system, 292 lesions, 351–352, 355, 358 Wharton’s ducts, 121 White rami, 32, 233 Wilson disease, 322, 323 “Winged scapula,” 35, 187 Withdrawal reflex, 260 WNT4 gene, 3 Wolffian ducts, 3, 4, 136 embryology, 134, 136 duct of Gartner, 147 Wrist median nerve lesion, 186 radiology, 193 ulnar nerve lesion, 186 “wrist drop,” 185, 187 Writer’s cramp, 323
Y Y chromosome Sry gene, 3 Yolk sac derivatives, 12, 229 gonad embryology, 4 hypoblast origins, 8–9 primitive gut tube, 94, 96
Z Zona occludens, 16, 18. See also Tight junctions Zona pellucida acrosome enzymes, 159 cortical reaction, 8 fertilization, 7, 8 follicular development, 166, 167, 168 graafian follicle, 166, 168 implantation, 8 polar body, 168 Zonula adherens, 16, 17, 18 Zygapophyseal joints, 21, 24 Zygotes, 7, 8 Zymogen granules, 121
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USMLE
®
Step 1
Lecture Notes
2019
Behavioral Science and Social Sciences
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USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the National Board of Medical Examiners (NBME), which neither sponsor nor endorse this product. This publication is designed to provide accurate information in regard to the subject matter covered as of its publication date, with the understanding that knowledge and best practice constantly evolve. The publisher is not engaged in rendering medical, legal, accounting, or other professional service. If medical or legal advice or other expert assistance is required, the services of a competent professional should be sought. This publication is not intended for use in clinical practice or the delivery of medical care. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. © 2019 by Kaplan, Inc. Published by Kaplan Medical, a division of Kaplan, Inc. 750 Third Avenue New York, NY 10017 10 9 8 7 6 5 4 3 2 1 Course ISBN: 978-1-5062-3648-3 All rights reserved. The text of this publication, or any part thereof, may not be reproduced in any manner whatsoever without written permission from the publisher. This book may not be duplicated or resold, pursuant to the terms of your Kaplan Enrollment Agreement. Retail ISBN: 978-1-5062-3610-0 Kaplan Publishing print books are available at special quantity discounts to use for sales promotions, employee premiums, or educational purposes. For more information or to purchase books, please call the Simon & Schuster special sales department at 866-506-1949.
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Editors Behavioral Science
Alice Akunyili, MD Assistant Professor, Department of Cell Biology and Pharmacology FIU Herbert Wertheim College of Medicine Miami, FL
Alina Gonzalez-Mayo, MD Psychiatrist Department of Veterans Administration Bay Pines, FL
Mark Tyler-Lloyd, MD, MPH Executive Director of Academics Kaplan Medical New York, NY
Basic Science of Patient Safety
Ted A. James, MD, MS, FACS Chief, Breast Surgical Oncology Vice Chair, Academic Affairs Department of Surgery Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA
The editors would like to acknowledge Kevin Schuller, MD, Irfan Sheikh, MD, and Kevin Yang, MD for their contributions.
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We want to hear what you think. What do you like or not like about the Notes? Please email us at [email protected].
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Table of Contents
Part I: Epidemiology and Biostatistics
Chapter 1: Epidemiology �������������������������������������������������������������������������������� 3
Chapter 2: Biostatistics������������������������������������������������������������������������������������25
Part II: Behavioral Science
Chapter 3: Developmental Life Cycle ������������������������������������������������������������53
Chapter 4: Theories of Learning and Behavioral Modification������������������ 65
Chapter 5: Defense Mechanisms������������������������������������������������������������������� 71
Chapter 6: Psychological Health and Testing ������������������������������������������������77
Chapter 7: Substance Use Disorders������������������������������������������������������������ 83
Chapter 8: Sleep and Sleep Disorders���������������������������������������������������������� 93
Chapter 9: Psychiatric (DSM-5) Disorders �������������������������������������������������� 99
Chapter 10: Psychopharmacology��������������������������������������������������������������� 117
Chapter 11: Brain Function and Neurocognitive Disorders����������������������� 125
Chapter 12: Ethics, Law, and Physician Behavior��������������������������������������� 135
Chapter 13: Health Care Delivery Systems������������������������������������������������� 157
Part III: Social Sciences
Chapter 14: Basic Science of Patient Safety ������������������������������������������������ 161
Index ��������������������������������������������������������������������������������������������������������������������������193
Additional resources available at www.kaptest.com/usmlebookresources
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PART I
Epidemiology and Biostatistics
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Epidemiology
1
Learning Objectives ❏❏ Answer questions about epidemiologic measures ❏❏ Use knowledge of screening tests ❏❏ Explain information related to study designs
EPIDEMIOLOGIC MEASURES Epidemiology is the study of the distribution and determinants of health-related states within a population. It refers to the patterns of disease and the factors that influence those patterns. • Endemic: the usual, expected rate of disease over time; the disease is
maintained without much variation within a region
• Epidemic: occurrence of disease in excess of the expected rate; usually
presents in a larger geographic span than endemics (epidemiology is the study of epidemics)
• Pandemic: worldwide epidemic • Epidemic curve: visual description (commonly histogram) of an epi-
demic curve is disease cases plotted against time; classic signature of an epidemic is a “spike” in time
The tools of epidemiology are numbers; the numbers in epidemiology are ratios converted into rates. The denominator is key: who is “at risk” for a particular event or disease state. To determine the rate, compare the number of actual cases with the number of potential cases: Actual cases Numerator = = RATE Potential cases Denominator Rates are generally, though not always, per 100,000 persons by the Centers for Disease Control (CDC), but can be per any multiplier. (Vital statistics are usually per 1,000 persons.) A disease may occur in a country at a regular annual rate, which makes it endemic. If there is a sudden rise in the number of cases in a specific month, we say that there is an epidemic. As the disease continues to rise and spread to other countries, it becomes a pandemic. Thus the terminology is related to both the number of cases and its geographical distribution.
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Medical Genetics
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The graph below represents the incidence of 2 diseases (cases in 100,000). Disease 1 is endemic as the rate of disease is consistent month to month with minor variation in the number of cases. Disease 2 experiences an epidemic in March and April in which the number of cases is in excess of what is expected. January
February
March
April
May
June
July
August
3
4
3
4
4
4
3
3
5
5
8
8
5
5
5
5
Although the data is in 100,000 cases, the variation in disease 1 is still consistent when compared to disease 2.
Figure 1.1 Epidemic vs. Endemic Cases
Consider the following scenario. A Japanese farmer begins to sell meat that is infected with salmonella. Within 2 days, hundreds of villagers begin to experience crampy abdominal pain. This is an example of an epidemic. The sudden rise of salmonella gastroenteritis in this village is much higher than the average incidence for the given time period. Now what if the farmer ships 1,000 pounds of infected beef to other regions of Japan before he realizes what happened? What can one anticipate would happen? The answer is there would be no change to the endemic rate of gastroenteritis. The farmer is only shipping out 1,000 pounds of beef to a few cities nationwide. Unlike the earlier scenario which addressed the population of a village, this would be the entire nation. Assuming that every person who consumes the beef gets gastroenteritis, that number would not significantly increase the national average of cases and would therefore not significantly change the incidence of the disease nationwide.
Incidence and Prevalence Incidence rate (IR) is the rate at which new events occur in a population. • The numerator is the number of new events that occur in a defined period. • The denominator is the population at risk of experiencing this new
event during the same period.
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Chapter 1
Incidence rate =
l
Epidemiology
Number of new events in a specified period × 10n Number of persons “exposed to risk” of becoming new cases during this period
The IR includes only new cases of the disease that occurred during the specified period, not cases that were diagnosed earlier. This is especially important when working with infectious diseases such as TB and malaria. If, over the course of a year, 5 men are diagnosed with prostate cancer, out of a total male study population of 200 (with no prostate cancer at the beginning of the study period), the IR of prostate cancer in this population would be 0.025 (or 2,500 per 100,000 men-years of study). Attack rate is the cumulative incidence of infection in a group of people observed over a period of time during an epidemic, usually in relation to food-borne illness. It is measured from the beginning of an outbreak to the end of the outbreak. Attack rate =
Number of exposed people infected with the disease Total number of exposed people
Attack rate is also called attack ratio; consider an outbreak of Norwalk virus in which 18 people in separate households become ill. If the population of the 18 community is 1,000, the overall attack rate is × 100% = 1.8%. 1,000
Figure 1.2 Reported Cases of Hepatitis C in the United States
Figure 1.3 Cumulative Incidence 2005–2015
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Prevalence is all persons who experience an event in a population. The numerator is all individuals who have an attribute or disease at a particular point in time (or period of time). The denominator is the population at risk of having the attribute or disease at that point in time or midway through the period. Prevalence =
All cases of a disease at a given point / period ×10 n Total population “at risk” for being cases at a given point / period
Prevalence, in other words, is the proportion of people in a population who have a particular disease at a specified point in time (or over a specified period of time). The numerator includes both new cases and old cases (people who remained ill during the specified point or period in time). A case is counted in prevalence until death or recovery occurs. This makes prevalence different from incidence, which includes only new cases in the numerator. Prevalence is most useful for measuring the burden of chronic disease in a population, such as TB, malaria and HIV. For example, the CDC estimated the prevalence of obesity among American adults in 2001 at approximately 20%. Since the number (20%) includes all cases of obesity in the United States, we are talking about prevalence.
Note Prevalence is a measurement of all individuals (new and old) affected by the disease at a particular time, whereas incidence is a measurement of the number of new individuals who contract a disease during a particular period of time.
Point prevalence is useful for comparing disease at different points in time in order to determine whether an outbreak is occurring. We know that the amount of disease present in a population changes over time, but we may need to know how much of a particular disease is present in a population at a single point in time (“snapshot view”). Perhaps we want to know the prevalence of TB in Community A today. To do that, we need to calculate the point prevalence on a given date. The numerator would include all known TB patients who live in Community A that day. The denominator would be the population of Community A that day. Period prevalence, on the other hand, is prevalence during a specified period or span of time. The focus is on chronic conditions. In the “prevalence pot,” incident (or new) cases are monitored over time. New cases join pre-existing cases to make up total prevalence.
Incident Cases General Population at Risk Recovery
Recovery with Immunity
Prevalent Cases
Mortality
Figure 1-4. Prevalence Pot
Prevalent cases leave the prevalence pot in one of 2 ways: recovery or death.
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Table 1-1. Incidence and Prevalence What happens if:
Incidence
Prevalence
New effective treatment is initiated
no change
decrease
New effective vaccine gains widespread use decrease
decrease
Number of persons dying from the condition increases
no change
decrease
Additional Federal research dollars are targeted to a specific condition
no change
no change
Behavioral risk factors are reduced in the population at large
decrease
decrease
decrease
decrease
no change
no change
Recovery from the disease is more rapid than it was one year ago
no change
decrease
Long-term survival rates for the disease are increasing
no change
increase
Contacts between infected persons and noninfected persons are reduced For airborne infectious disease? For noninfectious disease?
Note Morbidity rate is the rate of disease in a population at risk (for both incident and prevalent cases), while mortality rate is the rate of death in a population at risk (incident cases only).
Lung Cancer Cases in a Cohort of Heavy Smokers Disease course, if any, for 10 patients 1 2 3 4
5 6 7
8 9 10 1/1/2006 Key:
Onset
1/1/2007 Duration
Terminal Event
Figure 1-2. Calculating Incidence and Prevalence
Figure 1-5. Calculating Incidence and Prevalence
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Based on the graph above, calculate the following: • Prevalence of lung cancer from 1/1/2006–1/1/2007 –– N umber of patients who “had” lung cancer in this time period from the graph: (7) –– N umber of patients at risk in this time period: (9) [exclude patient #2 who died before the time period] –– Prevalence: (7/9) –– Type of prevalence: (period prevalence)
• Incidence of lung cancer from 1/1/2006–1/1/2007 –– Number of patients who developed lung cancer in this time period: (4) –– N umber of patients at risk in this time period: (6) [exclude patients who were already sick at the start of the time period and those who died before the time period] –– Incidence: (4/6)
Recall Question Prevalence can be defined as which of the following? A. Number of new events in a specified period over the number of persons at risk of becoming new cases during the same period B. Number of exposed people infected with a disease over the total number of exposed people C. All cases of a disease at a given point over the total population at risk for being cases at the same point D. Number of actual cases over potential cases E. Rate of death in a population at risk Answer: C
Crude, Specific, and Standardized Rates Note Use caution using the crude rate. Imagine that in a given city, there are a lot of older, retired people—the crude rate of myocardial infarction will appear higher, even though the rate for each age group has not actually changed.
Crude rate is the actual measured rate for a whole population, e.g., rate of myocardial infarction for a whole population. Specific rate is the actual measured rate for a subgroup of population, e.g., “age-specific” or “sex-specific” rate. For instance, the rate of myocardial infarction among people age >65 in the population or the rate of breast cancer among the female population. If you are provided specific rates, you can calculate the crude rate. The crude rate of an entire population is a weighted sum of each of the specific rates. The weighted specific rates that are added together is calculated in the table below.
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Standardized rate (or adjusted rate) is adjusted to make groups equal on some factor, e.g., age; an “as if ” statistic for comparing groups. The standardized rate adjusts or removes any difference between two populations based on the standardized variable. This allows an “uncontaminated” or unconfounded comparison. Table 1-2. Types of Mortality Rate Crude mortality rate
Deaths Population
Deaths in a city in 2016 per population of the city
Crude rate of people dying in the population
Cause-specific mortality rate
Deaths from cause Population
Deaths from lung cancer in a city in 2016 per population of the city
Specific rate of people dying from a particular disease in the population
Deaths from Ebola in a city per number of persons with Ebola
How likely you are to die from the disease, i.e., fatality
Deaths from diabetes mellitus in a city per total deaths in the city
How much a disease contributes to the mortality rate, i.e., what proportion of the mortality rate is due to that disease
Case-fatality rate
Deaths from cause Number of persons with the disease/cause
Proportionate mortality rate (PMR)
Deaths from cause All deaths
For example, the city of Hoboken, New Jersey has a population of 50,000. In 2016, the total number of deaths in Hoboken was 400. The number of deaths from lung cancer in Hoboken was 10, while the number of patients with lung cancer diagnosis was 30. Calculate the following: • Mortality rate in Hoboken for 2016: (400/50,000 × 1,000) • Cause specific mortality rate for lung cancer in Hoboken for 2016:
(10/50,000 × 100,000)
• CFR for lung cancer in Hoboken in 2016: (10/30 × 100) • PMR for lung cancer in Hoboken in 2016: (10/400 × 100)
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PREVENTION The goals of prevention in medicine are to promote health, preserve health, restore health when it is impaired, and minimize suffering and distress. These goals aim to minimize both morbidity and mortality. • Primary prevention promotes health at both individual and com-
munity levels by facilitating health-enhancing behaviors, preventing the onset of risk behaviors, and diminishing exposure to environmental hazards. Primary prevention efforts decrease disease incidence. Examples include implementation of exercise programs and healthy food programs in schools.
• Secondary prevention screens for risk factors and early detection
of asymptomatic or mild disease, permitting timely and effective intervention and curative treatment. Secondary prevention efforts decrease disease prevalence. Examples include recommended annual colonoscopy for patients age >65 and HIV testing for health care workers with needlestick injuries.
• Tertiary prevention reduces long-term impairments and disabilities
and prevents repeated episodes of clinical illness. Tertiary prevention efforts prevent recurrence and slow progression. Examples include physical therapy for spinal injury patients and daily low-dose aspirin for those with previous myocardial infarction.
Consider a new healthcare bill that is being funded to help wounded war veterans gain access to prosthetic limb replacement. That would be considered tertiary prevention. The patients who would have access to the service have already been injured. The prosthetic devices would help reduce complications of amputation and help their rehabilitation. By improving quality of life and reducing morbidity, that is an implementation of tertiary prevention. Now consider a medical student who is asked to wear a nose and mouth mask before entering the room of a patient with meningococcal meningitis. That would be considered primary prevention. Because the bacteria in this case can be spread by respiratory contact, the use of the mask will prevent the student from being exposed.
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SCREENING TESTS Screening tests help physicians to detect the presence of disease, e.g., an ELISA test for HIV, the results of which are either positive or negative for disease. The efficacy of a screening test is assessed by comparing the results to verified sick and healthy populations. For HIV, we would use a Western blot as a gold-standard. The qualifier “true” or “false” is used to describe the correlation between the test results (positive or negative) and the disease (presence or absence). True-positive (TP): tested positive, actually sick • In other words, the positive result is true.
False-positive (FP): tested positive, is actually healthy • In other words, the positive result is false.
True-negative (TN): tested negative, actually healthy • In other words, the negative result is true.
False-negative (FN): tested negative, is actually sick • In other words, the negative result is false. Table 1-3. Screening Results in a 2 × 2 Table Disease Present Screening Test Results
Absent
Totals
Positive
TP
60
FP
70
TP + FP
Negative
FN
40
TN
30
TN + FN
Totals
TP + FN
TN + FP
TP + TN + FP + FN
Measures of Test Performance Sensitivity and specificity are measures of the test performance (and in some cases, physical findings and symptoms). They help to provide additional information in cases where it is not possible to use a gold-standard test and instead a cheaper and easier (yet imperfect) screening test is used. Think about what would happen if you called the cardiology fellow to do a cardiac catheterization (the gold standard test to diagnose acute myocardial ischemia) on a patient without first having an EKG. Sensitivity is the probability of correctly identifying a case of disease. In other words, it is the proportion of truly diseased persons in the screened population who are identified as diseased by the screening test. This is also known as the “true positive rate.” Sensitivity = TP/(TP + FN) = true positives/(true positives + false negatives) • Measures only the distribution of persons with disease • Uses data from the left column of the 2 × 2 table • Note: 1-sensitivity = false negative rate
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If a test has a high sensitivity, then a negative result indicates the absence of the disease. For example, temporal arteritis (TA), a large vessel vasculitis that involves branches of the external carotid artery seen in those age >50, always shows elevated ESR. So 100% of patients with TA have elevated ESR. The sensitivity of an abnormal ESR for TA is 100%. If a patient you suspect of having TA has a normal ESR, then the patient does not have TA. If there are 200 sick people, the sensitivity of a test tells us the capacity of the test to correctly identify these sick people. If a screening test identifies 160 of them as sick (they test positive), then the sensitivity of the test is 160/200 = 80%. Sick Not Sick
Test
Figure 1-6. Sensitive Test
Note Mnemonics
• Clinical use of sensitivity: SN-N-OUT (sensitive test- negative rules out disease) • Clinical use of specificity: SP-I-N (specific test-positive rules in disease) For any test, there is usually a trade-off between SN-N-OUT and SPIN. The trade-off can be represented graphically as the screening dimension curves and ROC curves.
Specificity is the probability of correctly identifying disease-free persons. Specificity is the proportion of truly nondiseased persons who are identified as nondiseased by the screening test. This is also known as the “true negative rate.” Specificity = TN/(TN + FP) = true negatives/(true negatives + false positives) • Measures only the distribution of persons who are disease-free • Uses data from the right column of the 2 × 2 table • Note: 1-specificity = false positive rate
If a test has a high specificity, then a positive result indicates the existence of the disease. For example, CT angiogram has a very high specificity for pulmonary embolism (97%). A CT scan read as positive for pulmonary embolism is likely true.
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Sick Not Sick
Test
Figure 1-7. Specific Test
The separation between the sick and healthy in a given population isn’t always clear; there is a measure of overlap, as in the figure above. In order to create a test that is specific and identifies only sick people as positive, it must do the following: • Correctly identify all the healthy people • Not inaccurately identify healthy people as sick
In other words, the more specific the test, the fewer false-positives (i.e., healthy people incorrectly identified as sick) it will have). Specificity is, therefore, the capacity of a test to correctly exclude healthy people with negative test results.
Recall Question A good screening test should have which of the following epidemiological properties? A. High specificity B. Low specificity C. Low sensitivity D. High sensitivity E. High positive predictive value F. Low negative predictive value Answer: D
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Post-Test Probabilities Positive predictive value (PPV) is the probability of disease in a person who receives a positive test result. The probability that a person with a positive test is a true positive (i.e., has the disease) is referred to as the “predictive value of a positive test.”
PPV = TP/(TP + FP) = true positives/(true positives + false positives) PPV measures only the distribution of persons who receive a positive test result. Negative predictive value (NPV) is the probability of no disease in a person who receives a negative test result. The probability that a person with a negative test is a true negative (i.e., does not have the disease) is referred to as the “predictive value of a negative test.”
NPV = TN/(TN + FN) = true negatives/(true negatives + false negatives) NPV measures only the distribution of persons who receive a negative test result. Accuracy is the total percentage correctly selected, the degree to which a measurement, or an estimate based on measurements, represents the true value of the attribute that is being measured. Accuracy = (TP + TN)/(TP + TN + FP + FN) = (true positives + true negatives)/total screened patients
Review Questions Questions 1–3 A screening test identifies 150 out of 1,000 patients to have tuberculosis. When tested with the gold standard diagnostic test, 200 patients test positive, including 100 of those identified by the screening test. 1. What is the sensitivity of the screening test? 2. What is the specificity of the screening test? 3. What is the positive predictive value?
Answers and Explanations 1. Answer: 50%. Sensitivity would be true positives divided by all sick people. Only 100 of the 150 positive results were actually true, so true positives would be 100. Total sick people is 200. So we have 100/200, making sensitivity 50%. 2. Answer: 93.75%. Specificity would be true negatives divided by all healthy people. Only 100 of the 150 positive results were actually true, so false positives (healthy people with a positive result) would be 50. Total people is 1,000. So we have 1,000 – 200 sick, making 800 healthy. True negatives = 800 – 50 so 750. Specificity = 750/800 so 93.75%.
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3. Answer: 66%. Positive predictive value is true positives divided by all positives. Only 100 of the 150 positive results were actually true, so true positives would be 100. The total who tested positive would be 150. Therefore, PPV is 100 divided by 150 so 66%.
Effective Prevalence Prevalence, which is a quantified measure of disease or cases in the population, is a relevant pre-test probability of disease within the population. The more disease in a population, i.e., high prevalence, the greater the probability that a positive test represents actual disease (= greater PPV). The less disease in a population, i.e., lower prevalence, the higher the probability that a negative result is true (= greater negative predictive value). Consider this example: Among 80-year-old diabetic patients, the prevalence of kidney failure is higher than in the general population. This increased prevalence makes a physician more likely to believe the results of a screening test that shows kidney failure for an 80-year-old diabetic patient. We intuitively understand that the PPV is higher because this cohort of patients has a higher prevalence of disease. Conversely, if a 15-year-old girl tests positive for a myocardial infarction, a physician will find the results strange and will thus repeat the test to confirm the positive result is not a false-positive. That is because the prevalence of myocardial infarction among teenage girls is so low that a positive result is more likely to be a mistake than a case of an actual myocardial infarction. In a teenage girl, a negative result for myocardial infarction is more likely to be true (high negative predictive value) because there is a very low prevalence of disease in this age group population. Incidence is a measure of new cases in a population. Increasing the incidence would have no effect on sensitivity or PPV because a screening test can only detect the current presence or absence of disease, not its onset. Prevalence has no effect on the sensitivity or specificity of a test. Those are metrics of the test and can be changed only by changing the test itself.
Double Hump Graph In the graph below, which cutoff point provides optimal sensitivity? A
B
Healthy
Low
C
D
E
Diseased
Blood Pressures
High
Figure 1-3. Healthy and Diseased Populations
Figure 1-8. Healthy and Diseased Populations Along a Screening Dimension Along a Screening Dimension
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Cutoff point B correctly identifies all the sick patients. It has the highest sensitivity (identifies all the sick patients). Cutoff D would be the most specific test (it identifies only sick people). Cutoff C where the 2 curves intersect is the most accurate. Note, the point of optimum sensitivity equals the point of optimum negative predictive value, while the point of optimum specificity equals the point of optimum positive predictive value. Consider another example. Which of the following curves indicates the best screening test?
Sensitivity (True Positive Rate)
1.0 0.9
E
0.8
D
0.7
C
0.6
B
0.5 0.4
A
0.3 0.2 0.1 0.1
0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 – Specificity (False Positive Rate)
Figure 1-4. Receiver Operating Characteristic (ROC) Curves
Figure 1-9. Receiver Operating Characteristic (ROC) Curves
Curve E achieves the highest sensitivity (y-axis) without including too many false-positives (x-axis).
STUDY DESIGNS Bias in Research Bias in research is a deviation from the truth of inferred results. It can be done intentionally or unintentionally. Reliability is the ability of a test to measure something consistently, either across testing situations (test-retest reliability), within a test (split-half reliability), or across judges (inter-rater reliability). Think of the clustering of rifle shots at a target (precision). Validity is the degree to which a test measures that which was intended. Think of a marksman hitting the bull’s-eye. Reliability is a necessary, but insufficient, condition for validity (accuracy).
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Types of bias When there is selection bias (sampling bias), the sample selected is not representative of the population. Examples: • Predicting rates of heart disease by gathering subjects from a local
health club
• Using only hospital records to estimate population prevalence (Berkson
bias)
• Including people in a study who are different from those who are not
included (nonrespondent bias)
• Solution: random, independent sample; weight data
When there is measurement bias, information is gathered in a manner that distorts the information. Examples: • Measuring patient satisfaction with their physicians by using leading
questions, e.g., “You don’t like your doctor, do you?”
• Subjects’ behavior is altered because they are being studied; this is only
a factor when there is no control group in a prospective study (Hawthorne effect).
• Solution: have a control group
When there is experimenter expectancy (Pygmalion effect), experimenters’ expectations are inadvertently communicated to subjects, who then produce the desired effects. Solution: use double-blind design, where neither the subject nor the investigators know which group receives the intervention. Lead-time bias gives a false estimate of survival rates, e.g., patients seem to live longer with the disease after it is uncovered by a screening test. Actually, there is no increased survival, but because the disease is discovered sooner, patients who are diagnosed seem to live longer. Solution: use life-expectancy to assess benefit.
Diagnosis Onset Unscreened
0
Screened, early treatment not effective
0
Screened, early treatment is effective
0
Early
Usual
Death
DX DX
Lead time
DX
Improved survival
Figure 1-5. Diagnosis, Time, and Survival
Figure 1-10. Diagnosis, Time, and Survival
When there is recall bias, subjects fail to accurately recall events in the past. For example: “How many times last year did you kiss your mother?” This is a likely problem in retrospective studies. Solution: confirmation.
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When there is late-look bias, individuals with severe disease are less likely to be uncovered in a survey because they die first. For example, a recent survey found that persons with AIDS reported only mild symptoms. Solution: stratify by disease severity. When there is confounding bias, the factor being examined is related to other factors of less interest. Unanticipated factors obscure a relationship or make it seem like there is one when there is not. More than one explanation can be found for the presented results. For example, compare the relationship between exercise and heart disease in 2 populations when one population is younger and the other is older. Are differences in heart disease due to exercise or to age? Solution: combine the results from multiple studies, meta-analysis. When there is design bias, parts of the study do not fit together to answer the question of interest. The most common issue is a non-comparable control group. For example, compare the effects of an anti-hypertensive drug in hypertensives versus normotensives. Solution: random assignment, i.e., subjects assigned to treatment or control group by a random process.
Table 1-4. Type of Bias in Research Type of Bias
Definition
Important Associations
Solutions
Selection
Sample not representative
Berkson’s bias, nonrespondent bias
Random, independent sample
Measurement
Gathering the information distorts it
Hawthorne effect
Control group/placebo group
Experimenter expectancy
Researcher’s beliefs affect outcome
Pygmalion effect
Double-blind design
Lead-time
Early detection confused with increased survival
Benefits of screening
Measure “back-end” survival
Recall
Subjects cannot remember accurately
Retrospective studies
Multiple sources to confirm information
Late-look
Severely diseased individuals are not uncovered
Early mortality
Stratify by severity
Confounding
Unanticipated factors obscure results
Hidden factors affect results
Multiple studies, good research design
Design
Parts of study do not fit together
Non-comparable control group
Random assignment
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TYPES OF RESEARCH STUDIES Observational Study In an observational study, nature is allowed to take its course, i.e., there is no intervention. • Case report: brief, objective report of a clinical characteristic/outcome
from a single clinical subject or event, n = 1, e.g., 23-year-old man with treatment-resistant TB; there is no control group
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Note • Random error is unfortunate but okay and expected (a threat to reliability). • Systematic error is bad and biases result (a threat to validity).
• Case series report: objective report of a clinical characteristic/outcome
from a group of clinical subjects, n >1, e.g., patients at local hospital with treatment-resistant TB; there is no control group
• Cross-sectional study: the presence or absence of disease (and other
variables) are determined in each member of the study population or representative sample at a particular time; co-occurrence of a variable and the disease can be examined –– Disease prevalence, not incidence, is recorded –– C annot usually determine temporal sequence of cause and effect, e.g., who in the community now has treatment-resistant TB
• Case-control study: a group of people with the disease is identified
and compared with a suitable comparison group without the disease; almost always retrospective, e.g., compares cases of treatment-resistant TB with those of nonresistant TB –– C annot usually assess incidence or prevalence of disease, but it can help determine causal relationships –– V ery useful for studying conditions with very low incidence or prevalence
• Cohort study: population group of those who have been exposed to
risk factor is identified and followed over time and compared with a group not exposed to the risk factor. Outcome is disease incidence in each group, e.g., following a prison inmate population and marking the development of treatment-resistant TB –– Prospective, meaning that subjects are tracked forward in time –– C an determine incidence and causal relationships, and must follow population long enough for incidence to appear
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Past risk factor
Present disease
Future
Case Control
Figure 1-11. Retrospective Study
Past
Present risk factor
Future disease Cohort Study
Figure 1-12. Prospective Study
Cohort Study
Cohort Study Risk Factor
No Risk Factor
Disease No Disease 60 A
240 B
60 C
540 D
Relative risk (RR) is a comparative probability asking, “How much more likely?” To find it, calculate the IR of the exposed group divided by the IR of the unexposed group. How much greater chance does one group have of contracting the disease compared with the other group? Attributable risk (AR) is a comparative probability asking “How many more cases in one group?” To find it, calculate the IR of exposed group minus the IR of the unexposed group. Note: Both relative and attributable risk tell us if there are differences, but they do not tell us why those differences exist.
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Interpretation: for every 100 people treated, 1 case will be prevented. Let’s first consider RR. If we compare a group of 100 children who live near a chemical plant (risk factor) to a group of 100 children who do not (no risk factor), and follow them over time to see who develops asthma, we can calculate how much more likely it is for those exposed to the risk factor to develop disease, i.e., RR. In this example, say 20 children near the chemical plant and 5 children not living near the plant all develop asthma. RR = =
Incidence in exposed group (risk factor) Incidence in unexposed group (no risk factor) 20 5 ÷ = 4 100 100
Interpretation: a child living near the chemical plant is 4x more likely to develop asthma than a child not living near the plant Now let’s consider AR. Are all 20 cases among those living near the plant due to the proximity of the plant? We know that 5 children developed asthma even though they did not live next to plant, meaning that some of the 20 cases are not necessarily due to the risk factor itself (in this case, the chemical plant). How many of the 20 cases are due to the risk factor or, in other words, are attributable to the risk factor? AR = Incidence in exposed group − Incidence in unexposed group 20 5 15 − = 100 100 100 Interpretation: for every 100 children exposed to the risk factor, 15 cases are attributable to the risk factor itself; in other words, when we expose 100 children, 15 cases of asthma will be caused by the exposure. So what is the NNH? NNH is the inverse of the attributable risk. =
100 = 6.66 = 7 (always round up) 15
Interpretation: for every 7 people exposed to the risk factor, there will be 1 case.
Recall Question Which of the following is a solution for sampling bias? A. Have a control group B. Select participants randomly C. Do a double-blind study D. Use life-expectancy to assess benefit E. Stratify the study groups by disease severity Answer: B
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Case Control Study For a case-control study, use odds ratio (OR), which looks at the increased odds of getting a disease with exposure to a risk factor versus nonexposure to that factor. Find the odds of exposure for cases divided by odds of exposure for controls, e.g., the odds that a person with lung cancer was a smoker versus the odds that a person without lung cancer was a smoker. Table 1-5. Case-Control Study: Lung Cancer and Smoking Lung Cancer
No Lung Cancer
Smokers
659 (A)
984 (B)
Nonsmokers
25 (C)
348 (D)
Odds ratio =
A/C AD = B/D BC
Use OR = AD/BC as the working formula. For the above example: OR =
659 × 348 AD = 9.32 = BC 984 × 25
Interpretation: the odds of having been a smoker are over 9x greater for someone with lung cancer compared with someone without lung cancer. Odds ratio does not so much predict disease as it does estimate the strength of a risk factor. How would you analyze the data from the following case-control study? Case-Control Study: Colorectal Cancer and Family History No Colorectal Cancer
Colorectal Cancer
TOTALS
Family History of Colorectal Cancer
120
60
180
No Family History of Colorectal Cancer
200
20
220
TOTALS
320
80
400
(60)(200) (120)(20)
OR = 5.0
ANSWER:
AD BC
Interpretation: the odds of having a family history of colorectal cancer are 5x greater for those who have the disease than for those who do not.
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Table 1-6. Differentiating Observational Studies Characteristic Time
Cross-Sectional Studies
Case-Control Studies
Cohort Studies
One time point
Retrospective
Prospective
Incidence
NO
NO
YES
Prevalence
YES
NO
NO
Causality
NO
YES
YES
Prevalence of disease
Begin with disease
End with disease
Association of risk factor and disease
Many risk factors for single disease
Single risk factor affecting many diseases
Chi-square to assess association
Odds ratio to estimate risk
Relative risk to estimate risk
Role of disease Assesses Data analysis
Clinical Trials Researchers design clinical trials to answer specific research questions related to a medical product. A control group (often the placebo group) will includes subjects who do not receive the intervention under study, used as a source of comparison to be certain the experiment group is being affected by the intervention and not by other factors. Control group subjects must be as similar as possible to intervention group subjects. For a medical product to receive approval by the Food and Drug Administration (FDA), 3 phases must be passed. • Phase 1: testing safety in healthy volunteers • Phase 2: testing protocol and dose levels in a small group of patient
volunteers
• Phase 3 (definitive test): testing efficacy and occurrence of side effects
in a larger group of patient volunteers
Post-FDA approval, marketing surveys will collect reports of drug side effects among populations commonly using the product. In a randomized controlled clinical trial (RCT), subjects are randomly allocated into “intervention” and “control” groups to receive or not receive an experimental/preventive/therapeutic procedure or intervention. This is generally regarded as the most scientifically rigorous type of study available in epidemiology. A double-blind RCT is the type of study least subject to bias, but also the most expensive to conduct. Double-blind means that neither subjects nor researchers know whether the subjects are in the treatment or comparison group. A double-blind study has 2 types of control groups: • Placebos (25–40% often show improvement in placebo group) • Standard of care (current treatment versus new treatment)
A community trial is an experiment in which the unit of allocation to receive a preventive or therapeutic regimen is an entire community or political subdivision. Does the treatment work in real-world circumstances?
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A cross-over study is one in which, for ethical reasons, no group involved can remain untreated. All subjects receive the intervention but at different times (making recruitment of subjects easier). Assume double-blind design. For example, an AZT trial, where group A receives AZT for 3 months while group B is the control. For the second 3 months, group B receives AZT and group A is the control.
A
B
+
0
+
0
Figure 1-13. Cross-Over Study
Recall Question Which of the following study types is least susceptible to bias? A. Double-blind randomized controlled trial B. Single-blind randomized controlled trial C. Case-control study D. Cohort study E. Cross-sectional study Answer: A
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Biostatistics
2
Learning Objectives ❏❏ Demonstrate understanding of key probability rules ❏❏ Summarize data ❏❏ Solve problems using inferential statistics ❏❏ Use knowledge of nominal, ordinal, interval, and ratio scales ❏❏ Answer questions about statistical tests
KEY PROBABILITY RULES Independent Events Events are independent if the occurrence of one tells you nothing about the occurrence of the other. Combine probabilities for independent events by multiplication. The issue here is the intersection of 2 sets; e.g., if the chance of having blond hair is 0.3 and the chance of having a cold is 0.2, the chance of meeting a blond-haired person with a cold is: 0.3 × 0.2 = 0.06 (or 6%). If events are nonindependent, multiply the probability of one event by the probability of the second, assuming that the first has occurred; e.g., if a box has 5 white balls and 5 black balls, the chance of picking 2 black balls is: 5 × 4 = 0.5 × 0.44 = 0.22 (or 22%) 10 9
Mutually Exclusive Events Events are mutually exclusive if the occurrence of one event precludes the occurrence of the other. Combine probabilities for mutually exclusive outcomes by addition. The issue here is the union of two sets; e.g., if a coin lands on heads, it cannot be tails; the events are mutually exclusive. If a coin is flipped, the chance that it will be either heads or tails is 0.5 + 0.5 = 1.0 (or 100%).
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If 2 events are not mutually exclusive, add them together and subtract out the multiplied probabilities to get the combination of probabilities. For example, if the chance of having diabetes is 10% and the chance of being obese is 30%, the chance of meeting someone who is obese or has diabetes or both is 0.1 + 0.3 − (0.1 × 0.3) = 0.37 (or 37%).
Mutually Exclusive A
B
Nonmutually Exclusive A
B
Figure 2-1. Venn Diagram Representations of Mutually Exclusive and Figure 2-1.Nonmutually Venn Diagram of Mutually Exclusive and Exclusive Events
Nonmutually Exclusive Events
Review Questions 1. If the prevalence of diabetes is 10%, what is the chance that 3 people selected at random from the population will all have diabetes? 2. Chicago has a population of 10,000,000. If 25% of the population is Latino, 30% is African American, 5% is Arab American, and 40% is of European extraction, how many people in Chicago are classified as other than of European extraction? 3. At age 65, the probability of surviving for the next 5 years is 0.8 for a white man and 0.9 for a white woman. For a married couple who are both white and age 65, the probability that the wife will be a living widow 5 years later is: A. B. C. D. E.
90% 72% 18% 10% 8%
4. If the chance of surviving for 1 year after being diagnosed with prostate cancer is 80% and the chance of surviving for 2 years after diagnosis is 60%, what is the chance of surviving for 2 years after diagnosis, given that the patient is alive at the end of the first year? A. B. C. D. E.
20% 48% 60% 75% 80%
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Answers and Explanations 1. Answer: 0.001. 0.1 × 0.1 × 0.1 = 0.001 2. Answer: 6,000,000. 25% + 30% + 5% = 60%. 60% × 10,000,000 = 6,000,000 3. Answer: C. You’re being asked for the joint probability of independent events; therefore, the probabilities are multiplied. Chance of the wife being alive: 90%, and chance of the husband being dead: 100% − 80% = 20%. Therefore, 0.9 × 0.2 = 18%. 4. Answer: D. The question tests knowledge of “conditional probability.” Out of 100 patients, 80 are alive at the end of 1 year and 60 at the end of 2 years. The 60 patients alive after 2 years are a subset of those that make it to the first year. Therefore, 60/80 = 75%.
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DESCRIPTIVE STATISTICS Distributions Statistics deals with the world as distributions. These distributions are summarized by a central tendency and variation around that center. The most important distribution is the normal or Gaussian curve. This “bell-shaped” curve is symmetric, with one side the mirror image of the other. Symmetric
Md X Figure 2-2. Measures of Central Tendency Figure 2-2. Measures of Central Tendency
Measures of central tendency Central tendency describes a single value which attempts to describe a set of data by identifying the central (or middle) value within that set. (Colloquially, measures of central tendency are often called averages.) There are several valid measures: • Mean (X) (or average): sum of the values of the observations divided by
the numbers of observations
• Median (Md): point on the scale which divides a group into 2 parts
(upper and lower half); the measurement below which half the observations fall is 50th percentile
• Mode: most frequently occurring value in a set of observations
Given the distribution of numbers: 3, 6, 7, 7, 9, 10, 12, 15, 16, the mode is 7, the median is 9, and the mean is 9.4. Not all curves are normal; sometimes the curve is skewed positively or negatively. • A positive skew has the tail to the right, and the mean greater than the
median.
• A negative skew has the tail to the left, and the median greater than
the mean.
For skewed distributions, the median is a better representation of central tendency than is the mean.
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Positively skewed
X Md
Md X
Figure 2-3. Skewed Distribution Curves
Figure 2-3. Skewed Distribution Curves
Measures of variability The simplest measure of variability in statistics is the range, the difference between the highest and the lowest score. However, the range is unstable and can change easily. A more stable and more useful measure of dispersion is the standard deviation (S or SD). To calculate the SD: • First subtract the mean from each score to obtain deviations from the
mean. This will give us both positive and negative values.
• Then square the deviations to make them all positive. • Add the squared deviations together and divide by the number of
cases.
• Take the square root of this average, and the result is the SD:
s=
∑(X − X )
2
n −1
The square of the SD (s2) equals the variance.
Figure 2-4. Comparison of 2 Normal Curves with the Same Means, but Different Standard Deviations Figure 2-4. Two Normal Curves with the Same Mean but Different SDs
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X2
X1
Note On the exam you will not be asked to calculate SD and variance, but you will need to understand how they relate to the normal curve. Also, be able to combine the given SD constants to answer basic questions.
X3
Figure 2-5. Comparison of 3 Normal Curves with the Same Figure 2-5. Three NormalDeviations, Curves withbut Same SD but Different Means Standard Different Means
In any normal curve, a constant proportion of the cases fall within 1, 2, and 3 SDs of the mean: within 1 SD 68%; within 2 SDs 95.5%; and within 3 SDs 99.7%. 99.7% 95.5% 68%
0.15%
:3s
13.5%
2.4%
:2s
:1s
34%
34% X
13.5%
+1s
+2s
2.4%
0.15%
+3s
Figure 2-6. Percentage of Cases within 1, 2, and 3 Standard Figure 2-6. Percentage of Cases within 1, 2, and 3 SDs Deviations of the Mean in a Normal Distribution
of the Mean in a Normal Distribution
Review Questions 5. In a normal distribution curve, what percent of the cases are below 2 SDs below the mean? 6. In a normal distribution curve, what percent of the cases are above 1 SD below the mean? 7. A student who scores at the 97.5 percentile falls where on the curve? 8. A student took 2 tests: On test A his results were score 45%, mean 30%, and SD 5%. On test B the results were score 60%, mean 40%, and SD 10%. On which test did the student do better, relative to his classmates?
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Answers and Explanations 5. Answer: 2.5% 6. Answer: 84% 7. Answer: 2 SDs above the mean 8. Answer: On test A, he scored 3 SDs above the mean versus only 2 SDs above the mean for test B.
INFERENTIAL STATISTICS The purpose of inferential statistics is to designate how likely it is that a given finding is simply the result of chance. Inferential statistics would not be necessary if investigators could study all members of a population. However, because that can rarely be done, using select samples that are representative of an entire population allows us to generalize the results from the sample to the population.
Confidence Interval Confidence interval is a way of admitting that any measurement from a sample is only an estimate of the population, i.e., although the estimate given from the sample is likely to be close, the true values for the population may be above or below the sample values. A confidence interval specifies how far above or below a sample-based value the population value lies within a given range, from a possible high to a possible low. Reality, therefore, is most likely to be somewhere within the specified range. To calculate the confidence interval: study result +/− Z score × standard error Study result might be a mean, a relative risk or any other relevant measure that is the result of the data from the study itself. Z score depends on the level of confidence required. In medicine, the requirement is at least a 95% confidence interval. So the options are as follows: • Z score for 95% confidence interval = 1.96 = 2 • Z score for 99% confidence interval = 2.58 = 2.5
While the SD measures the variability within a single sample, the standard error estimates the variability between samples. The standard error is usually provided. The smaller the standard error, the better and more precise the study. The standard error is affected by 2 factors: the SD and the sample size (n). The greater the SD, (high variation in the data), the greater the standard error, and the larger the sample size, the smaller the standard error. Standard Error =
SD n
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Epidemiology and Biostatistics
Behavioral Science/Social Sciences
Suppose 100 students in the 9th grade have just taken their final exam, and the mean score was 64% with SD 15. The 95% confidence interval of the mean for 9th grade students in the population would be as follows: • Mean = 65 • Z score for 95% confidence = 2 (rounded up Z score) • SD = 15 • Sample size = 100
SD Plug in the numbers: Mean + / − Z score n or 65 + / − 2(15/10) = 65 + / − 3 What this means is that we are 95% sure that the mean score of 9th graders in the population will fall somewhere between 62 and 68. Assuming the graph below presents 95% confidence intervals, which groups, if any, are statistically different from each other? High
Blood Pressure
Low Drug A
Drug B
Drug C
Figure 2-7. Blood Pressures at End of Clinical Trial for 3 Drugs
Figure 2-7. Blood Pressure at End of Clinical Trial for 3 Drugs
Recall Question For a skewed distribution curve, what is the best representation of central tendency? A. Mean B. Mode C. Standard deviation D. Variance E. Median Answer: E
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Biostatistics
When comparing 2 groups, any overlap of confidence intervals means the groups are not significantly different. If the graph represents 95% confidence intervals, drugs B and C are no different in their effects; drug B is no different from drug A and drug A has a better effect than drug C. For the confidence interval for relative risk and odds ratios, consider the following: If the given confidence interval contains 1.0, then there is no statistically significant effect of exposure. For example: Relative Risk
Confidence Interval
Interpretation
1.77
(1.22 − 2.45)
Statistically significant (increased risk)
1.63
(0.85 − 2.46)
NOT statistically significant (risk is the same)
0.78
(0.56 − 0.94)
Statistically significant (decreased risk)
If RR >1.0, then subtract 1.0 and read as percent increase. So 1.77 means one group has 77% more cases than the other. If RR 0.05, do not reject the null hypothesis (has not reached statistical
significance).
p = 0.13 (computed p value)
Possible Outcome #2
Do NOT reject null hypothesis. Risk of type II, β error p girls. • Gender role is determined by behaviors exhibited by a child. It can be
congruent or incongruent to the child’s gender identity (usually congruent).
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Sexual orientation is determined by gender identity and attraction to other gender identities: • Homosexuality: same gender identity (can be ego-syntonic or ego-dystonic; when ego-dystonic, is pathological) • Heterosexuality: opposite gender identity • Bisexuality: either gender identity • Asexuality: neither gender identity
Masturbation is normal at all ages and equal in both genders. When it interferes with normal functioning, it is pathological. Exploring human sexuality is normal, especially during teenage years, even with same sex partners. Because the onset and progression of puberty are so variable, the Tanner Stages of Development (developed by pediatrician James Tanner) help to determine whether development is normal for a given age. Boys and girls are rated on a 5-point scale; boys for genital development and pubic hair growth, and girls for breast development and pubic hair growth. Table 3-4. Tanner Stages of Development Female
Both
Male
Stage
Breast
Pubic hair
Genitalia
I
Preadolescent
None
Childhood size
II
Breast bud
Sparse, long, straight
Enlargement of scrotum, testes
III
Areolar diameter enlarges, breast elevates
Darker, curling, increased amount
Penis grows in length; testes continue to enlarge
IV
Secondary mound; separation of contours
Coarse, curly, adult type
Penis grows in length/breadth; scrotum darkens, testes enlarge
V
Mature female
Adult, extends to thighs
Adult shape/size
AGING The human body undergoes significant changes with age that have both medical and psychological implications for your patients. The leading causes of death for patients age >65 include: • Heart disease • Malignancy • Cerebrovascular disease • Chronic lower respiratory disease
As such, preventive care and primary or secondary prevention becomes crucial to patient health, improved quality of life, and survival.
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Developmental Life Cycle
Some factors can be modified by behavioral change: • Smoking = smoking cessation • Poor diet = low sodium diet (CHF), low cholesterol diet (ACS), low
sugar diet (DM)
• Physical inactivity = exercise
Geriatrics is the subspecialty dedicated to the science of providing medical care to the elderly. As a physician, regardless of specialty, you are likely to encounter and treat elderly patients.
Medical Medical care of the geriatric population includes preventive care, vaccinations, and screening. • Preventive care may include aspirin therapy and lipid management. • Vaccinations: illness is usually associated with higher morbidity and
mortality with older patients, so it is important they receive certain vaccinations. –– Tetanus –– Diphtheria –– Pneumococcus –– Influenza –– Varicella/zoster
• Screening: the 2 main areas of screening are cancer and abdominal
aortic aneurysm. For older patients, the rule of thumb is to evaluate comorbidities, functionality, and life expectancy before making recommendations for screening tests. In general, the survival screening benefit is not seen unless the patient’s life expectancy is >5 years. –– Cancer screening: ages for screening are usually standardized: ºº Breast cancer: women age >40 ºº Colorectal cancer: men and women age >50 –– Abdominal aortic aneurysm screening: men age 65–75, especially if they have ever smoked
Psychiatric • Depression screening
–– Age >65 is a risk factor for suicide. –– Screening appropriate especially when patients have a terminal or debilitating illness. • Adjustment disorder
–– Many life changes can be stressors that require coping mechanisms. –– Some life changes (e.g., retirement, even when voluntary; illness, etc.) can cause an adjustment disorder.
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Physiological On the exam, you will be expected to recognize physiological changes that are not pathological, but rather due to aging. • Sexuality –– Sexual interest and activity does not decline significantly with aging –– Best predictor of sexual activity in the elderly is availability of a partner –– Changes in men: slower erection, longer refractory period, more stimulation needed –– Changes in women: vaginal dryness and thinning • Sleep
–– Early morning wakefulness –– Less deep sleep –– REM sleep does not significantly decrease until age >85
Financial Several factors contribute to financial instability in the elderly: • Inadequate fixed income –– Social Security (government-provided earned benefit): eligible adults who have worked >40 quarters; dependents of eligible adult (typically the spouse who was a homemaker) –– Pensions (employer-provided earned benefits) –– Investment income • High medical costs • Low financial literacy: elderly can be exploited by unscrupulous
investment advisors and sometimes family members
End-of-Life Care Talking about life expectancy and end-of-life treatment and expectations is important. • Patients should be asked about DNR status. • Patients may have a living will or assign a health power of attorney in
the event they can no longer make decisions themselves.
• You have an obligation to tell the patient everything. • Do not give false hope to patients, but recognize that they might hope
for things other than a cure: quality of life, less pain, a painless death.
• Allow patients to talk about their feelings. • Encourage patients to avoid social isolation and stay engaged in
different activities.
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Patients may cycle through the Kübler-Ross stages of adjustment. The stages need not occur in order. • Denial • Anger • Bargaining • Depression • Acceptance
Hospice care is care for terminally-ill patients with a life expectancy ≤6 months. It provides care and support for patients (and their families) with advanced disease; the goal is to help dying patients with peace, comfort, and dignity. Hospice care consists of medical care, psychological support, and spiritual support. It may be delivered at specialized facilities or at home. In the United States, payment for hospice care varies: • Medicare hospice benefit • Medicaid hospice benefit • Private insurance
DEATH AND BEREAVEMENT Attachment and Loss in Children According to Bowlby’s theory of attachment, children are predisposed at birth to form attachments with others. Over the first 2 years of life, they form attachments with their primary caregiver. Separation from a child can lead to the following: • Protest (usually seen during short-term separation, e.g., up to 2 weeks) –– Crying, screaming, and clinging when parents leave –– Anger toward parent upon return • Despair
–– Protesting stops –– Despondency and sadness –– Child appears calmer but may be withdrawn and disinterested • Detachment
–– If separation continues, the child will start to engage with others but will reject caregiver and remain angry –– Indifference upon caregiver’s return
Mourning and Loss in Adults Adults who are bereaved or are mourning the loss of a loved one also go through a period of adjustment. People move back and forth through the stages of adjustment (Kübler-Ross). Not everyone passes through all stages or reaches adequate adjustment.
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Table 3-5. Normal Grief vs. Depression Normal Grief
Depression
Normal up to 1 year
After 1 year, sooner if symptoms severe
Crying, decreased libido, weight loss, insomnia
Same but more severe
Longing, wish to see loved one, may think they hear or see loved one in a crowd (illusion)
Abnormal overidentification, personality change
Loss of other
Loss of self
Suicidal ideation is rare
Suicidal ideation is common
Self-limited, usually 50 D. Abdominal aortic aneurysm screening in female smokers age 65–75 E. All of the above are correct Answer: C
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SUICIDE Suicide is the 10th leading cause of death in the United States. Men > women; however, women attempt suicide more often (pills/poison). • Elderly are most successful and attempt less frequently. • Adolescents attempt more frequently. • Ethnic group with the highest suicide rate is Native Americans; within
this group adolescents > elderly.
• Firearms account for >50% of all suicides. • 50% have seen a physician in the past month.
High risk factors for suicide include: • Previous suicide attempt • Age • Gender • High socioeconomic status (SES) • Unemployed • Medical/psychiatric comorbidities
Note
• Hopelessness
Decreased levels of 5-HIAA (serotonin metabolite) are associated with aggression and suicide.
• Isolation • Initiation of antidepressant pharmacotherapy (suicide window)
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Theories of Learning and Behavioral Modification
4
Learning Objectives ❏❏ Demonstrate understanding of theories of learning and how different reinforcers are applied ❏❏ Answer questions about behavioral modification, including classical and operant conditioning ❏❏ Answer questions about behavioral models of depression
LEARNING Learning results from a permanent change in behavior not due to fatigue, drugs, or maturation. There are two main types of learning: classical and operant.
Classical Conditioning In classical conditioning, a neutral stimulus is associated with an event that usually elicits an unconditioned response. The conditioned response is elicited by the conditioned stimulus after repeated pairings of the unconditioned stimulus (UCS) and conditioned stimulus (CS). The classic example is the Pavlovian experiment, which pairs the ringing of a bell with the bringing of food. Eventually the sound of the bell elicits the salivary response that previously occurred only with the sight of the food. Another example is when a patient receives chemotherapy (UCS), which induces nausea (UCR). Eventually, the sights and sounds of the hospital alone (CS) elicit nausea, now a conditioned response (CR). UCS 5-FU (chemotherapy)
UCR Nausea and vomiting
Hospital CS
Nausea and vomiting CR Figure 4-1. Classic Conditioning
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Operant Conditioning In operant conditioning (experiment by B. F. Skinner), learning occurs when a behavior is followed by an event. In the experiment: • A rat presses a lever to get a pellet of food. (The behavior is called operant because it operates on the environment.) • After receiving the food, the rat becomes more likely to press the lever
because the food is a reinforcing event.
• The role of the reinforcer is to increase the likelihood of a response.
A primary reinforcer is the key motivator for behavior. It is often a physiological or psychological necessity, e.g., food, water, and sex. A secondary reinforcer is a stimulus or situation that has acquired its function as a reinforcer after pairing with a stimulus that functions as a reinforcer. Examples often include tokens and money. Behavior
→
Drug experimentation
Reinforcement Pleasure
→
Response Drug addiction
Types of Reinforcers There are 2 types of reinforcers, both of which increase the probability of a response. Typically, a positive reinforcer adds a desirable stimulus, while a negative reinforcer removes an aversive stimulus. No stimulus is universal. • A positive reinforcer is a stimulus that, when applied following an operant response, strengthens the probability of that response occurring. –– A woman gets a bonus at work after completing a big project; that will make her happy and more likely to perform well again. • A negative reinforcer is a stimulus that, when removed following an
operant response, strengthens the probability of that response occurring. –– A child cleans up his room (response/desired behavior) in order to stop his mother’s nagging (negative reinforcer).
Behavioral response to the same stimulus can be different (increased or decreased) from person to person. Do not rely on subjective evaluations of whether the stimulus is unpleasant. An introvert might find a party aversive, while an extrovert would not. Punishment is a stimulus that will decrease the probability of the response. It usually uses an aversive stimulus to the individual. In punishment, you want to decrease the response. • A man drives over the speed limit and gets a speeding ticket. The goal of the ticket is for the man to reduce his driving speed. Extinction refers to the disappearance of a response when it is no longer being reinforced. This can occur in classical or operant conditioning.
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Learning theory
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Theories of Learning and Behavioral Modification
Extinction occurs when you
Effect
Classic conditioning
Unpair the unconditioned stimulus (food) with the conditioned stimulus (bell)
Dog does not salivate when bell is rung.
Operant conditioning
Remove reinforcer (food)
Rat stops pressing the lever looking for food.
Types of Reinforcement In continuous reinforcement, every response is followed by a reinforcement. This results in fast learning (acquisition) and fast extinction when reinforcement is stopped. In intermittent (or partial) reinforcement, not every response is reinforced. Learning is slower and response is harder to extinguish. Suppose a child often throws tantrums, and in the hope that he will stop, the parents ignore him for long periods of time. They don’t want to reinforce such behavior with attention. However, if their patience eventually wears thin and they attend to him, they are putting the child on an intermittent reinforcement schedule, which will make it harder to extinguish the tantrums.
Fixed interval Interval Variable interval Intermittent Reinforcement
Fixed ratio Continuous
Ratio Variable ratio
Figure 4-2. Reinforcement
Reinforcement Schedules Interval schedules are based on the passage of time before reinforcement is given. • A fixed interval schedule reinforces the response that occurs after a fixed period of time elapses. Responses are slow in the beginning of the interval and faster immediately prior to reinforcement (end-of-year bonus). • A variable interval schedule delivers reinforcement after unpredictable
time periods elapse (surprise bonus you can get anytime).
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Ratio schedules are based on the number of behaviors elicited before reinforcement is given. • A fixed ratio schedule delivers reinforcement after a fixed number of responses. It produces a high response rate (getting a bonus after every three projects completed). • A variable ratio schedule delivers reinforcement after a changing
number of responses. It produces the greatest resistance to extinction (getting a bonus after completing undisclosed number of projects).
Table 4-1. Reinforcement Schedules Interval Schedule
Examples
Fixed interval
• Weekly paycheck • Bonus during holiday season • Gift with each purchase • Weekly quiz
Variable interval
• Surprise bonus • Pop quiz • Listening to radio for favorite song
Ratio Schedule
Examples
Fixed ratio
• Piecemeal work • Free sandwich after 10 sandwiches bought • $5,000 to a salesman after each sale of 5 automobiles
Variable ratio
• Slot machines • Door-to-door salesman • Unknown sales bonus
Modeling In modeling, learning occurs through observation. Watching someone else get reinforcement is enough to change behavior.
BEHAVIORAL MODIFICATION Classical Conditioning Systematic desensitization usually begins with imagining oneself in a progression of fearful situations and using relaxation strategies that compete with anxiety. It is often used to treat anxiety and phobias, and is based on the concept of counterconditioning. • Patients start by creating a list of fear-eliciting stimuli from least stressful to most stressful. • They then pair their fear-eliciting stimulus with behaviors that elicit
unconditioned responses (relaxation).
• When they are relaxed in the presence of the feared stimulus, the fear
response disappears.
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Exposure is treatment by forced exposure to the feared object; maintained until fear response is extinguished. If you are afraid of heights, you will climb to greater and greater heights until you can conquer your fear; there is a hierarchy to progress through. Flooding, or massive exposure, is where patients are exposed to a maximum intensity anxiety-producing situation. If imagined, it is called implosion. If you are afraid of bugs, you will be locked in a room with millions of bugs. Contrary to exposure, there is no hierarchy. Aversive conditioning occurs when a stimulus that produces undesired behavior is paired with an aversive stimulus. In treatment of alcoholism, patients are given disulfiram, which makes them sick when they drink alcohol.
Operant Conditioning Shaping (or successive approximations) achieves final target behavior by reinforcing successive approximations of the desired response. Reinforcement is gradually modified to move behaviors from the more general to the specific responses desired. A boy with autism is rewarded when he utters one word and subsequently has to utter more words to obtain the same reward. Stimulus control is where a stimulus inadvertently acquires control over behavior. When this is true, removal of that stimulus can extinguish the response. Watching TV while eating will increase weight, so in order to lose weight you must stop watching TV. Biofeedback (neurofeedback) uses external feedback via instruments to provide usually unperceived biological information subsequently used to modify internal physiologic states. Certain functions of the autonomic nervous system (pulse, blood pressure, muscle tone, pain perception) can be manipulated through the technique of biofeedback. Fading is gradually removing the reinforcement without the individual becoming aware of the difference. • Patients receive pain medication after surgery, but each dose is smaller until discontinuation. • Nicotine patch begins with 21 mg and is later reduced to 14 mg and
then 7 mg.
• Patients are unaware during this process that they are receiving less nicotine.
Behavioral Models of Depression Learned helplessness (or the animal model of depression) is where all normal avoidance responses are extinguished. If a rat is shocked and not allowed to escape, eventually the rat will not take an obvious avoidance route even when it is offered.
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Symptoms of helplessness in animals include passivity, norepinephrine depletion, and difficulty learning responses that produce relief and weight/appetite loss. • Characterized in people by an attitude of “when nothing works, why bother.” A woman in an abusive relationship who perceives she cannot escape the abuse will give up and become depressed. • Increased levels of GABA in hippocampus decrease the likelihood of
learned helplessness response.
Low rate of response-contingent reinforcement is another explanation for depression. The person receives too little predictable positive reinforcement and may lack the social skills necessary to elicit this positive reinforcement. Depression can be seen as a prolonged extinction schedule; it results in passivity. • A man who feels he receives no positive reinforcement from his spouse can become depressed, even if he seems otherwise successful. • A caring and giving father who feels unappreciated by his family might
become depressed.
Recall Question A 26-year-old medical student is studying for a medical licensing exam. His mother rewards him when he scores well on his question bank. Which of the following reinforcement schedules would produce the greatest resistance to extinction? A. Variable ratio schedule B. Fixed ratio schedule C. Fixed interval schedule D. Variable interval schedule E. Positive reinforcement Answer: A
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Defense Mechanisms
5
Learning Objectives ❏❏ Define the components of psychic structures ❏❏ Describe how the different defenses are used to manage internal conflict
PSYCHIC STRUCTURES Psychic structures are based on Freudian theory. The id controls primitive instincts and drives (what we want to do): • Present at birth • Influences sex and aggression
The ego tries to “accommodate” reality: • Rational • Resolves conflicts between id and superego (tries to find ways that will
benefit in the long-term rather than bring grief through impulsive id decisions)
The superego determines our conscience or moral compass (what we ought to do): • Begins development by age 5 • Learned from caretakers • Insists on socially acceptable behavior, sometimes to the point of
individual deprivation
• Can be punitive
DEFENSE MECHANISMS Defenses are the primary tools of the ego used to manage the internal conflicts between the id and superego. They are the means by which the ego wards off anxiety, and controls instinctive urges and unpleasant effects (emotions). • All defenses are unconscious, with one exception: suppression. • Defenses change over time; we are only aware of our defenses in
retrospect.
• Defenses are adaptive as well as maladaptive.
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Narcissistic Defenses Projection is when a person attributes his own wishes, desires, thoughts, or emotions to someone else. Internal states are perceived as a part of someone else or of the world in general. • A cheating spouse accuses partner of cheating. • A girl talks about her doll as having certain feelings, which are really
what the girl feels.
This is the main defense mechanism seen in paranoid personality disorder. Paranoia results from the use of projection. Denial is not allowing reality to penetrate to avoid acknowledgment of a painful aspect of reality. • After surviving a heart attack, a patient insists on continuing his lifestyle as if nothing had happened. • A woman prepares dinner for her husband expecting him to come
home, even though he died a month earlier.
• Substance users are often “in denial,” claiming that they are not
addicted and do not have a problem in the face of clearly dysfunctional or dangerous behavior.
Denial is often the first response to bad news, such as the impending death of a loved one or oneself. Splitting is when people and things in the world are idealized (all good) or devalued (all bad). The world is pictured in extreme terms rather than a more realistic blend of good and bad qualities. • “This doctor is a miracle worker, but that doctor is totally incompetent.” • “He’s just so perfect and wonderful,” says a teenage girl in love. • “No one from that family will ever amount to anything; they are all
just plain no good.”
This is the main defense mechanism seen in borderline personality disorder. Prejudice and behavioral stereotypes are also a result of splitting.
Immature Defenses Blocking is a temporary, or transient, block in thinking or an inability to remember. • A student is unable to recall the fact needed to answer the exam question, although he recalls it as he walks out of the exam. • In the middle of a conversation, a woman pauses, looks confused, and
asks what she was just talking about.
• In a conversation you forget someone’s name.
Blocking often happens in embarrassing moments.
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Defense Mechanisms
Regression is returning to an earlier stage of development you have already completed (unconscious childish behavior in an adult). • A husband speaks to his wife in “baby talk” when he is sick. • A man assumes a fetal position after a traumatic event. • A previously toilet trained child wets the bed following the birth of a
new sibling.
Somatization is when psychological conflict is converted into bodily symptoms. • A student gets a headache while taking an exam. • A woman feels queasy and nauseated before asking someone out on
a date.
• A man who witnesses a traumatic event becomes blind.
This is the main defense mechanism of somatic symptom disorders. Introjection (identification) is when we acquire characteristics of others as our own. It is the unconscious form of imitation. Introjection is the opposite of projection. • A resident dresses and acts like the attending physician. • A child scolds her friend out loud in the same manner that she was
scolded by her mother.
• A teenager adopts the style and mannerisms of a rock star.
This defense mechanism is used in psychotherapy.
Anxiety Defenses Displacement is when the target of an emotion or drive changes to a substitute target. • A recently disciplined employee yells at his wife instead of his boss. • A woman watching a movie featuring love scenes with a handsome
actor goes out and seduces an unattractive man.
• In family therapy, one child in a family is often singled out and blamed
for all the family’s problems, i.e., treated as a scapegoat.
This is the defense mechanism seen in phobias. Repression is when an idea or feeling is withheld from consciousness. It is also called unconscious forgetting. • A child who was abused by her mother and treated for the abuse now has no memory of any mistreatment by her mother. • A man who survived 6 months as a hostage cannot recall anything
about his life during that time period.
This is one of the most basic defense mechanisms.
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Isolation of affect is the separation of an idea or event from the emotions (affect) that accompany it. • A child who has been beaten discusses the beatings without any display of emotion. • A combat pilot is calm while ejecting out of his plummeting aircraft. • A patient who recently severed his finger in an accident describes the
incident to his physician with no emotional reaction.
This is an important adaptive defense mechanism for self-preservation. Intellectualization is when facts and logic are used to avoid confronting emotions. • A patient with a bone protruding from his leg focuses on the physics that allow such an event to occur. • A medical student speaks excessively about medical details in order to
avoid the emotional content of a bad diagnosis.
• A boy who, for the first time, is about to ask a girl out talks with his friend
about the importance of mating rituals for the long-term survival of the species and the mechanisms by which societies arrange for these rituals.
Physicians who are too concerned with the technical aspects of the profession and not enough with the patient may well be using intellectualization. Acting out is when an emotional or behavioral outburst masks underlying feelings or ideas. • A child throws temper tantrum when abandoned • New-onset drug use in an adolescent boy after parents’ divorce • “Whistling in the dark” to hide underlying fear
This is a defense mechanism that can be seen in borderline and antisocial personality disorders. Rationalization is when rational explanations are used to justify attitudes, beliefs, or behaviors that are unacceptable. This is not a reasoned action, but a search for reasons to allow an unacceptable action. • A murderer saying, “Yes, I believe killing is wrong but I killed him because he really deserved it.” • A teenage girl who makes a vow of chastity until marriage tells herself
that oral sex is not really sex, and can give a string of reasons.
• An alcoholic man tells his wife that he drinks because of stress at work.
This defense mechanism is seen in substance use disorders.
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Defense Mechanisms
Reaction formation is when an unacceptable impulse is transformed into its opposite. Excessive overreaction can be a sign of reaction formation. • A student who always wanted to be a physician expresses relief and says, “This is the best news I’ve ever heard,” after not being accepted into medical school. • A teenage boy intrigued by “dirty pictures” organizes an anti-
pornography campaign.
• Two coworkers fight all the time because they are actually very
attracted to each other.
This defense mechanism is commonly seen in obsessive-compulsive disorder and anxiety disorders. Undoing is performing an act to undo a previous unacceptable act or thought. • A man who is sexually aroused by a woman he meets immediately leaves and buys his wife flowers. • Can include superstitions such as throwing salt over your shoulder to
avoid bad luck.
• A man repeatedly checks to make sure the burners on the stove are
turned off before leaving the house because he is fearful the house will burn down.
This defense mechanism is seen in obsessive-compulsive disorder. Passive-aggression is when hostility is expressed covertly. • A patient angry with her physician shows up late for appointments. • A student agrees to share class notes with classmates but goes home
without sharing them after they upset her in class.
• A communications director does not take questions from people who
challenge his views.
The feelings of hostility are unconscious, and the person using the defense is generally unaware of them. If you consciously set someone up, it is not a defense, but simply being mean. This defense mechanism is seen in borderline personality disorders and young children. Dissociation separates the self from one’s experience to avoid emotional distress. • A woman who was raped reports that she felt “as if she was floating on the ceiling” watching it happen. • The survivor of an automobile accident tells of the feeling that every-
thing happened in slow motion.
• A child who was sexually abused recalls only the “bad man who came
to her in her dreams.”
This is the primary defense mechanism in dissociative disorders.
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Mature Defenses Humor permits the overt expression of feelings and thoughts without personal discomfort. • A student smiles when he realizes that a particularly intimidating professor looks like a penguin. • An overweight comedian makes jokes about being fat.
Laughter covers the pain and anxiety. Sublimation is when impulse gratification is achieved by channeling the unacceptable or unattainable impulse into a socially acceptable direction. • Jack the Ripper becomes a surgeon. • A patient with exhibitionist fantasies becomes a stripper.
Many forms of art and literature spring from sublimation, considered by some to be the most mature defense mechanism. Suppression is the conscious decision to forget or ignore. • A student with a pending exam decides to forget about it and go out for the evening. • A woman who is afraid of heights ignores the drop of a steep cliff to
appreciate the beautiful view.
• A terminally-ill cancer patient puts aside his anxiety and enjoys a
family gathering.
Suppression is the only conscious defense mechanism.
Recall Question A 32-year-old man sees his psychiatrist for a follow-up visit. He states that when he talks to his wife he is often angry on the inside but never expresses it. This behavior is most representative of which defense mechanism? A. Displacement B. Introjection C. Intellectualization D. Acting out E. Isolation of affect Answer: E
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Psychological Health and Testing
6
Learning Objectives ❏❏ Answer questions about stress and how it affects the body ❏❏ Demonstrate understanding of how to calculate intelligence testing ❏❏ Demonstrate understanding of the various types of personality t esting
STRESS Physiologic changes in response to stress include key stress response pathway: hypothalamic-pituitary-adrenal axis. • Cortisol levels rise, then fall, within 24 hours after stressor. • Cortisol levels spike again 48–72 hours after stressor. • Mood issues including anger, depression, irritability • Lack of energy, concentration problems, sleeping issues, headaches • Mental issues including anxiety disorders and panic attacks • Increased blood pressure, increased heart rate, higher cholesterol • Risk of heart attack In the immune system, reduced ability to fight and recover from illness
Stomach cramps, reflux, and nausea
• Loss of libido, lower sperm production for men • Increased period pain for women Aches and pains in the joint and muscles
Decreased bone density
Figure 6-1. Effects of Stress on the Body
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Type A and B Personalities Type A personality is a cluster of behavioral traits that has been associated with increased prevalence and incidence of coronary heart disease. • Tends to be impatient, competitive, preoccupied with deadlines, and highly involved with work • Key component of type A behavior: how they handle hostility • Has increased incidence of coronary heart disease, even after control-
ling for the major risk factors (systolic blood pressure, cigarette smoking, cholesterol)
• If they survive a first heart attack, less likely than type B to have a
second attack
Type B personality lives at lower stress levels. When faced with competition, they do not mind losing.
Stress and Illness Mentally healthy individuals do not deteriorate in physical health as quickly as do those in poor mental health. Chronic anxiety, depression, and emotional maladjustment predict negative health events later in life. The Holmes and Rahe scale is used to quantify stressful life events. • Different life events contribute different weightings to the total score. • The death of a spouse is weighed as the most stressful event. • There is a positive correlation between stressful life events and
developing illness.
Table 6-1. Holmes and Rahe Life Stress Inventory Life Event
Mean Value
Death of spouse
100
Divorce
73
Marital separation from mate
65
Detention in jail or other institution
63
Death of a close family member
63
Major personal injury or illness
53
Marriage
50
Being fired at work
47
Marital reconciliation
45
Retirement from work
45
Major change in the health or behavior of a family member
44
Pregnancy
40
Sexual difficulties
39
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Gaining a new family member (birth, adoption, older adult moving in, etc.)
39
Major business adjustment
39
Major change in financial state (a lot worse or better than usual)
38
Death of a close friend
37
Changing to a different line of work
36
Major change in number of arguments with spouse (a lot more or less)
35
Taking on a mortgage (for home, business)
31
Foreclosure on a mortgage or loan
30
Major change in responsibilities at work (promotion, demotion)
29
Son or daughter leaving home (marriage, college, military)
29
In-law troubles
29
Outstanding personal achievement
28
Spouse beginning or ceasing work outside the home
26
Beginning or ceasing formal schooling
26
Major change in living conditions (new home, remodeling, deterioration, etc.)
25
Revision of personal habits (dress, associations, quit smoking, etc.)
24
Troubles with the boss
23
Major changes in working hours or conditions
20
Changes in residence
20
Changing to a new school
20
Major change in usual type and/or amount of recreation
19
Major change in church activity (a lot more or less)
19
Major change in social activities (clubs, movies, visiting)
18
Taking on a loan (car, TV, freezer)
17
Major change in sleeping habits (a lot more or less)
16
Major change in number of family get-togethers (a lot more or less)
15
Major change in eating habits (a lot more or less, eating hours, surroundings)
15
Vacation
13
Major holidays
12
Minor violations of the law (traffic ticket, jaywalking)
11
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To find your score, add up all your points: • 300 points: odds increase to 80% chance of a major stress-induced
health problem in next 2 years
TESTING Intelligence Testing Intelligence quotient (IQ) is a general estimate of the functional capacity of a person; 70% is inherited, with recent studies suggesting it is mostly from the mother. IQ is not an absolute score, but a comparison among people. Distribution mean is 100, and standard deviation is 15. To calculate IQ, use the following: • Mental age (MA) method: IQ = MA/CA (chronological age) × 100 • Deviation from the norm method: mean IQ = 100 and SD = 15
–– Intellectual disability women). • Alcohol is most widely used illicit drug for teenagers (marijuana is
most widely used illicit drug overall).
• Binge drinking is becoming more common; proportion of heavy
drinkers age 75 Delta sleep—1/2Delta toK2 complexes cps-delta waves>75 Sleep spindles
Delta sleep—1/2 to 2 cps-delta waves>75 Delta sleep—1/2 to 2 cps-delta waves>75
Table 8-1. Sleep Facts Stage 2
Longest stage of sleep
Stage 3
• Deepest stage of sleep; delta sleep is restorative • Tends to decrease in the elderly
Sleep latency
About 5–15 min from time one goes to bed and falls asleep
REM latency
About 90 min from time one falls asleep to first REM period
REM
• First REM period of night is 5–15 min and last one is 20–40 min • REM increases as night goes on • Greater amounts in second half of night • Easiest to arouse • Memories are consolidated by hippocampus
NREM
Greater amounts in first half of night
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Sleep and Sleep Disorders
Awake Stage 1 & REM
Stage 2 Stage 1 sleep and REM sleep (purple) are graphed on the same level because . their EEG patterns are very similar.
Delta 1
2
3
4 Hours
5
6
7
8
Figure 8-3. Sleep Architecture Diagram
Sleep Deprivation The cerebral cortex shows the greatest effects of sleep deprivation but has the capacity to cope with one night’s sleep loss. In sleep-deprived individuals: • Cortisol levels rise • Blood pressure rises • Glucose tolerance is reduced • Greater amygdala activation • Lower prefrontal cortical activity • Increased negative mood
Neurotransmitters Serotonin helps to initiate sleep. Acetylcholine (ACh) is higher during REM sleep (associated with erections in men). Norepinephrine (NE) is lower during REM sleep. • Ratio of ACh and NE is biochemical trigger for REM sleep. • NE pathway begins in the pons, which regulates REM sleep.
Dopamine produces arousal and wakefulness. Dopamine levels rise upon waking. Orexin (or hypocretin) is a neurotransmitter that regulates arousal, wakefulness, and appetite. Activation of orexin triggers wakefulness, while low levels of orexin at night serve to drive sleep. A deficiency of orexin results in sleepstate instability, leading to sleep disorders like narcolepsy.
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Melatonin is converted from serotonin in the pineal gland in the brain under directions from the body’s internal circadian clock. • Melatonin production is inhibited by activation of photoreceptors cells in the retina. • Melatonin production increases in the evening, causing drowsiness. • Melatonin secretion regulates the sleep-wake cycle by inhibiting the
circadian alerting system in the suprachiasmatic nucleus.
• Bright environmental light, capable of suppressing human melatonin,
reverses the winter depressive symptoms of patients with seasonal affective disorder (SAD).
Drugs That Alter Sleep Dopamine increases wakefulness. Dopamine blockers (e.g., antipsychotics) increase sleep. Benzodiazepines cause limited decrease in REM and Stage 4 sleep. If used chronically and then stopped, sleep latency will increase. • Moderate alcohol consumption leads to early sleep onset and increased wakefulness during the second half of the night. Intoxication decreases REM; REM rebound (with nightmares) occurs during withdrawal. • Barbiturates decrease REM; REM rebound, including nightmares,
occurs in withdrawal.
• Major depression increases REM, decreases REM latency (45 rather
than 90 minutes), and decreases Stages 3 and 4 sleep. It also leads to early morning waking and multiple awakenings during the night.
SLEEP DISORDERS Narcolepsy Narcolepsy is a neurological disorder that decreases the ability to control the sleep-wake cycle. It is a REM disorder; patients typically enter REM within 10 minutes. It is linked to a deficiency in hypocretin (also known as orexin). Narcolepsy patients experience 4 main symptoms (narcoleptic tetrad): • Sleep attacks and excessive daytime sleepiness (most common symptoms) • Cataplexy (pathognomonic sign): sudden loss of consciousness and
symptoms ranging from slurred speech to total body collapse (can be triggered by loud noise, emotions, etc.)
• Hypnopompic and hypnogogic hallucinations (common) • Sleep paralysis: the inability to move or speak while falling asleep or
waking up from sleep
Treatment is modafinil or psychostimulants to treat the sleepiness and an antidepressant to treat the cataplexy.
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Sleep and Sleep Disorders
Sleep Apnea With sleep apnea, individuals have episodes of apnea during the night causing them to have difficulties breathing. It is characterized by a loud snore and common in obese, middle-aged men. • Obstructive or upper airway sleep apnea: airway collapses or becomes blocked during sleep • Central sleep apnea: area of the brain that controls breathing does not
send the correct signals to the breathing muscles; often associated with medical problems
• Mixed sleep apnea: patients experience both obstructive and central
sleep apnea
Clinical presentation includes: • High risk of sudden death during sleep • Development of severe nocturnal hypoxemia • Pulmonary and systemic hypertension (with elevated diastolic pressure) • Nocturnal cardiac arrhythmias (potentially life-threatening) • Bradycardia, then tachycardia
Symptoms commonly include dry mouth, headaches, and daytime tiredness. Restlessness and loud snoring are typically reported by sleep partners. To diagnose, patients are referred to nocturnal polysomnography or home sleep tests to monitor pulse, oxygen level, etc. Treatment may be limited to diet or smoking cessation (mild cases); CPAP (continued positive airway pressure) in moderate to severe cases; and surgery in cases due to obstructive reasons.
Insomnia Insomnia is characterized by difficulty initiating and maintaining sleep (DIMS). • Primary insomnia • Secondary insomnia (most common) is caused by medical problems,
psychiatric problems, medications, etc.
Symptoms of insomnia include sleepiness during the day, general tiredness, irritability, and problems with concentration or memory. Treatment varies: • Sleep hygiene • Behavior modification: stimulus control • Pharmacotherapy: zaleplon, zolpidem, eszopiclone (work on sleep
receptors to help individual to fall and stay asleep)
• Ramelteon, a melatonin receptor-agonist, works on the sleep wake
cycle and has less incidence of dependence
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Table 8-2. Parasomnias Diagnosis
Sleep Stage
Features
Treatment
Memory for Event
Night terror
3
• Common in young boys
Benzodiazepines
No
• Familial • Wake up in middle of night and scream Nightmares
REM
Common during stressful times
Antidepressants
Yes
Somnambulism (sleepwalking)
3
• Confused and disoriented if awakened
Benzodiazepines
N/A
Teeth guards
N/A
• Common in children • May harm themselves Bruxism (teeth grinding)
2
Usually stress-related
Recall Question A 25-year-old man is being evaluated for difficulty sleeping by his primary care physician. Upon questioning he states to having excessive daytime sleepiness with sleep attacks and episodes of sudden loss of consciousness. In which of the following neurotransmitters is he most likely deficient? A. Serotonin B. Acetylcholine C. Hypocretin D. Norepinephrine E. Dopamine Answer: C
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Psychiatric (DSM-5) Disorders
9
Learning Objectives ❏❏ Demonstrate understanding of the different psychiatric disorders that are identified in childhood and adolescence ❏❏ Demonstrate understanding of the different thought disorders that affect interpretation of reality ❏❏ Demonstrate understanding of the different mood and anxiety disorders ❏❏ Answer questions about the features of obsessive-compulsive disorder ❏❏ Answer questions about different eating disorders ❏❏ Answer questions about somatic symptom, dissociative, and personality disorders ❏❏ Demonstrate understanding about the types of sexual disorders
CHILDHOOD AND ADOLESCENCE Intellectual Disability The most common known cause of intellectual disability is fetal alcohol syndrome (FAS), while the most common genetic causes are Down and fragile-X syndromes. Table 9-1. Intellectual Disability Levels Level
Functioning
Mild (85% of intellectually disabled; 2:1 male:female)
Self-supporting with some guidance; usually diagnosed first year in school
Moderate
Benefits from vocational training but needs supervision; sheltered workshops
Severe
Vocational training not helpful, can learn to communicate and manage basic self-care habits
Profound
Needs highly structured environment with constant nursing care and supervision
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Autism Spectrum Disorders The hallmark of autism spectrum disorders is an inability to connect with others. It is usually diagnosed age girls. Clinical features include: • Problems with communication and reciprocal social interaction –– Abnormal or delayed language development; impairment in verbal and non-verbal communication –– No separation anxiety; problems with relationships –– Pronoun reversal –– Fails to assume anticipatory posture, shrinks from touch –– Poor eye contact • Restrictive and repetitive behaviors (RRBs), interests, or activities
–– Stereotype or repetitive movements (echolalia, lining up toys) –– Inflexibility –– Oblivious to external world –– Preference for inanimate objects With autism, monozygotic concordance is greater than dizygotic concordance. Severity correlates to IQ deficiency. EEG may be abnormal. Seizures are present in 25% of patients. Differential diagnosis includes: • Rett syndrome –– Girls > boys –– Microcephaly • Social communication disorder
–– Communication disorder –– Absence of RRBs Treatment is behavioral techniques (shaping) and antipsychotics (for aggression only), e.g., risperidone.
Tourette Syndrome Tourette syndrome is characterized by multiple motor and vocal tics that occur many times per day or intermittently for >1 year. Men > women 3:1. • Mean onset is age 7 (onset must be age women 10:1. Impairment must occur in at least 2 settings. • Symptoms >6 months • Symptoms age girls
Boys > girls (pre-puberty) Boys = girls (post-puberty)
Symptoms
• 6 months of aggressive behavior • Violation of rules of society • Destruction of property
• 6 months of negative, hostile, and defiant behaviors toward authority figures
• Deceitfulness or theft Etiology
Genetic
Recall Question An 8-year-old boy comes for evaluation to his primary care physician. He is suspected of having Tourette syndrome. Which of the following is a characteristic feature of this syndrome? A. More common in girls than in boys B. Restrictive and repetitive behaviors C. Abnormal or delayed language development D. Failure to keep eye contact E. Increased levels of dopamine Answer: E
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THOUGHT DISORDERS Thought disorders are disorders that affect one’s thinking, behavior, and interpretation of reality.
+
Mood (depression/bipolar)
Schizophreniform (1–6 months)
Schizophrenia (>6 months)
Schizoaffective (>2 weeks psychotic without mood)
Negative symptoms
Negative symptoms, change in level of functioning
Psychosis (hallucinations, delusions, disorganization, catatonia)
Brief psychotic disorder (1–30 days)
Figure 9-1. Thought Disorders Table 9-3. Classification of Thought Disorders Diagnosis
Symptoms
Duration of Symptoms
Treatment
Brief psychotic disorder
Hallucinations, delusions, disorganized behavior or thinking
>1 day but 1 month but 6 months
Antipsychotics
Schizoaffective disorder
• Schizophrenia symptoms such as hallucinations and delusions PLUS mood disorder symptoms such as depression and mania • Must have at least 2 weeks of psychotic symptoms in the absence of mood symptoms
Antipsychotics and mood stabilizers if bipolar type or antidepressants if depressed type
Schizophrenia Schizophrenia is seen in 1% of population. Men = women. Age of onset is age 15–25 (men) and age 25–35 (women). Around 90% of patients with schizophrenia are age 15–55. • Persons with schizophrenia have higher mortality rate from accident and natural causes. • Persons with schizophrenia are more likely to have been born in winter
or early spring (increased risk of schizophrenia after exposure to influenza).
• Lifetime prevalence of substance abuse >50%. • >90% of schizophrenics smoke (nicotine may reduce positive symp-
toms and improve some cognitive impairments).
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There are several theories of schizophrenia: • Genetic: monozygotic greater than dizygotic • Viral: more born in winter and early spring • Social: downward drift and social causation theories • Neurochemical/biochemical: associated with increased levels
of dopamine
Table 9-4. Biochemical Theories of Schizophrenia Neurotransmitter
Dopamine
Serotonin
Glutamate
Nicotine
GABA
Change
Increase
Increase
Increase/decrease
Decrease
Decrease
Effects
Positive symptoms
Positive and negative symptoms
PCP (glutamate antagonist) leads to schizophrenia-like symptoms
Cognition
Leads to hyperactivity of dopaminergic neurons
Table 9-5. Schizophrenia-Associated Neuropathology Brain Area
Ventricles
Symmetry
Limbic System
Prefrontal Cortex
Thalamus
Basal Ganglia and Cerebellum
Change
Increase
Decrease
Decrease
Decrease
Decrease
Increase/decrease
MOOD DISORDERS Major Depressive Disorder • Women > men • Symptoms >2 weeks and affect level of functioning (must include
depressed mood or anhedonia, plus other symptoms such as low energy, poor concentration, sleeplessness, loss of appetite or libido, suicidal ideation)
• Associated with decreased levels of NE, dopamine, and serotonin • Suicide rate 15%
Treatment is antidepressants. Major depressive disorder with seasonal pattern is associated with abnormalities in melatonin. It is common in the Northern hemisphere during the winter months. Treatment is bright light therapy (phototherapy).
Persistent Depressive Disorder Persistent depressive disorder is less severe than major depressive disorder. • Symptoms >2 years; depressive symptoms experienced most days • Hospitalization not usually needed; functioning not significantly impaired
Treatment is primarily psychotherapy.
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Bipolar Disorder Bipolar disorder is the most genetic of all the psychiatric disorders. Men = women. • Symptoms of mania >1 week, with loss of functioning. Symptoms of mania >1 week, with loss of functioning. Manic symptoms include increased energy, decreased sleep, euphoria, delusions of grandeur, increased libido, distractibility, flight of ideas, increased self-esteem. • Symptoms of major depressive disorder are very common but not
necessary for diagnosis.
There are 2 types of bipolar disorder: bipolar I involves mania and depression, while bipolar II involves hypomania and depression. Table 9-6. Bipolar Disorder Classification Mania
Hypomania
Symptoms
Severe
Less severe
Level of functioning
Not functional
Functional
Hospitalization
Yes
No
Cyclothymic Disorder • Symptoms >2 years characterized by:
–– Mood swings –– Periods of hypomania alternating with periods of milder depression (neither meets criteria for mania or major depressive disorder) Treatment is primarily psychotherapy. Table 9-7. Mood Disorders Duration
Major depressive disorder
2 weeks
Mood Chart
Mood
Diagnosis
1 yr Time 2 years
Mood
Persistent depressive disorder
2 yrs Time
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Duration
Bipolar I disorder (mania)
1 week
Psychiatric (DSM-5) Disorders
Mood Chart
Mood
Diagnosis
●
2 weeks Time Months
Mood
Bipolar II disorder
Time 2 years
Mood
Cyclothymic disorder
Months
3 yrs Time
Recall Question A 24-year-old man with a known history of schizophrenia presents to his psychiatrist for routine follow-up. His psychiatrist suspects a substance use disorder. Which of the following substances is a patient with schizophrenia most likely to abuse? A. Nicotine B. Phencyclidine C. Cocaine D. Inhalants E. Alcohol Answer: A
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ANXIETY DISORDERS Anxiety disorders are linked to abnormalities in serotonin, norepinephrine, and GABA. Women > men (especially young women).
Panic Disorder Panic disorder is defined as the presence of panic attacks for >1 month. • Involves worry about having more attacks and significant maladaptive
behavioral changes related to the attack
• Panic attacks are short-lived and out of the blue, with increased
autonomic hyperactivity: –– Increased pulse –– Hyperventilation –– Palpitations –– Tremors –– Diaphoresis
–– Dissociative symptoms Treatment is benzodiazepines (for panic attack) or SSRIs (for panic disorder). If hyperventilating, the patient should be instructed to breathe into a paper bag.
Generalized Anxiety Disorder Generalized anxiety disorder is a constant sense of worry for >6 months about things one should not have to worry about. The anxiety interferes with daily life: • Problems with sleep • Decreased concentration • Irritability
Treatment is SSRIs and buspirone.
Phobias Phobias are irrational fears of things or situations and the need to avoid them. Specific phobias include fear of things or objects, such as animals, heights, and elevators. Treatment is a behavioral modification technique such as systematic desensitization or flooding.
Social Anxiety Social anxiety is fear of being embarrassed or humiliated in a social situation, such as in a public restroom or restaurant, or public speaking (called stage fright or performance anxiety only if related to performance in public). Treatment is antidepressants and beta-blockers (for stage fright, given before an event).
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OBSESSIVE-COMPULSIVE DISORDER AND RELATED DISORDERS Obsessive-Compulsive Disorder • Obsessions: thoughts that are intrusive, senseless and time consuming
–– Ego-dystonic –– Thoughts are distressing –– Increases anxiety –– Most common thoughts include contamination and doubt –– Defense mechanism: reaction formation • Compulsions: acts that are repetitive, time consuming
–– Ego-dystonic –– Reduces the anxiety associated with the obsessive thoughts –– Most common include washing and checking –– Defense mechanism: undoing • Equal incidence in men and women
Treatment is antidepressants and behavioral modification (exposure and response prevention).
Body Dysmorphic Disorder Body dysmorphic disorder is belief that some part of one’s body is abnormal, defective, or misshapen. It is associated with serotonin. It must be differentiated from body image disturbance seen in anorexia nervosa. Treatment is psychotherapy and SSRIs.
Hoarding Disorder Hoarding disorder is difficulty parting with one’s possessions regardless of their value; level of functioning changes as a result of clutter in the home. There is distress when thinking of getting rid of items. Treatment is SSRIs and psychotherapy.
Trichotillomania Trichotillomania is an irresistible urge to pull out one’s own hair followed by a sense of relief. Many patients eat or chew the hair. The most common areas of hair pulling are the scalp, eyebrows, eyelashes, beard, and pubic area.
TRAUMA AND STRESSOR-RELATED DISORDERS Post-Traumatic Stress Disorder and Acute Stress Disorder Stress disorders result from exposure to actual or threatened death, serious injury, or sexual violation in one of the following ways: • Direct experience • Repeated exposure (first responders)
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• Witnessing the event • Learning of violent or accidental traumatic event involving a close
family member or friend
Exposure may lead to re-experiencing of symptoms in the form of nightmares or flashbacks. Women > men. Symptoms include: • Phobic avoidance • Hypervigilance • Increased startle reflex • Mood instability • Sleep disturbances • Dissociative symptoms
Treatment is exposure therapy and SSRIs. Post-Traumatic Stress Disorder
Acute Stress Disorder
Onset
Anytime
>3 days but 15–20% loss of ideal body weight or BMI boys. • Body image disturbance (patients feel fat even though they are very thin) • Fear of gaining weight • Poor sexual adjustment • Medical complications include:
–– Abnormal electrolytes –– Lanugo hair –– Abnormal hormones –– Low blood pressure –– Heart failure –– Osteoporosis Treatment is hospitalization, behavioral modification, SSRIs, and family therapy.
Bulimia Nervosa Bulimia nervosa is characterized by binge eating followed by purging. Weight is normal. Most patients recover. Girls > boys. In bulimia, defense mechanisms are involved, e.g., purge: undoing. Character ized by: • Binge (rapid ingestion of food) • Purge (compensatory behavior)
–– Vomiting (signs of repetitive emesis include abrasions and callous in fingers/hands, esophageal tears, enlarged parotid glands, and dental cavities) –– Exercising –– Fasting –– Use of laxatives –– Use of diuretics Treatment is behavioral modification and SSRIs.
Binge Eating Disorder Binge eating disorder is binge eating without the compensatory behavior seen in bulimia nervosa. Weight is above normal. Treatment is stimulants.
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SOMATIC SYMPTOM AND RELATED DISORDERS Somatic Symptom Disorder • Excessive thoughts, feelings, and behavior related to the somatic
symptoms
• Duration >6 months • Functioning impaired • May be only one symptom; could be related to medical illness • Main focus is how you react to the symptom
Treatment should be by one identified physician along with psychotherapy.
Illness Anxiety Disorder Illness anxiety disorder is characterized by the belief that one has an underlying illness, despite constant reassurance. • Duration >6 months • Somatic symptoms are not present; if present, mild
Treatment is psychotherapy.
Conversion Disorder Conversion disorder is the development of neurological symptoms following a psychological stressor that cannot be medically explained. • All work-up tests will be negative. • Patients will be indifferent to symptoms (la belle indifference).
Treatment is psychotherapy.
Factitious Disorder Factitious disorder is the conscious production of signs and symptoms of a mental or physical illness. There are 2 types: imposed on self and imposed on others. • Unconscious motivation (without knowing why) • No obvious external gains • Most patients become angered when confronted, will leave hospital
against medical advice
Treatment is psychotherapy.
Malingering Malingering is not a mental illness. It is the conscious production of signs and symptoms of a mental or physical illness. • Conscious motivation • Obvious external gains: money, avoiding prison, time off from work or
school
• Most patients become angered when confronted
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Table 9-8. Somatic Symptom Disorder vs. Factitious Disorders and M alingering Somatic Symptom
Factitious
Malingering
Symptom production
Unconscious
Intentional
Intentional
Motivation
Unconscious
Unconscious
Intentional
DISSOCIATIVE DISORDERS In dissociative disorders, the defense mechanism used is dissociation. It involves the splitting off of brain from consciousness, typically caused by traumatic events. • Amnesia: inability to recall important personal information –– Dissociative identity disorder (multiple personality): presence of ≥2 distinct identities; will have lapses in memory • Depersonalization disorder: recurrent experiences of being detached
from or outside of one’s body –– “Out of body” experiences –– Reality testing stays intact
–– Causes significant impairment • Fugue (may appear with all subtypes): involves sudden unexpected
travel, an inability to recall one’s past, or confusion of identity
PERSONALITY DISORDERS Personality disorders are maladaptive patterns of behavior. They are egosyntonic and lifelong.
Cluster A: Odd, Eccentric Type Paranoid: long-standing suspiciousness or mistrust of others; a baseline of mistrust • Preoccupied with issues of trust, reluctant to confide in others • Reads hidden meaning into comments or events • Carries grudges
Schizoid: lifelong pattern of social withdrawal; they like it that way • Seen by others as eccentric, isolated, and withdrawn • Has restricted emotional expression
Schizotypal: very odd, strange, weird • Magical thinking (including ESP and telepathy) • Ideas of reference, illusions • Socially anxious and isolated; lacks close friends • Incongruous affect • Odd speech • May have short-lived psychotic episodes
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Cluster B: Dramatic and Emotional Histrionic: colorful, dramatic, and extroverted • Unable to maintain long-lasting relationships • Attention-seeking • Desires spotlight • Uses seductive behavior
Narcissistic: grandiose sense of self-importance • Preoccupied with fantasies of unlimited wealth, power, love • Demands constant attention • Has fragile self-esteem • Prone to depression • Meets criticism with indifference or rage • Genuinely surprised and angered when others don’t do as they want • Can be charismatic
Borderline: very unstable affect, behavior, self-image • In constant state of crisis, chaos • Self-detrimental impulsivity: promiscuity, gambling, overeating,
substance-related disorders
• Unstable but intense interpersonal relationships • Have great difficulty being alone • Self-injurious behavior • Multiple suicide attempts • History of sexual abuse • Defense mechanisms: splitting, passive–aggression • Women > men 2:1
Antisocial: unable to conform to rules of society (only personality disorder that requires age 18 for diagnosis) • Criminal acts: delinquency, theft • Truancy • Running away • Unable to hold a job • Unable to maintain enduring attachments • Reckless • Aggressive • Show lack of remorse • Men > women
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Cluster C: Anxious and Fearful Avoidant: extreme sensitivity to rejection; sees self as socially inept • Excessively shy, has high anxiety • Socially isolated but has an intense, internal desire for affection and
acceptance
• Tends to stay in same job, same life situation, and same relationships
Obsessive-compulsive: characterized by orderliness and perfectionism • Inflexible, control freak • Loves lists, rules, order; wants to keep routine • Rigid and excessively stubborn
Dependent: gets others to assume responsibility • Subordinates own needs to others • Unable to express disagreement • Greatly fearful of having to care for self • May be linked to abusive spouse
SEXUAL DISORDERS Sexual Desire/Arousal Disorders In male hypoactive sexual desire disorder, men experience a deficiency or absence of fantasies or desires. Reasons: low testosterone, CNS depressants, depression, marital discord; common post-surgery. In female sexual interest/arousal disorder, women are unable to achieve adequate vaginal lubrication. Reasons include possible hormonal connection (many women report peak sexual desire just prior to menses) and antihistamine/ anticholinergic medications, which can reduce vaginal lubrication. Male erectile disorder (impotence) has 10–20% lifetime prevalence; point prevalence is 3%. Half of men treated for sexual disorder complain of impotence. • Incidence is 8% young adult and 75% men age >80 • 50% more likely in smokers
Be sure to check alcohol usage, diabetes, and marital conflict, as it must be determined whether the cause is organic or psychological. Assessment is made with the postage stamp test, snap gauge (to test physiological vs. psychological). Treatment is sildenafil, vardenafil, and tadalafil.
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Orgasm Disorders Female orgasm disorder is an inability to achieve orgasm. Overall prevalence from all causes is 30%. About 5% of married women age >35 have never achieved orgasm. Treatment is fantasy, vibrators. In premature ejaculation, the man ejaculates before or immediately after entering vagina. It is more common if early sexual experiences were in the backseat of car or with a prostitute, or there is anxiety about the sexual act. Treatment is stop-and-go technique, squeeze technique, and SSRIs.
Paraphilic Disorders • Pedophilia: sexual urges toward children; most common paraphilia • Exhibitionism: recurrent desire to expose genitals to stranger • Voyeurism: sexual pleasure from watching others who are naked,
grooming, or having sex; begins early in childhood
• Sadism: sexual pleasure derived from others’ pain • Masochism: sexual pleasure derived from being abused or dominated • Fetishism: sexual focus on objects, e.g., shoes, stockings; transvestite
fetishism involves fantasies or actual dressing by heterosexual men in female clothes for sexual arousal
• Frotteurism: male rubbing of genitals against fully clothed woman to
achieve orgasm; subways and buses
• Zoophilia: animals preferred in sexual fantasies or practices • Coprophilia: combining sex and defecation • Urophilia: combining sex and urination • Necrophilia: preferred sex with cadavers • Hypoxyphilia: altered state of consciousness secondary to hypoxia
while experiencing orgasm; achieved with autoerotic asphyxiation, poppers, amyl nitrate, nitric oxide
Genito-Pelvic Pain Disorders Genito-pelvic pain/penetration disorders involve involuntary muscle constriction of the outer third of the vagina which prevents penile insertion. Psychological in origin, they involve recurrent and persistent pain before, during, or after intercourse. • Diagnosed only in women • Not diagnosed if caused by a medical conditions
Treatment is relaxation and Hegar dilator.
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Recall Question A 17-year-old girl is brought to her primary care physician by her mother for complaints of weight loss. Her mother explains that her daughter has lost 40 pounds in the past 2 months, spending all day staring in the mirror and being concerned that she is gaining weight. The physician suspects anorexia nervosa. Which of the following is the best treatment? A. Antipsychotics B. Appetite stimulants C. Exposure and response prevention D. Selective serotonin reuptake inhibitors E. Individual and family therapy Answer: E
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Psychopharmacology
10
Learning Objectives ❏❏ Define the side effect profile of different receptors ❏❏ Demonstrate understanding of the types of antipsychotics and how they work ❏❏ Demonstrate understanding of the types of antidepressants and how they work ❏❏ Demonstrate understanding of the types of mood stabilizers and how they work ❏❏ Demonstrate understanding of the types of anxiety medications and how they work
SIDE EFFECT PROFILE Receptor
Effects
Histamine
Sedation, weight gain
Muscarine
Anticholinergic (dry mouth, blurry vision, constipation, confusion, etc.)
Alpha 1
Dizziness, hypotension
ANTIPSYCHOTIC (NEUROLEPTIC) MEDICATIONS Antipsychotic medications are used to treat 2 types of conditions: • Schizophrenia and other psychotic disorders • Hiccups, Tourette syndrome, and bipolar disorders
The mechanism of action is dopamine blockage at the postsynaptic receptors.
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Table 10-1. Medication Side Effects Side Effect
Peak
Treatment
Dystonic reaction
Hours to days
Anticholinergics: benztropine, trihexyphenidyl, diphenhydramine
Rigidity
3 weeks
Lower dose or anticholinergics
Tremors
6 weeks
Lower dose or anticholinergics
Akathisia
10 weeks
B-blockers, benzodiazepines; lower dose or switch to atypical
Tardive dyskinesia
>3–6 months
Switch to atypical or clozapine
Neuroleptic malignant syndrome
Any time
May be lethal; dantrolene or bromocriptine
Dopamine tracts include: • Mesolimbic/mesocortical: reduces psychotic symptoms • Nigrostriatal: increases movement disorder • Tuberoinfundibular: increases prolactin (galactorrhea, amenorrhea,
gynecomastia)
Types of Antipsychotics Note
Table 10-2. Typical vs. Atypical Antipsychotics Typical
Atypical
• Choreiform: jerky movements
Dopamine
Dopamine and serotonin
• Athetoid: slow, continuous movements
Treats mostly positive symptoms
Treats positive and negative symptoms
More side effects
Fewer side effects
Extrapyramidal reactions include:
• Rhythmic: stereotypical movements
The potency of typical antipsychotic medications is as follows:
Potency
Extrapyramidal Symptoms
Anticholinergic Effects
High (haloperidol)
High
Low
Low (chlorpromazine)
Low
High
Typical antipsychotics have movement and prolactin side effects. • Haloperidol • Fluphenazine
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• Chlorpromazine • Mesoridazine • Thioridazine (additional increased risk of retinitis pigmentosa and
retrograde ejaculation)
Atypical antipsychotics are known for weight gain, increased risk of diabetes, and metabolic syndrome, but also cause movement and prolactin side effects. • Clozapine (additional increased risk of agranulocytosis (2.5 meq/L, consider dialysis as the treatment of choice. • Potassium-sparing diuretics have no effect; loop diuretics will produce
increased serum levels.
• Side effects include:
–– Tremor, thirst, anorexia, GI distress –– Polyuria, polydipsia, edema –– Acne –– Hypothyroidism –– Nephrotoxicity –– Teratogenicity (Ebstein’s anomaly affecting the tricuspid valve) –– Diabetes insipidus –– If toxic, ataxia, seizures and confusion may be seen.
Valproic Acid Valproic acid is used to treat bipolar disorders and rapid cycling bipolar disorders. The mechanism of action involves augmentation of GABA in CNS. • Side effects include sedation, weight gain, tremors, alopecia, GI distress, and teratogenicity (neural tube defects). • If toxic, may cause confusion, coma, or cardiac arrest. • Monitor blood levels, as it can cause hepatotoxicity (liver function
impairment).
Carbamazepine The mechanism of action involves blocking sodium channels in neurons with action potential; it alters central GABA receptors. • Side effects include GI distress, rash, mild leukopenia, agranulocytosis, and aplastic anemia. • If toxic, may cause hypotension, tachycardia, respiratory depression,
or coma.
• Monitor blood levels and signs of rash.
Lamotrigine Lamotrigine is associated with Stevens-Johnson syndrome.
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ANTIANXIETY MEDICATIONS Benzodiazepines Benzodiazepines are used to treat anxiety disorders, sleep disorders, alcohol withdrawal, and seizures. The mechanism of action is depression of the CNS at the limbic system, RAS, and cortex. Benzodiazepines bind to GABA-chloride receptors, facilitating the action of GABA. • All benzodiazepines undergo hepatic microsomal oxidation (except for lorazepam, oxazepam, and temazepam, which undergo glucuronide conjugation). • Side effects include sedation, insomnia, addiction, falls (elderly),
confusion, and disinhibition.
Buspirone Buspirone is used for generalized anxiety disorder and other anxiety disorders when possible abuse of benzodiazepines is a concern. It has no withdrawal effect and is not potentiated by alcohol. The mechanism of action works on serotonin, not on GABA. • Full effect is seen >7 days • Some sedation is seen • Has low-abuse potential
Recall Question A 25-year-old G1P1 woman presents to the clinic for a follow-up. She has a well-documented history of bipolar disease for which she takes lithium. Which of the following potential cardiac-relevant teratogenic effects does lithium have on the fetus? A. Ventral septal defect B. Tetralogy of Fallot C. Transposition of the great arteries D. Atrial septal defect E. Displacement of the tricuspid valve Answer: E
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Brain Function and Neurocognitive Disorders
11
Learning Objectives ❏❏ Demonstrate understanding of left and right brain dominance ❏❏ Be able to correlate specific function with corresponding part of the brain ❏❏ Demonstrate understanding of how healthy parts of the brain differ from injured parts ❏❏ Answer questions about how dominant parietal lobe dysfunction differs from non-dominant dysfunction ❏❏ Demonstrate understanding of the different neurotransmitters and how they affect the brain ❏❏ Demonstrate understanding about how the neurocognitive disorders differ
LEFT AND RIGHT BRAIN DOMINANCE The left hemisphere is dominant in language and calculation-type problem solving. It is dominant in 97% of the population (60–70% in left-handed persons). • Stroke damage to the left hemisphere is more likely to lead to depression. The right hemisphere is dominant in perception, artistic, and visual–spatial tasks. It is activated for intuition-type problem solving. • Stroke damage to the right hemisphere is more likely to lead to apathy and indifference.
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AREAS OF THE BRAIN Motor Area • Control of voluntary muscles
Parietal Lobe • Sensations • Language • Perception • Body awareness • Attention
Sensory Area • Skin sensations (temperature, pressure, pain) Frontal Lobe • Movement • Problem solving • Concentrating, thinking • Behavior, personality, mood
Occipital Lobe • Vision • Perception Wernicke Area • Language comprehension
Broca Area • Speech control
Cerebellum • Posture • Balance • Coordination of movement
Temporal Lobe • Hearing • Language • Memory Brain Stem • Consciousness • Breathing • Heart rate
Figure 11-1. Functional Areas of the Brain
Frontal lobe
Parietal lobe
Occipital lobe
Healthy Brain
Injured Brain
• Personality/emotions
• Loss of movement (paralysis)
• Intelligence
• Repetition of a single thought
• Attention/concentration
• Unable to focus on a task
• Judgment
• Mood swings, irritability, impulsiveness
• Body movement
• Changes in social behavior and personality
• Problem-solving
• Difficulty problem solving
• Speech (speaking and writing)
• Difficulty with language; cannot get the words out (aphasia)
• Sense of touch, pain, and temperature
• Difficulty distinguishing left from right
• Distinguishing size, shape, and color
• Difficulty with eye-hand coordination
• Spatial perception
• Problems reading, writing, naming
• Visual perception
• Difficulty with mathematics
Vision
• Defects in vision or blind spots
• Lack of awareness or neglect of certain body parts
• Blurred vision • Visual illusions/hallucinations • Problems reading and writing
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Temporal lobe
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Brain Function and Neurocognitive Disorders
Healthy Brain
Injured Brain
• Speech (understanding language) • Memory
• Difficulty understanding language and speaking (aphasia)
• Hearing
• Difficulty recognizing faces
• Sequencing
• Difficulty identifying/naming objects
• Organization
• Problems with short- and long-term memory • Changes in sexual behavior • Increased aggressive behavior
Cerebellum
• Balance
• Difficulty coordinating fine movements
• Coordination
• Difficulty walking • Tremors • Dizziness (vertigo) • Slurred speech
Brainstem
• Breathing
• Changes in breathing
• Heart rate
• Difficulty swallowing food and water
• Alertness/consciousness
• Problems with balance and movement
APHASIA Aphasia is an impairment of language affecting one’s ability to speak/understand speech, read, or write. • Dominant (left) parietal lobe dysfunction (in most right-handed and some left-handed patients): –– Language disorders (aphasia, alexia) –– Gerstmann syndrome (dyscalculia, dysgraphia, finger agnosia, right-left confusion) –– Apraxia • Non-dominant (right) parietal lobe dysfunction:
–– Hemispatial neglect –– Sensory and visual inattention –– Constructional and dressing apraxia (more severe for right-sided lesions)
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Aphasia
Non-fluent: limited ability to produce speech; effortful and with few words
Fluent: able to produce connected speech
Good Understanding of Language (spoken and written)
Poor Understanding of Language (spoken and written)
Good Understanding of Language (spoken and written)
Poor Understanding of Language (spoken and written)
• Broca Aphasia (cannot repeat words or sentences)
• Mixed Non-Fluent Aphasia (some ability to produce speech)
• Conduction Aphasia (numerous phonemic paraphasias such as “poon,” “soon,” or “pone” for “spoon”)
• Wernicke Aphasia (cannot repeat words or sentences)
• Transcortical Motor Aphasia (can repeat words or sentences)
• Global Aphasia (most severe; little to no comprehension or expression)
• Anomic Aphasia (primary limitation is difficulty retrieving desired words when communicating; “it’s on the tip of my tongue”)
• Transcortical Sensory Aphasia (can repeat words or sentences; speech produced resembles a “word salad” many words and ideas, but doesn’t generally make sense)
Figure 11-2. Aphasia
Recall Question A 76-year-old man is brought to the emergency department with signs and symptoms of a stroke. On physical examination he is noted to have difficulty with hand-eye coordination and has finger-to-nose-finger dysmetria, difficulty walking and vertigo. Which area of the brain is most likely injured? A. Brainstem B. Cerebellum C. Temporal lobe D. Parietal lobe E. Frontal lobe Answer: B
NEUROTRANSMITTERS Acetylcholine (ACh) ACh is a neurotransmitter at nerve-muscle connections for all voluntary muscles of the body and also many of the involuntary (autonomic) nervous system synapses. The exact role of ACh in the brain is unclear. It plays a significant role in Alzheimer disease.
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• Cholinergic neurons concentrated in the RAS and basal forebrain • Neurocognitive disorder in general associated with decreased ACh
concentrations in amygdala, hippocampus, and temporal neocortex
• Associated with erections in men • Muscarinic and nicotinic receptors • In the corpus striatum, ACh circuits are in equilibrium with dopamine
neurons
Norepinephrine Norepinephrine (NE) is one of the catecholamine neurotransmitters. It is a transmitter of the sympathetic nerves of the autonomic nervous system, which mediate emergency response. • Acceleration of the heart • Dilatation of the bronchi • Elevation of blood pressure
NE is implicated in altering attention, perception, and mood. The key pathway is locus ceruleus in upper pons. It is implicated in monoamine hypothesis of affective disorders. • Depletion of NE leads to depression • Excess of NE (and serotonin) leads to mania • Based on 2 observations: reserpine depletes NE and causes depression;
antidepressant drugs block NE reuptake, thus increasing the amount of NE available postsynaptically
Receptors: • Alpha-1: sympathetic (vasoconstriction) • Alpha-2: on cell bodies of presynaptic neurons, inhibit NE release • Beta-1: excitatory for heart, lungs, brain • Beta-2: excitatory for vasodilatation and bronchodilation
Dopamine Dopamine is the other catecholamine neurotransmitter, synthesized from the amino acid tyrosine. • D2 receptors most important • D1 and D5 stimulate G-protein and increase cAMP and excitation • D2, D3, and D4 inhibit G-protein and decrease cAMP and excitation
Three pathways of known psychiatric importance: • Nigrostriatal pathway: blockade leads to tremors, muscle rigidity, bradykinesia • Mesolimbic-cortico pathway: blockade leads to reduction of psychotic
symptoms
• Tuberoinfundibular system: blockade leads to increases in prolactin
(DA = PIF)
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Serotonin (5-Hydroxytryptamine, 5-HT) Serotonin is the transmitter of a discrete group of neurons that all have cell bodies located in the raphe nuclei of the brain stem. Changes in the activity of serotonin neurons are related to the actions of psychedelic drugs. It is involved in the therapeutic mechanism of action of antidepressant treatments (most are 5-HT reuptake inhibitors; a few new ones are 5-HT agonists). • Has inhibitory influence; linked to impulse control • Low 5-HT = low impulse control • Has role in regulation of mood, sleep, sexual activity, aggression,
anxiety, motor activity, cognitive function, appetite, circadian rhythms, neuroendocrine function, and body temperature
Glutamic Acid Glutamic acid is one of the major amino acids in general metabolism and protein synthesis; it is also a neurotransmitter. • Stimulates neurons to fire • Is the principal excitatory neurotransmitter in the brain and the
neurotransmitter of neuronal pathways connecting the cerebral cortex and corpus striatum
• Is the transmitter of the granule cells, the most numerous neurons in
the cerebellum
There is evidence that glutamic acid is the principal neurotransmitter of the visual pathway. It may have a role in producing schizophrenic symptoms; is the reason for PCP symptoms (antagonist of NMDA glutamate receptors). Glutamate agonists produce seizures in animal studies.
Enkephalins Enkephalins are composed of 2 peptides, each containing 5 amino acids. They are normally occurring substances that act on opiate receptors, mimicking the effects of opiates. Neurons are localized to areas of the brain that regulate functions influenced by opiate drugs.
Note
Substance P
There is a new class of antidepressant medications being tested to work on substance P.
Substance P is a peptide containing 11 amino acids and is a major transmitter of sensory neurons that convey pain sensation from the periphery, especially the skin, into the spinal cord; also found in numerous brain regions. Opiates relieve pain in part by blocking the release of substance P.
Gamma Aminobutyric Acid Gamma aminobutyric acid (GABA) is one of the amino acid transmitters in the brain. It occurs almost exclusively in the brain, reduces the firing of neurons, and is the brain’s principle inhibitory neurotransmitter (present at 25–40% of all synapses in the brain). GABA is associated with anxiety, cannabis, and benzodiazepines.
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Brain Function and Neurocognitive Disorders
NEUROCOGNITIVE DISORDERS Delirium is an acute onset of impaired cognitive functioning that is fluctuating, brief, and reversible. Neurocognitive disorder is a loss of cognitive abilities, impairment of social functioning, loss of memory, and/or change in personality that may be progressive or static. It is reversible only 15% of the time. Mild neurocognitive disorder is moderate cognitive decline that has minimal interaction with functioning. Major neurocognitive disorder is significant cognitive decline that interferes with functioning and independence.
Neurocognitive Disorder Due to Alzheimer Disease • Neurocognitive disorder due to Alzheimer disease is seen in >50% of
nursing-home patients and 50–60% of those with neurocognitive disorder.
• Risk factors: female, family history, head trauma, Down syndrome • Neuroanatomic findings: cortical atrophy, flattened sulci, enlarged ventricles • Histopathology: senile plaques (amyloid deposits), neurofibrillary tangles,
neuronal loss, synaptic loss, granulovacuolar degeneration of neurons
• Associated with chromosome 21 (gene for the amyloid precursor protein) • Decreased ACh and NE • Deterioration is gradual; average duration from onset to death ~8 years • Focal neurologic symptoms rare
Treatment is long-acting cholinesterase inhibitors such as donepezil, rivastigmine, galantamine, and memantine. Antipsychotic medications may be helpful when psychotic symptoms are present but contraindicated to control behavior.
Vascular Neurocognitive Disorder (Multi-Infarct Neurocognitive Disorder) Vascular neurocognitive disorder is seen in 15–30% of those with neurocognitive disorder. • Risk factors: male, advanced age, hypertension or other cardiovascular disorders • Affects small and medium-sized vessels • Examination may reveal carotid bruits, fundoscopic abnormalities, and
enlarged cardiac chambers
• MRI may reveal hyperintensities and focal atrophy suggestive of old
infarctions
• Deterioration may be stepwise or gradual, depending on underlying
pathology
• Focal neurologic symptoms (pseudobulbar palsy, dysarthria, and
dysphagia are most common)
• Abnormal reflexes and gait disturbance often present
Treatment is directed toward the underlying condition and lessening cell damage. Control of risk factors such as hypertension, smoking, diabetes, hypercholesterolemia, and hyperlipidemia is useful.
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Table 11-1. Alzheimer Disease vs. Vascular Disorder Alzheimer
Vascular
Women
Men
Older age
Younger age
Chromosome 21
Hypertension
Linear or progressive deterioration
Stepwise or patchy deterioration
No focal deficits
Focal deficits
Treatment is supportive
Treat underlying condition
Recall Question An 18-year-old drug addict presents to the methadone clinic. The physician prescribes him a novel medication which has properties of a neurotransmitter that mimics the effects of opiates. Which neurotransmitter has properties that mimic the effects of opiates? A. Enkephalins B. Substance P C. Gamma aminobutyric acid D. Glutamic acid E. 5-hydroxytryptamine Answer: A
Frontotemporal Neurocognitive Disorder (Pick Disease) • Neuroanatomic findings: atrophy in frontal and temporal lobes • Histopathology: Pick bodies (intraneuronal argentophilic inclusions)
and Pick cells (swollen neurons) in affected areas of brain
• Etiology unknown • Most common in men with family history of Pick disease • Difficult to distinguish from Alzheimer disease • May see features of Klüver-Bucy syndrome (hypersexuality,
hyperphagia, passivity)
Neurocognitive Disorder Due to Prion Disease • Rare spongiform encephalopathy caused by a slow virus (prion) • Presents with neurocognitive disorder, myoclonus, and EEG
a bnormalities (e.g., sharp, triphasic, synchronous discharges and, later, periodic discharges)
• Symptoms progress over months from vague malaise and personality
changes to neurocognitive disorder and death
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Brain Function and Neurocognitive Disorders
• Findings include visual and gait disturbances, choreoathetosis or other
abnormal movements, and myoclonus
• Other prions causing neurocognitive disorder (e.g., Kuru) may exist
Neurocognitive Disorder Due to Huntington Disease • Rare, progressive neurodegenerative disease that involves loss of
GABAergic neurons of the basal ganglia; manifested by choreoathetosis, neurocognitive disorder, and psychosis
• Caused by a defect in an autosomal dominant gene located on
chromosome 4
• Atrophy of the caudate nucleus, with resultant ventricular enlargement,
is common
• Clinical onset ~age 40 • Suicidal behavior fairly common
Neurocognitive Disorder Due to Parkinson Disease • Common, progressive, neurodegenerative disease that involves loss of
dopaminergic neurons in the substantia nigra
• Clinical onset ~age 50–65 • Motor symptoms include resting tremor, rigidity, bradykinesia, and
gait disturbances
• Neurocognitive disorder occurs in 40% of cases; depressive symptoms
common
• Destruction of dopaminergic neurons in the substantia nigra is a key
pathogenic component; may be caused by multiple factors including environmental toxins, infection, genetic predisposition, and aging
Treatment of Parkinson disease involves use of dopamine precursors (e.g., levodopa, carbidopa), dopamine agonists (e.g., bromocriptine), anticholinergic medications (e.g., benztropine, trihexyphenidyl), amantadine, and selegiline. Antiparkinsonian medications can produce personality changes, cognitive changes, and psychotic symptoms.
Neurocognitive Disorder with Lewy Bodies • Hallucinations, parkinsonian features, and extrapyramidal signs • Antipsychotic medications may worsen behavior • Patients typically have fluctuating cognition, as well as REM sleep
behavior disorder
Neurocognitive Disorder Due to HIV Infection • HIV directly and progressively destroys brain parenchyma. • Becomes clinically apparent in at least 30% of those with AIDS,
Note (LBD) 1 yr ← PD → 1 yr (PDD)
starting with subtle personality changes.
• Diffuse and rapid multifocal destruction of brain structures occurs;
delirium is often present.
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• Motor findings include gait disturbance, hypertonia and hyperreflexia,
pathologic reflexes (e.g., frontal release signs), and oculomotor deficits.
• Mood disturbances in those with HIV infection are apathy, emotional
liability, or behavioral disinhibition.
Wilson Disease • Ceruloplasmin deficiency • Hepatolenticular degeneration • Kayser-Fleischer rings in the eye • Asterixis
Normal Pressure Hydrocephalus • Enlarged ventricles • Normal pressure • Neurocognitive disorder, urinary incontinence, and gait apraxia
Treatment is shunt placement.
Pseudodementia • Typically seen in elderly patients with a depressive disorder who appear
to have symptoms of neurocognitive disorder
• Improvement should be seen after treatment with antidepressants • Onset of symptoms can usually be dated Table 11-2. Delirium vs. Neurocognitive Disorder Delirium
Neurocognitive Disorder
Acute onset
Insidious onset
Fluctuating course
Chronic course
Lasts days to weeks
Lasts months to years
Recent memory problems
Recent then remote memory problems
Disrupted sleep-wake cycle
Less disorientation at first
Disorientation
Normal sleep-wake cycle
Hallucinations common
Hallucinations, sundowning
Treat underlying condition
Supportive treatment
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Ethics, Law, and Physician Behavior
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Learning Objectives ❏❏ Demonstrate understanding of how important court cases have shaped medical care ❏❏ Demonstrate understanding of important elements of physician behavior and how they can affect patient care ❏❏ Answer questions about unconscious interactions and how they can affect patient care
LEGAL ISSUES Selected Important Court Cases Karen Ann Quinlan: Substituted Judgment Standard In the Quinlan case, Karen Ann was in a persistent vegetative state, being kept alive only by life support. Her father asked to have her life support terminated according to his understanding of what Karen Ann would want. The court found that “if Karen herself were miraculously lucid for an interval . . . and perceptive of her irreversible condition, she could effectively decide upon discontinuance of the life support apparatus, even if it meant the prospect of natural death.” • The court therefore allowed termination of life support—not because the father asked but because it held that the father’s request was most likely the expression of Karen Ann’s own wishes. • Substituted judgment begins with the premise that decisions belong to the competent patient by virtue of the rights of autonomy and privacy. • In this case, however, the patient is unable to decide and a decision-maker who is the best representative of her wishes must be substituted. • In legal terms, the patient has the right to decide but is incompetent to do so. Therefore, the decision is made for the patient on the basis of the best estimate of his or her subjective wishes. The key here is not who is the closest next of kin, but who is most likely to represent the patient’s own wishes.
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Brother Fox (Eichner v. Dillon): Best Interest Standard In its decision of Eichner v. Dillon, the New York Court of Appeals held that trying to determine what a never-competent patient would have decided is practically impossible. Obviously, it is difficult to ascertain the actual (subjective) wishes of incompetents. Therefore, if the patient has always been incompetent, or no one knows the patient well enough to render substituted judgment, the use of substituted judgment standard is questionable, at best. Under these circumstances, decisions are made for the patient using the best interest standard, the object of which is to decide what a hypothetical “reasonable person” would decide after weighing the benefits and burdens of each course of action. The issue of who makes the decision is less important here. All persons applying the best interest standard should come to the same conclusions.
Infant Doe: Foregoing Lifesaving Surgery, Parents Withholding Treatment As a general rule, parents cannot withhold life- or limb-saving treatment from their children. Yet, in this exceptional case they did. Baby Boy Doe was born with Down syndrome (trisomy 21) and with a tracheoesophageal fistula. The infant’s parents were informed that surgery to correct his fistula would have “an even chance of success.” Left untreated, the fistula would soon lead to the infant’s death from starvation or pneumonia. The parents, who also had 2 healthy children, chose to withhold food and treatment and “let nature take its course.” Court action to remove the infant from his parents’ custody (and permit the surgery) was sought by the county prosecutor. The court denied such action, and the Indiana Supreme Court declined to review the lower court’s ruling. Infant Doe died at 6 days of age, as Indiana authorities were seeking intervention from the U.S. Supreme Court. Note that this case is simply an application of the best interest standard. The court agreed with the parents that the burdens of treatment far outweighed any expected benefits.
Roe v. Wade (1973): The Patient Decides Known to most people as the “abortion legalizing decision,” the importance of this case is not limited to its impact on abortion. Faced with a conflict between the rights of the mother and the rights of the putative unborn child, the court held that in the first trimester the mother’s rights are paramount and that states may, if they wish, have the mother’s rights remain paramount for the full term of the pregnancy. • B ecause the mother gets to decide even in the face of threats to the fetus, by extension all patients get to decide about their own bodies and the health care they receive. • In the United States, the locus for decision-making about health care resides with the patient, not the physician.
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Note that courts have held that a pregnant woman has the right to refuse care (e.g., blood transfusions) even if it places her unborn child at risk.
Tarasoff Decision: Duty to Warn and Duty to Protect A student visiting a counselor at a counseling center in California states that he is going to kill someone. When he leaves, the counselor is concerned enough to call the police but takes no further action. The student subsequently kills the person he threatened. The court found the counselor and the center liable because they did not go far enough to warn and protect the potential victim. • The counselor should have called the police and then tried in every way possible to notify the potential victim of the potential danger. • In similar situations, first try to detain the person making the threat. Next, call the police. Finally, notify and warn the potential victim. All three actions should be taken, or at least attempted.
Autonomy Autonomy is the central principle for ethics in health care. The origins of the word autonomy are from the Greek words: “autos” and “nomos,” meaning selfrule or self-determination. In ethics, this translates to the principle that every competent individual has the right to make his or her own health care decisions without coercion or coaxing. In medical practice, competent patients are required to provide informed consent for any treatment or procedure.
Informed Consent Informed consent is a complete discussion of proper information related to a treatment or procedure between a physician and patient, where the patient voluntarily agrees to the care plan and is free of coercion. –– Full, informed consent requires that the patient has received and understood 5 components of information: –– Nature of the procedure: What is the procedure or treatment? –– Purpose or rationale: Why the procedure is being performed? or Why the drug is being administered? –– Risks of the treatment regimen –– Benefits of the treatment regimen –– Alternatives to the recommended treatment regimen –– A signed paper granting informed consent that the patient does not read or does not understand does NOT constitute informed consent: ºº It is not simply enough for a physician to “give” the patient information. ºº The patient needs to understand what he is being treating with, why the physician recommends this treatment, and the risks, benefits, and alternatives to treatment. ºº The patient must understand all 5 components of information.
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–– The physician cannot discuss treatment options that are not approved. For example, the physician should not discuss with the patient a homeopathic treatment option for cancer. –– Informed consent may be written or oral. –– Informed consent can be withdrawn at any time. It does not matter if the patient has signed all the necessary paperwork and is on the way to the operating room; he can decide to not have the procedure done for any reason. There are 4 situations in which a physician does not need to obtain informed consent from a patient in order to perform a procedure or another treatment, i.e., there are special situations in which informed consent is not required. • Emergency situation –– In an emergency situation, the physician should do what is in the best interest of the patient. –– If the patient is unconscious and needs a life-saving or limb-saving procedure, the procedure should be performed (consent is implied). • Waiver is provided by patient
–– The patient “waives” his right to receive information related to the treatment. In other words, the patient trusts that you will do what is in his best interest. • Patient is incompetent
–– Some patients do not have the capacity to provide informed consent: ºº Are unconscious ºº Have attempted suicide ºº Are in a grossly psychotic or dysfunctional state ºº Are intoxicated with drugs and/or alcohol ºº Are in physical or mental state which prevents simple communication –– Incompetence is determined by a judge based on a physician’s assessment of capacity. • Therapeutic privilege
–– The physician will deprive the patient of autonomy in the interest of health. In other words, if the physician truly believes the patient is not able to make good decisions for himself AND other physicians agree, the physician can treat without informed consent. –– The physician can invoke therapeutic privilege and move beneficence, nonmaleficence, and justice above patient autonomy.
Committed Patients A committed mentally ill adult has the following legal rights: • Must have treatment available –– Patient should be informed on a regular basis what treatment options are available.
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• Can refuse treatment
–– Patient with a severe form of schizophrenia still has the right to refuse to take antipsychotic medication (except when patients are a danger to themselves or others). • Can request a legal hearing to determine sanity
–– Competence is a legal matter; only a court can determine competence. –– Patient has the right to demand a trial to determine sanity. • Loses only the civil liberty to “come and go”
–– Patient does not have the right to leave. –– Patient can “choose” to take his medication; however, he cannot “choose” to leave. Table 12-1. Decision-Making Standards What It Means
Who Makes the Determination
Capacity
An assessment of your decisionmaking ability
Physician
Competence
A legal assessment of your ability to make medical decisions for yourself
Judge
Sanity
A verdict on your ability to make decisions and be held accountable for the consequences of those decisions
Jury
Assume the patient is competent unless you have clear behavioral evidence that indicates otherwise. • Competence is a legal issue. • We do not determine competence on a medical basis. • From an ethical and legal standpoint, all adult patients are considered
competent unless specifically proven otherwise.
• Only a court of law can make that assessment.
Any physician—not just a psychiatrist—can determine whether a patient has the capacity to understand the medical issues (and related treatment) pertaining to his condition. The physician is able to determine whether there is an organic delirium affecting the patient’s capacity to understand, i.e., caused by a medical condition such as alcohol/drug intoxication, meningitis, or a psychiatric disorder. The conclusions made by the physician will be based primarily on a neurological exam, as well as an assessment of the patient’s comprehension, memory, judgment, and reasoning skills. It should be noted that a diagnosis such as schizophrenia by itself tells you little about a patient’s competence. If the patient is diagnosed with schizophrenia and controlled on medication, the patient may very well be competent. So a diagnosis alone cannot render a patient incompetent.
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Clear behavioral evidence of incompetence includes: • An attempted suicide • Gross impairment in reality (psychosis) and dysfunctionality and/or
physical or mental state preventing patient from having simple conversation
Patients who attempt suicide, for example, may be admitted to the hospital against their will for psychiatric evaluation.
Note A physician is permitted to “detain” a patient for up to 48 hours.
If, as the physician, you are unsure, you must assume the patient is competent. The patient does not have to prove to you that he is competent. There must be clear evidence to assume that he is not. When patients are unable to make medical decisions for themselves, someone called a surrogate needs to make those decisions for them. In order for a surrogate to make a decision, three conditions must be present: • The patient must be incapacitated. • The patient must not have made an advance directive. • The surrogate must know what the patient would truly want if he
were competent.
Suppose a woman is unconscious as a result of a severe car accident. The surrogate will be asked, “What do you think the patient would want if she were conscious?” Based on the response, the patient will be appropriately treated or treatment measures will be withdrawn. When a surrogate makes a decision for a patient, use the following criteria and in this order: 1. Subjective standard 2. Substituted judgment 3. Best interests standard There is a set priority, i.e., an order, of who can serve as a surrogate. First is a person’s spouse. Second is a person’s adult children: 1. Spouse 2. Adult children 3. Parents 4. Adult siblings 5. Other relatives Suppose the patient mentioned earlier is determined to be “brain dead” as a result of the car accident, and it is determined that she had no advance directive. Her spouse would be the first person asked about potentially terminating life support and allowing nature to take its course. A subjective standard is based on the premise that a decision is being made based on the actual wishes of the patient. You should consider the following questions: • Is there an actual intent or advance directive? • What did the patient say in the past? Can that be verified?
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Always follow the advance directives outlined in a living will or by a Health Care Power of Attorney (HCPOA). A substituted judgment begins with the premise that decisions belong to the competent patient by virtue of the rights of autonomy and privacy. You should consider the following questions: • Who best represents the patient?
Note An advance directive can be given in writing or given orally.
• What would the patient say if she were competent?
In both ethical and legal terms, the patient has the right to make medical decisions but is now unable to do so by virtue of incompetence. The key here is not to identify the closest next of kin, but to identify the person most likely to represent the patient’s own wishes, i.e., the person who knows the patient best. For a best interest standard, the primary objective is to decide what action a hypothetical “reasonable person” would take after weighing the benefits and burdens of a particular medical decision or course of action. The issue of who actually makes the decision is less important, as all those applying the principles of best interest standard should come to the same conclusion. You should consider the following question: • Are these in the best interest of the patient and not in the best interest of the decision-maker?
Recall Question A 91-year-old woman presents to the emergency department with nausea, vomiting, and abdominal pain. Laboratory tests and imaging studies confirm a diagnosis of acute pancreatitis. Given the new diagnosis, she changes her code status from full code to do not resuscitate. Which of the following describes patient autonomy? A. Assessment of a patient’s decision-making ability B. Legal assessment of a patient to make medical decisions C. Verdict on a patient’s ability to make decisions and be held accountable for the consequences of those decisions D. A patient’s financial ability to pay for healthcare E. Right of a competent patient to make his own health care decisions Answer: E
Advance Directives An advance directive is a set of instructions given by a patient in anticipation of the need for a medical decision in the event the patient becomes incompetent. There are three primary forms of advance directive: • An oral advance directive includes statements made by a patient prior to incapacitation.
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–– Problems can arise from variance and interpretation; e.g., was the patient properly informed before she became incapacitated? How specific was the directive? –– Good rule to follow: the more people who heard the oral directive, the more valid the directive. • A living will is a written advance directive detailing the treatment
measures the patient would want to receive (or not receive) should decision-making capacity be lost.
–– A family member cannot override patient’s wishes; i.e., if the patient’s living will indicates she does not want to be intubated in the event she becomes incapacitated but the patient’s family requests intubation, the physician cannot intubate. • A medical power of attorney or HCPOA is a designated agent assigned
by the patient to make medical decisions in the event she loses decision-making capacity.
–– Assumption is that the agent fully understands the wishes of the patient and essentially “speaks with the patient’s voice.” –– The physician must follow the directives of this individual, irrespective of other family members’ wishes. Do not resuscitate (DNR) orders are made by the patient or the surrogate. DNR refers only to cardiopulmonary resuscitation. –– In many instances, the physician may not be aware of DNR decisions. –– If DNR order is in place, cardiopulmonary resuscitation measures must be stopped as soon as the physician becomes aware of the order. –– All other treatment measures should be continued.
Patient Confidentiality Patient confidentiality is absolute. Physicians require patients to divulge private information, and in doing so are required to keep all discussions confidential. Breach of trust can cause irreparable harm to the physician-patient relationship. • Physicians must strive to ensure that others cannot access patient
information.
–– Patient care must not be discussed with another health care provider in a public venue, where others can overhear the conversation (lunch room, elevator). –– Patient’s physical and electronic medical records must be protected. –– Health care provider owns the medical records, but patient must be given access or copy upon request. • If you receive a court subpoena, show up in court but do not divulge
information about your patient. When asked personal health information questions about a patient, you should maintain patient confidentiality.
There a few exceptions to patient confidentiality. • Duty to warn and to protect (Tarasoff case)
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–– If patient is a threat to self or others, the physician must break confidentiality. –– There is a duty (on the part of the physician) to warn and protect innocent people from harm that could be imposed by “your patient.” • Specific threat to a specific person • Suicide, homicide, and child/elder abuse • Infectious diseases may need to be reported to public officials or an
innocent third party
• Impaired drivers Table 12-2. Rules of Privacy in Health Care Situation
Appropriate Response
Questions from insurance company
Obtain a release from patient
Questions from patient’s family
Requires explicit permission from patient
When to withhold information from patient
Never, i.e., under no circumstances (if concerned about negative reaction by patient, figure out a way to explain and mitigate negative outcome)
Note The Health Insurance Portability and Accountability Act (HIPAA) protects the privacy of individually identifiable health information. HIPAA violations can result in imprisonment and substantial fines.
Treatment of Minors Children age 13 and taking care of self (i.e., living alone, responsible for all aspects of own life), he is essentially treated as an adult. • Person age 65), disabled, and dependents of disabled
• When/if patient is ill, insurance company will pay for bulk of the medical bills
• Part A pays for hospital care • Part B pays for physician services • Annual deductibles and copayments are applicable Medicaid
Joint state/federal program that covers all care for those on welfare
• Covers hospital stays, physician services, medication, and nursing homes • There are no deductibles or copayments
Health Maintenance Organization (HMO)
Prepaid group practice that hires hysicians or contracts with physicians p to provide services
• Payment is made by capitation: fixed payment for the number of patients in their care • Physicians receive only minor additional compensation for care when it is provided • Preventive care is incentivized
Preferred provider organization (PPO)
Fee-for-service at a discount
• Provider makes money on volume, i.e., less money per patient but more patients • Efficiency is rewarded
DEFINITIONS Deductible Before insurance assistance begins, patients must pay a certain amount called a deductible. After the detectible is “met,” the remainder of the bill is divided between the patient and insurance company (co-insurance).
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• In an annual deductible, patient pays certain amount each year • In a per-occurrence deductible, patient pays certain amount each time
services are rendered
• Copayment is a flat fee due at time of service that is based on type and
location of service (e.g., primary care $25, specialist $45)
• Coinsurance is the portion, or percentage, of final bill that patient and
insurance are each responsible for paying (e.g., 80/20 = insurance covers 80% of remaining bill and patient is responsible for 20%) (full coverage means insurance covers 100% of bill)
Capitation Capitation is a fixed, pre-arranged monthly payment made for each patient. • Physicians are paid for number of patients they are responsible for, not for how “much” they do for each patient. • Same payment is made whether services are used or not. • No additional (or only minimal) payment is made when services are used. • Physicians make money when patients stay well and require no services. • Under-treatment is incentivized, but also more likely to foster
preventive medicine.
Catastrophic Coverage Catastrophic coverage is insurance for big medical events. • It is more appealing for younger patients who do not expect to have medical expenses. • Insurance premiums are lower, but out-of-pocket costs are larger if one
becomes sick.
Medically Indigent Adults Medically indigent adults (MIAs) do not have private health insurance. They are not eligible for other health care coverage, such as Medicaid or Medicare.
Recall Question A 70-year-old woman presents to her primary care physician for a follow-up. She has no form of private insurance. Which form of payer system is she most likely to use? A. Blue Cross-Blue Shield B. Medicaid C. HMO D. Medicare E. PPO Answer: D 158
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Learning Objectives ❏❏ Answer questions about scope of patient safety problems ❏❏ Describe the categories of medical error ❏❏ Answer questions about the systems approach to medical error and failure analysis ❏❏ Analyze cases concerning error disclosure and reporting ❏❏ Demonstrate understanding of principles of quality improvement ❏❏ Explain the leadership role of physician to lead change in patient safety
INTRODUCTION Case 1: Care done well A 3-year-old girl falls into an icy fishpond in a small Austrian town in the Alps. She is lost beneath the surface for 30 minutes before her parents find her on the pond bottom and pull her up. CPR is started immediately by the parents on instruction from an emergency physician on the phone, and EMS arrives within 8 minutes. The girl has a body temperature of 19 C and no pulse. Her pupils are dilated and do not react to light. A helicopter takes the patient to a nearby hospital where she is wheeled directly to an operating room. A surgical team puts her on a heart-lung bypass machine, her body temperature increases nearly 10 degrees, and her heart begins to beat. She requires placement on extracorporeal membrane oxygenation. Over the next few days her body temperature continues to rise to normal, and the organs start to recover. She suffered extensive neurologic deficits; however, by age 5, after extensive outpatient therapy, she recovers completely and is like any other little girl again.
Case 2: Failure of the medical system A newborn baby boy is first noted to be jaundiced through visual assessment hours after delivery, but a bilirubin test is not done. At the time of discharge from the hospital, the child is described as having “head to toe jaundice,” but a bilirubin test had still not been done, nor had his blood type or Coombs test been performed. The parents are instructed that the jaundice is normal and they should not worry, and to simply place the infant in the window for sunlight. A few days later the baby’s mother calls the newborn nursery stating that her son is still yellow,
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lethargic, and feeding poorly. She is asked if she is a “first-time mom” and then assured that there was no concern. The mother continues to notice that the child is not well. At age 5 days, the mother’s concerns are acknowledged and a pediatrician admits the baby boy to the pediatric unit. On day 6 in the afternoon, the child has a high pitched cry, respiratory distress, and increased tone. He also starts to arch his neck in a way that is characteristic of opisthotonos. The child is ultimately diagnosed with classic textbook kernicterus, resulting in permanent brain damage. The 2 real cases above represent the reality of our current health care system and the issues of patient safety. In one case a series of complex processes result in an excellent outcome, while in another a patient suffers preventable injury. What are the factors that cause a good versus poor outcome? The field of patient safety seeks to answer this question and take steps to prevent future patients from being harmed by medical errors. Patients are at risk for sustaining harm from the health care system and do so at an alarmingly high rate. Injury can range from minor to severe incidents, including death. The cause of these adverse events is not usually intentional injury (i.e., someone intending to harm patients), but rather is due to the complexity of the health care system combined with the inherent capability of human error. The prevalence of medical errors in the United States is a significant and ongoing problem. Media reports of catastrophic injury resulting in disability or death due to medical care often reach news headlines, and are a significant concern to patients, families, and members of the health care team. The causes of these errors are varied, and can include failures in the administration of medication, performing surgery, reporting laboratory results, and diagnosing patients, to name a few. Ensuring patient safety is the responsibility of every member of the health care team. To do so requires an understanding of safety science and quality improvement principles. Patients, providers, payers, and employers are all stakeholders in improving patient safety. Applying these principles to the study of medical errors can help health care professionals learn from past errors and develop systems that prevent future errors from harming subsequent patients. Systems in health care delivery can be redesigned to create safeguards and safety nets which make it difficult for members of the health care team to make errors that harm patients. The goal of health care should be to learn the strategies and systems that are currently being put into place to improve patient safety.
SCOPE OF THE PROBLEM In 1999 the Institute of Medicine (IOM) published its landmark publication, “To Err is Human: Building a Safer Health System,” reporting that at least 44,000 people—and perhaps as many as 98,000—die in hospitals each year as a result of medical errors that could have been prevented. This exceeds deaths attributed to breast cancer, motor vehicle collisions, and HIV. Approximately 1 in 10 patients entering the hospital will suffer harm from an adverse event. Patient harm from preventable medical errors is a serious concern in health care. The impact of these errors can have dramatically negative effects on p atients, their families, and the health care personnel involved. In addition to the toll on
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human suffering, medical errors also present a significant source of inefficiency and increased cost in the health care system. Medical errors are the eighth leading cause of wrongful death in the United States. The problem is not limited to this country, however; medical errors are a global problem. Some of the more common contributors to medical errors and adverse patient events are as follows: Medication errors represent one of the most common causes of preventable patient harm. An estimated 1.5 million deaths occur each year in the United States due to medication error. The IOM estimates that 1 medication error occurs per hospitalized patient each day. Common causes of medication error: • Poor handwriting technique on a prescription pad or order form,
resulting in a pharmacist or nurse administering the wrong drug or wrong dose
• Dosing or route of administration errors • Failure to identify that given patient is allergic to a prescribed medication • Look-alike or sound-alike drugs (e.g., rifampin/rifaximin)
Figure 17-1. ‘Look-Alike’ Medications Figure 14-1. “Look-Alike” Medications
Strategies that help to reduce or prevent medication errors are as follows. • The 5 Rs help to confirm several key points before the administration
of any medication. –– Right drug –– Right patient –– Right dose –– Right route –– Right time
• Computerized physician order entry (CPOE) involves entering medi-
cation orders directly into a computer system rather than on paper or verbally. The computer software (i.e., electronic health record) can automatically check for prescribing errors or allergies.
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Hospital-acquired infections (HAI) affect 5–15% of all hospitalized patients and 40% of patients in ICU. The World Health Organization (WHO) estimates that the mortality from health-care-associated infections ranges from 12–80%. HAI can occur in many forms, the most common of which in hospitalized patients is urinary catheter-related infection (UTI). UTI accounts for 40% of all HAI; >80% of these infections are attributable to use of an indwelling urethral catheter. Adhering to strict indications for using indwelling catheters, maintaining sterile technique during catheter insertion and exercising prompt removal of the catheter when it is no longer required can help reduce the risk of a urinary catheter-related infection. Central line associated bloodstream infection (CLABSI) is another common HAI, and among one of the most common infections observed in patients admitted to critical care units. It is estimated that 70% of hospital-acquired bloodstream infections occur in patients with central venous catheters. Symptoms include fever, chills, erythema at the skin surrounding the central line site and, in severe cases, hypotension secondary to sepsis. These infections can be associated with significant morbidity and mortality, increased length of hospital stay, and increased hospital cost. Checklists have been developed which provide best practices for the placement of central lines that lower the risk of infection (e.g., hand washing, gloving and gowning, sterile barriers, and early removal of central lines when possible). Hospital-acquired pneumonia (HAP) is an infection that occurs more ften in ventilated patients, typically ≥48 hours after admission to a hospio tal. These ventilator-associated pneumonias (VAP), a subtype of HAP, tend to be more serious because patients are often sicker and less able to mount effective immune responses. HAP is the second most common nosocomial infection. Common symptoms include coughing, fever, chills, fatigue, malaise, headache, loss of appetite, nausea and vomiting, shortness of breath, and sharp or stabbing chest pain that gets worse with deep breathing or coughing. Several methods have been undertaken to prevent HAP, including infection control (e.g., hand hygiene and proper use of gloves, gown, and mask), elevation of the head of the bed in ventilated patients, and other measures to reduce the risk of aspiration. Surgical site infections (SSI) occur following a surgical procedure in the part of the body where the surgery took place. Some SSIs are superficial and limited to the skin, while others are more serious and involve deep tissue under the skin, body cavities, internal organs, or implanted material (e.g., knee or hip replacements). Symptoms include fever, drainage of cloudy fluid from the surgical incision or erythema, and tenderness at the surgical site. Most superficial SSIs (e.g., cellulitis) can be treated with appropriate antibiotics, whereas deeper infections (i.e., abscess) require drainage. Pre- operative antibiotics have been effective in reducing the rate of SSIs. Patient falls are a common cause of injury in hospitals and other health care settings such as nursing homes. Over 1/3 of elderly people age >65 fall each year. Researchers estimate that >500,000 falls happen each year in U.S. hospitals, resulting in 150,000 injuries. Approximately 30% of inpatient falls result in injury, with 4–6% resulting in serious injury. Injuries can include bone fractures, head injury, bleeding, and even death. Injuries from falls also increase hospital costs.
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Assessing a patient’s fall risk helps to identify high-risk patients who can benefit from preventative resources. Some risk factors include advanced age (age >60), muscle weakness, taking >4 prescription medications (especially sedatives, hypnotics, antidepressants, or benzodiazepines), impaired memory, and difficulty walking (e.g., use of a cane or walker). Interventions such as increased observation, nonslip footwear, and making the environment safe all play a role in preventing injury from falls. Unplanned readmissions occur when patients unexpectedly return to the hospital 0. Medical Genetics
Chemical reactions have 2 independent properties: energy and rate. ∆G represents the amount of energy released or required per mole of reactant. The amount or sign of ∆G indicates nothing about the rate of the reaction. Table I-8-2. Energy versus Rate
Behavioral Science/Social Sciences
Energy (∆G)
Rate (v)
Not affected by enzymes
Increased by enzymes
∆G 0, thermodynamically nonspontaneous (energy required) ∆G = 0, reaction at equilibrium (freely reversible) ∆G0 = energy involved under standardized conditions
Free Energy
The rate of the reaction is determined by the energy of activation (∆G‡), which is the energy required to initiate the reaction. ∆G and ∆G‡ are represented in the figure below. Enzymes lower the energy of activation for a reaction; they do not affect the value of ∆G or the equilibrium constant for the reaction, Keq.
Enzyme catalyzed Uncatalyzed
Free Energy
Enzyme catalyzed Uncatalyzed
Gs
Gp
Gs ∆G Gp
∆G‡
∆G‡
∆G
Reaction Progress
Figure I-8-4. Energy Profile for a Catalyzed and Uncatalyzed Reaction Reaction Progress
Figure I-8-4. Energy ProfileI-8-4. for a Catalyzed and Uncatalyzed Reaction Figure Energy Profile for a Catalyzed and Uncatalyzed Reaction
Michaelis-Menten Equation The Michaelis-Menten equation describes how the rate of the reaction, V, depends on the concentration of both the enzyme [E] and the substrate [S], which forms product [P]. E+S⇋E-S→E+P V=
Vmax [ S ] k2 [ E ] [ S ] or, with [E] held constant, V = Km + [ S ] Km + [ S ]
Note: Vmax = k2[E]
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Amino Acids, Proteins, and Enzymes
Vmax is the maximum rate possible to achieve with a given amount of enzyme. The only way to increase Vmax is by increasing the [E]. In the cell, this can be accomplished by inducing the expression of the gene encoding the enzyme. The other constant in the equation, Km is often used to compare enzymes. Km is the substrate concentration required to produce half the maximum velocity. Under certain conditions, Km is a measure of the affinity of the enzyme for its substrate. When comparing two enzymes, the one with the higher Km has a lower affinity for its substrate. The Km value is an intrinsic property of the enzyme-substrate system and cannot be altered by changing [S] or [E]. When the relationship between [S] and V is determined in the presence of constant enzyme, many enzymes yield the graph shown below, a hyperbola.
50
V (µmol/sec)
Bridge to Medical Genetics
Vmax
A missense mutation in the coding region of a gene may yield an enzyme with a different Km.
25
Km 2
4
6
8
10
[S] (mM) Figure I-8-5.Michaelis-Menten Michaelis-MentenPlot Plot Figure I-8-5.
Recall Question Which of the following conditions will result in arginine becoming an essential amino acid? A. Diabetes B. Pregnancy C. Sepsis D. Starvation Answer: B
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Biochemistry
Lineweaver-Burk Equation The Lineweaver-Burk equation is a reciprocal form of the Michaelis-Menten equation. The same data graphed yield a straight line, as shown below.
Medical Genetics
Behavioral Science/Social Sciences
The actual data are represented by the portion of the graph to the right of the y-axis, but the line is extrapolated into the left quadrant to determine its intercept with the x-axis. The intercept of the line with the x-axis gives the value of –1/Km. The intercept of the line with the y-axis gives the value of 1/Vmax. Km 1 1 1 = + V Vmax [ S ] Vmax
(sec/µmol)
0.06
1
v
0.04
1 Vmax
0.02
:1.0 :
• The statin drugs (lovastatin, simvastatin), used to control blood cholesterol, competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. • Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. An example of a noncompetitive inhibitor is allopurinol, which noncompetitively inhibits xanthine oxidase.
1 Km
0.5
1 [S]
1.0 (mM:1)
Figure I-8-6. Lineweaver-Burk Plot Figure I-8-6. Lineweaver-Burk Plot
Note Many drugs are competitive inhibitors of key enzymes in pathways.
0
:0.5
Inhibitors and Activators Competitive inhibitors resemble the substrate and compete for binding to the active site of the enzyme. Noncompetitive inhibitors do not bind at the active site; they bind to regulatory sites on the enzyme. Table I-8-3. Important Classes of Enzyme Inhibitors Class of Inhibitor
Km
Vmax
Competitive
Increase
No effect
Noncompetitive
No effect
Decrease
The effects of these classes of inhibitors on Lineweaver-Burk kinetics are shown below. Notice that on a Lineweaver-Burk graph, inhibitors always lie above the control on the right side of the y-axis.
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1 V
1 V
; Inhibitor
0
No inhibitor present 0
Figure Plot Figure I-8-7. I-8-7. Lineweaver-Burk Lineweaver-Burk Plot of CompetitiveInhibition Inhibition of Competitive
Amino Acids, Proteins, and Enzymes
; Inhibitor
No inhibitor present 1 [S]
●
1 [S]
Figure Plot FigureI-8-8. I-8-8. Lineweaver-Burk Lineweaver-Burk Plot of Noncompetitive Inhibition Inhibition of Noncompetitive
Figure I-8-9 shows the effect on a Lineweaver-Burk plot of adding more enzyme. It might also represent adding an activator to the existing enzyme or a covalent modification of the enzyme. An enzyme activator is a molecule that binds to an enzyme and increases its activity. In these latter two cases the Km might decrease and/or the Vmax might increase but the curve would always be below the control curve in the right-hand quadrant of the graph.
Enzyme + substrate control curve
1 V
Add more enzyme, or activator
0
1 [S]
HY
HY
FigureI-8-9. I-8-9.Lineweaver-Burk Lineweaver-Burk Plot Figure PlotShowing Showingthe theAddition Addition MY ofofMore or the the Addition Addition of of an anActivator Activator MoreEnzyme Enzyme or
LY
Cooperative Enzyme Kinetics
High-Yield
Certain enzymes do not show the normal hyperbola when graphed MEDIUM YIELDon a Michaelis-Menten plot ([S] versus V), but rather show sigmoid kinetics owing to cooperativity among substrate binding sites. Cooperative enzymesLOW haveYIELD multiple subunits and multiple active sites. Enzymes showing cooperative k inetics are often regulatory enzymes in pathways (for example, phosphofructokinase-1 FUNDAMENTALS [PFK-1] in glycolysis). REINFORCEMENT
In addition to their active sites, these enzymes often have multiple sites for a variety of activators and inhibitors (e.g., AMP, ATP, citrate, fructose-2,6-bisphosphate [F2,6-BP]). Cooperative enzymes are sometimes referred to as allosteric enzymes because of the shape changes that are induced or stabilized by binding substrates, inhibitors, and activators.
MY LY
Bridge toYIELD Pharmacology HIGH Methanol poisoning (wood alcohol MEDIUM YIELD poisoning) is treated with ethanol administration. Both are substrates for LOW YIELD alcohol dehydrogenase (ADH), with ethanol having a much lower Km for FUNDAMENTALS the enzyme compared with methanol. This prevents methanol from being REINFORCEMENT converted to formaldehyde, which is toxic and not metabolized further.
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Biochemistry
Biochemistry
Activator
Medical Genetics
V
Control Inhibitor
Behavioral Science/Social Sciences
[S] Figure I-8-10. Cooperative Kinetics Figure I-8-10. Cooperative Kinetics
Transport Kinetics
H
HY MY LY
HIGH YIEL
High-Yield
The Km and Vmax parameters that apply to enzymes are alsoMEDIUM applicable to transYIELD porters in membranes. The kinetics of transport can be derived from the LOWtoYIELD Michaelis-Menten and Lineweaver-Burk equations, where Km refers the solute concentration at which the transporter is functioning at half its maximum activity. The importance of Km values for membrane transporters is exemplified FUNDAMENTALS with the variety of glucose transporters (GLUT) and their respective physiologREINFORCEMENT ic roles (see Chapter 12).
MEDIUM YIE
LOW Y
FUNDAMENT
REINFORCEM
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Amino Acids, Proteins, and Enzymes
Review Questions Select the ONE best answer. 1. The peptide ala-arg-his-gly-glu is treated with peptidases to release all of the amino acids. The solution is adjusted to pH 7, and electrophoresis is performed. In the electrophoretogram depicted below, the amino acid indicated by the arrow is most likely to be
–
+
A. glycine
Figure SQ-VIII-1
B. arginine C. glutamate D. histidine E. alanine 2. The reaction catalyzed by hepatic phosphofructokinase-1 has a ∆G0 value of –3.5 kcal/mol. This value indicates that under standard conditions this reaction A. is reversible B. occurs very slowly C. produces an activator of pyruvate kinase D. is inhibited by ATP E. has a low energy of activation F. will decrease in activity as the pH decreases G. cannot be used for gluconeogenesis H. shows cooperative substrate binding I. is indirectly inhibited by glucagon J. is stimulated by fructose 2,6-bisphosphate
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Biochemistry
3. The activity of an enzyme is measured at several different substrate concentrations, and the data are shown in the table below. [S] (mM)
Medical Genetics
0.010
V0 (mmol/sec) 2.0
0.050 Behavioral Science/Social Sciences
9.1
0.100
17
0.500
50
1.00
67
5.00
91
10.0
95
50.0
99
100.0
100
Km for this enzyme is approximately A. 50.0 B. 10.0 C. 5.0 D. 1.0 E. 0.5
4. Which of the diagrams illustrated below best represents the effect of ATP on hepatic phosphofructokinase-1 (PFK-1)?
+ATP
velocity
C
Fructose 6-P
D
+ATP
velocity
velocity
velocity
velocity
+ATP
+ATP
+ATP A
Fructose 6-P
B
Fructose 6-P
Fructose 6-P
E
Fructose 6-P
Figure SQ-VIII-2
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Amino Acids, Proteins, and Enzymes
5. Several complexes in the mitochondrial electron transport chain contain non-heme iron. The iron in these complexes is bound tightly to the thiol group of which amino acid? A. Glutamine B. Methionine C. Cysteine D. Tyrosine E. Serine Items 6–8 Consider a reaction that can be catalyzed by one of two enzymes, A and B, with the following kinetics. Km (M)
Vmax (mmol/min)
A. 5 × 10−6
20
B. 5 × 10−4
30
6. At a concentration of 5 × 10−6 M substrate, the velocity of the reaction catalyzed by enzyme A will be A. 10 B. 15 C. 20 D. 25 E. 30 7. At a concentration of 5 × 10−4 M substrate, the velocity of the reaction catalyzed by enzyme B will be A. 10 B. 15 C. 20 D. 25 E. 30 8. At a concentration of 5 × 10−4 M substrate, the velocity of the reaction catalyzed by enzyme A will be A. 10 B. 15 C. 20 D. 25 E. 30
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●
Biochemistry
9. A worldwide pandemic of influenza caused by human-adapted strains of avian influenza or bird flu is a serious health concern. One drug for treatment of influenza, Tamiflu (oseltamivir), is an inhibitor of the influenza viral neuraminidase required for release of the mature virus particle from the cell surface. Recent reports have raised concerns regarding viral resistance of Tamiflu compelling the search for alternative inhibitors. Another drug, Relenza (zanamavir), is already FDA approved for use in a prophylactic nasal spray form. The graph below show kinetic data obtained for viral neuraminidase activity (measured as the release of sialic acid from a model substrate) as a function of substrate concentration in the presence and absence of Relenza and Tamiflu. + Relenza 4
1/V
+ Tamiflu
3
(µmoles/min)
No inhibitor
2
1
0
10
20
30
40
1/[S] (µM)
Based on the kinetic data, which of the following statements is correct? A. Both drugs are competitive inhibitors of the viral neuraminidase. B. Both drugs are noncompetitive inhibitors of the viral neuraminidase. C. Tamiflu increases the Km value for the substrate compared to Relenza D. Relenza increases the Vmax value for the substrate compared to Tamiflu. E. Relenza is not an inhibitor of neuraminidase, but inhibits another viral enzyme.
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Amino Acids, Proteins, and Enzymes
Answers 1. Answer: B. Arginine is the most basic of the amino acids (pI~11) and would have the largest positive charge at pH 7. 2. Answer: G. The negative ∆G0 value indicates the reaction is thermodynamically favorable (irreversible), requiring a different bypass reaction for conversion of F1, 6BP to F6P in the gluconeogenic pathway. 3. Answer: E. Because the apparent Vmax is near 100 mmol/sec, Vmax/2 equals 50 mmol/sec. The substrate concentration giving this rate is 0.50 mM. 4. Answer: B. Sigmoidal control curve with ATP inhibiting and shifting curve to the right is needed. 5. Answer: C. Cysteine has a sulfhydryl group in its side chain. Although methionine has a sulfur in its side chain, a methyl group is attached to it. 6. Answer: A. At the concentration of 5 × 10–6 M, enzyme A is working at one-half of its Vmax because the concentration is equal to the Km for the substrate. Therefore, one-half of 20 mmol/min is 10 mmol/min. 7. Answer: B. At the concentration of 5 × 10–4 M, enzyme B is working at one-half of its Vmax because the concentration is equal to the Km for the substrate. Therefore, one-half of 30 mmol/min is 15 mmol/min. 8. Answer: C. At the concentration of 5 × 10–4 M, 100 × the substrate concentration at Km, enzyme A is working at its Vmax, which is 20 mmol/min. 9. Answer: C. Based on the graph, when the substrate is present, Tamiflu results in the same Vmax and higher Km compared to the line when no inhibitor added. These are hallmarks of competitive inhibitors of enzymes, which Tamiflu is. Noncompetitive inhibitors result in decreased Vmax and the same Km with no inhibitor added, which is shown by the Relenza line in the graph.
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9
Learning Objectives ❏❏ Understand concepts concerning hormones and signal transduction ❏❏ Interpret scenarios about mechanism of water-soluble hormones ❏❏ Answer questions about G-proteins and second messengers in signal transduction
HORMONES AND SIGNAL TRANSDUCTION Broadly speaking, a hormone is any compound produced by a cell, which by binding to its cognate receptor alters the metabolism of the cell bearing the hormone–receptor complex. Although a few hormones bind to receptors on the cell that produces them (autoregulation or autocrine function), hormones are more commonly thought of as acting on some other cell, either close by (paracrine) or at a distant site (telecrine). • Paracrine hormones are secreted into the interstitial space and
generally have a very short half-life. These include the prostaglandins and the neurotransmitters.
• Telecrine hormones are secreted into the bloodstream, generally have
Note The GI and endocrine hormones are discussed in detail in the GI and endocrinology chapters in the Physiology Lecture Notes. Although there is some overlap, this chapter presents basic mechanistic concepts applicable to all hormones, whereas coverage in the Physiology Notes emphasizes the physiologic consequences of hormonal action.
a longer half-life, and include the endocrine and gastrointestinal (GI) hormones. (The endocrine hormones are the classic ones, and it is sometimes implied that reference is being made to endocrine hormones when the word hormones is used in a general sense.)
Hormones are divided into 2 categories: those that are water soluble (hydrophilic) and those that are lipid soluble (lipophilic, or hydrophobic).
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Biochemistry
Table I-9-1. Two Classes of Hormones Water-Soluble
Lipid-Soluble
Receptor in cell membrane
Receptor inside cell
Second messengers often involved Protein kinases activated
Hormone–receptor complex binds hormone response elements (HRE) of enhancer regions in DNA
Protein phosphorylation to modify activity of enzymes (requires minutes)
—
Control of gene expression through proteins such as cAMP response element binding (CREB) protein (requires hours)
Control of gene expression (requires hours)
Examples:
Examples:
• Insulin
• Steroids
• Glucagon
• Calcitriol
• Catecholamines
• Thyroxines
Medical Genetics
Behavioral Science/Social Sciences
• Retinoic acid
H
HY
MECHANISM OF WATER-SOLUBLE HORMONES
Water-soluble hormones must transmit signals to affect metabolism and MYgene expression without themselves entering the cytoplasm. They often do so via secLY ond messenger systems that activate protein kinases.
HIGH YIEL
High-Yield
Protein Kinases
A protein kinase is an enzyme that phosphorylates otherMEDIUM proteins,YIELD changing their activity (e.g., phosphorylation of acetyl CoA carboxylase inhibits it). LOW YIELD Examples of protein kinases are listed in Table I-9-2 along with the second messengers that activate them. FUNDAMENTALS
Table I-9-2. Signal Transduction by Water-Soluble Hormones
REINFORCEMENT
Pathway
G Protein
Enzyme
Second Messenger(s)
Protein Kinase
Examples
cAMP
Gs (Gi)
Adenyl cyclase
cAMP
Protein kinase A
Glucagon Epinephrine (β, α-2) Vasopressin (V2, ADH) kidney
PIP2
Gq
Phospholipase C
DAG, IP3, Ca2+
Protein kinase C
Vasopressin (V1, V3) vascular smooth muscle Epinephrine (α1)
cGMP
None
Guanyl cyclase
cGMP
Protein kinase G
Atrial natriuretic factor (ANF)
MEDIUM YIE
LOW Y
FUNDAMENT
REINFORCEM
Nitric oxide (NO) Insulin, growth factors
Monomeric p21ras
—
—
Tyrosine kinase activity of receptor
Insulin Insulin-like growth factor (IGF) Platelet-derived growth factor (PDGF) Epidermal growth factor (EGF)
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Some water-soluble hormones bind to receptors with intrinsic protein kinase activity (often tyrosine kinases). In this case, no second messenger is required for protein kinase activation. The insulin receptor is an example of a tyrosine kinase receptor. Activation of a protein kinase causes: • Phosphorylation of enzymes to rapidly increase or decrease their activity. • Phosphorylation of gene regulatory proteins such as CREB to control
gene expression, usually over several hours. The typical result is to add more enzyme to the cell. CREB induces the phosphoenolpyruvate carboxykinase (PEPCK) gene. Kinetically, an increase in the number of enzymes means an increase in Vmax for that reaction. ATP
Protein kinase
Proteins: • Gene regulatory proteins • Enzymes Dephosphorylated
Pi
ADP
Proteins: • Gene regulatory proteins • Enzymes Different activity
Protein phosphatase
P
Phosphorylated
H 2O
Figure I-9-1. Protein Kinases and Phosphatases Figure I-9-1. Protein Kinases and Phosphatases
HY MY
Both represent strategies to control metabolism. The action of protein kinases is LY reversed by protein phosphatases.
Sequence of Events from Receptor to Protein Kinase G protein
HY MY LY
High-Yield
HIGH YIELD
MEDIUM YIELD
MEDIUM YIELD
LOW YIELD
Receptors in these pathways are coupled through trimetric G proteins in the membrane. The 3 subunits in this type of G protein are α, β, and γ. FUNDAMENTALS In its inactive form, the α subunit binds GDP and is in complex with the β and γ subunits. When a REINFORCEMENT hormone binds to its receptor, the receptor becomes activated and, in turn, engages the corresponding G protein (step 1 below). The GDP is replaced with GTP, enabling the α subunit to dissociate from the β and γ subunits (step 2 below).
LOW YIELD FUNDAMENTALS REINFORCEMENT
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Biochemistry
The activated α subunit alters the activity of adenylate cyclase. If the α subunit is αs, then the enzyme is activated; if the α subunit is αi, then the enzyme is inhibited. The GTP in the activated α subunit will be dephosphorylated to GDP (step 3 below) and will rebind to the β and γ subunits (step 4 below), rendering the G protein inactive.
Behavioral Science/Social Sciences
α
GDP
α
β
β
GTP
γ
γ
Inactive G protein
Active G protein
α
GTP
β
Enzyme (adenylate cyclase)
γ
α
GDP
Pi
Figure I-9-2.Trimeric TrimericG G Protein Cycle Figure I-9-2. Protein Cycle
Cyclic AMP (cAMP) and phosphatidylinositol bisphosphate (PIP2)
The receptors all have characteristic 7-helix membrane-spanning domains. The sequence of events, leading from receptor to activation of the protein kinase via the cAMP and PIP2 second messenger systems, is as follows: • Hormone binds receptor • Trimeric G protein in membrane is engaged • Enzyme (adenylate cyclase or phospholipase) activated • Second messenger generated • Protein kinase activated • Protein phosphorylation (minutes) and gene expression (hours)
An example of inhibition of adenylate cyclase via Gi is epinephrine inhibition (through its binding to α2 adrenergic receptor) of insulin release from β cells of the pancreas.
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cAMP System Receptor for: • Glucagon • Epinephrine β (Gs) • Epinephrine α2 (Gi)
+ NH3
+ NH3
Receptor for: • Vasopressin • Epinephrine α1 PIP2
α
COO– CREB
γ
Adenyl cyclase
β
Gs or Gi +
CREB Nucleus DNA
CREB CRE
Hormones
PIP2 System
Membrane Cytoplasm
●
P
α
ATP
COO–
γ
β
DAG
Phospholipase C
+
IP3
Gq
cAMP
Ca2+
+ + Protein kinase A
ER
+
P Gene ++
Gene expression
Ca2+
Protein kinase
Enzymes dephosphorylated
Gene expression in nucleus
Protein kinase C
+
P Enzymes phosphorylated
(phosphatase)
Figure I-9-3. I-9-3. Cyclic Cyclic AMP AMPand andPhosphatidylinositol PhosphatidylinositolBisphosphate Bisphosphate(PIP (PIP Figure 2) 2)
cGMP
Note
Atrial natriuretic factor (ANF), produced by cells in the atrium of the heart in response to distension, binds the ANF receptor in vascular smooth muscle and in the kidney. The ANF receptor spans the membrane and has guanylate cyclase activity associated with the cytoplasmic domain. It causes relaxation of vascular smooth muscle, resulting in vasodilation, and in the kidney it promotes sodium and water excretion.
Once generated, the second messengers cAMP and cGMP are slowly degraded by a class of enzymes called phosphodiesterases (PDEs).
Nitric oxide (NO) is synthesized by vascular endothelium in response to vasodilators. It diffuses into the surrounding vascular smooth muscle, where it directly binds the heme group of soluble guanylate cyclase, activating the enzyme. Both the ANF receptor and the soluble guanylate cyclase are associated with the same vascular smooth muscle cells.
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+ NH3 Medical Genetics
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Arginine
Receptors for atrial natriuretic factor (ANF)
Nitric oxide synthase
E. coli heat stable toxin (STa) A similar guanylate cyclase receptor in enterocytes is the target of E. coli heatstable toxin (STa). The toxin binds to, and stimulates, the guanylate cyclase increasing cGMP. This causes increased activity of CFTR and diarrhea.
Nitric oxide (NO)
Membrane Cytoplasm
Bridge to Microbiology
Drugs: • Nitroprusside • Nitroglycerine • Isosorbide dinitrate
GTP
COO– Receptor guanylate cyclase
cGMP
NO + Soluble guanylate cyclase
+
Vascular Smooth Muscle
Protein kinase G
GTP
Relaxation of smooth muscle (vasodilation) Figure I-9-4. Cyclic GMP Figure I-9-4. Cyclic GMP
The sequence from receptor to protein kinase is quite similar to the one above for cAMP, with 2 important variations: • The ANF receptor has intrinsic guanylate cyclase activity. Because no
G protein is required in the membrane, the receptor lacks the 7-helix HY membrane-spanning domain.
H
MY
• Nitric oxide diffuses into the cell and directly activates a soluble,
LY cytoplasmic guanylate cyclase, so no receptor or G protein is required.
The Insulin Receptor: A Tyrosine Kinase
HIGH YIEL
High-Yield
Insulin binding activates the tyrosine kinase activity associated withYIELD the cytoMEDIUM plasmic domain of its receptor. There is no trimeric G protein, enzyme, or second LOW YIELD messenger required to activate this protein tyrosine kinase activity: • Hormone binds receptor
FUNDAMENTALS • Receptor tyrosine kinase (protein kinase) is activated REINFORCEMENT • Protein phosphorylation (autophosphorylation and activation of other
MEDIUM YIE
LOW Y
FUNDAMENT
REINFORCEM
proteins)
Once autophosphorylation begins, a complex of other events ensues. An insulin receptor substrate (IRS-1) binds the receptor and is phosphorylated on tyrosine
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residues, allowing proteins with SH2 (src homology) domains to bind to the phosphotyrosine residues on IRS-1 and become active. In this way, the receptor activates several enzyme cascades, which involve: • Activation of phosphatidylinositol-3 kinase (PI-3 kinase), one of whose
effects in adipose and muscle tissues is to increase GLUT-4 in the membrane
• Activation of protein phosphatases. Paradoxically, insulin stimulation via
its tyrosine kinase receptor ultimately may lead to dephosphorylating enzymes
• Stimulation of the monomeric G protein (p21ras) encoded by the
normal ras gene
All these mechanisms can be involved in controlling gene expression, although the pathways by which this occurs have not yet been completely characterized.
ss
Insulin binding activates tyrosine kinase activity
ss
P
P
Tyrosine kinase
ss
P
ADP
ADP ATP
ss
P SH2
Autophosphorylation of receptor
P SH2 PI-3 kinase
P SH2
Protein
Enzymes dephosphorylated
P Enzymes phosphorylated
Insulin receptor substrate (IRS) binds receptor and is phosphorylated on tyrosine residues
IRS-1
ATP
Protein kinase
P
SH2-domain proteins bind phosphotyrosine residues on IRS
Protein
+
p21ras G protein
Protein + phosphatase
Translocation of GLUT-4 to membrane in: • Adipose • Muscle
Gene expression in nucleus Figure I-9-5. Insulin Receptor Figure I-9-5. Insulin Receptor
Tyrosine kinase receptors are also involved in signaling by several growth factors, including platelet-derived growth factor (PDGF) and epidermal growth factor (EGF).
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Biochemistry
Recall Question Epinephrine, through inhibition of adenylate cyclase, prevents the secretion of which of the following products?
Medical Genetics
A. Gastrin B. Glucagon
H
HY
C. Insulin
Behavioral Science/Social Sciences
MY
D. Lipoprotein lipase
LY
Answer: C
Functional Relationship of Glucagon and Insulin
HIGH YIEL
High-Yield
MEDIUM YIELD
MEDIUM YIE
Insulin (associated with well-fed, absorptive metabolism) and glucagon LOW YIELD (associated with fasting and postabsorptive metabolism), usually oppose each other with respect to pathways of energy metabolism. Glucagon works through the cAMP system to activate protein kinase A favoring phosphorylation FUNDAMENTALS of rate-limiting enzymes, whereas insulin often activates protein phosphatases REINFORCEMENT that dephosphorylate many of the same enzymes.
LOW Y
FUNDAMENT
REINFORCEM
Glucagon promotes phosphorylation of both rate-limiting enzymes (glycogen phosphorylase for glycogenolysis and glycogen synthase for glycogen synthesis). The result is twofold in that synthesis slows and degradation increases, but both effects contribute to the same physiologic outcome, release of glucose from the liver during hypoglycemia. Insulin reverses this pattern, promoting glucose storage after a meal. The reciprocal relationship between glucagon and insulin is manifested in other metabolic pathways, such as triglyceride synthesis and degradation. Glucagon +
Protein kinase A
ATP
Glycogen synthesis
(store glucose)
ADP
Glycogen phosphorylase (glycogenolysis) LESS ACTIVE
Glycogen phosphorylase (glycogenolysis) ACTIVE
Glycogen synthase (glycogen synthesis) ACTIVE
Glycogen synthase (glycogen synthesis) LESS ACTIVE
Pi
Protein phosphatase +
P
Glycogenolysis P
(release glucose)
H 2O
Insulin Figure I-9-6. Opposing Activities of Insulin and Glucagon
Figure I-9-6. Opposing Activities of Insulin and Glucagon
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G PROTEINS IN SIGNAL TRANSDUCTION Table I-9-2 seen earlier summarizes the major components of water-soluble hormone pathways reviewed in this section. There are several G proteins (GTP-binding) involved. Trimeric G proteins include Gs, Gi, Gq, and in the photoreceptor pathway reviewed in Chapter 10, Gt (transducin). Receptors that engage these all have the 7-helix membrane-spanning structure. Receptor stimulation causes the Gα subunit to bind GTP and become active. The Gα subunit subsequently hydrolyzes the GTP to GDP, terminating the signal. The p21ras G protein is monomeric. G-protein defects can cause disease in several ways. Table I-9-3. Abnormal G Proteins and Disease Defect
Example
Disease
• Cholera toxin
Gsα
Diarrhea of cholera
• E. coli toxin
Gsα
Traveler’s diarrhea
• Pertussis toxin
Giα
Pertussis (whooping cough)
Oncogenic mutations
p21ras (ras)
Colon, lung, breast, bladder tumors
ADP-ribosylation by:
ADP-Ribosylation by Bacterial Toxins
HY
HY MY
MY
LY
High-Yield
LY HIGH YIELD
Certain bacterial exotoxins are enzymes which attach theMEDIUM adenosine diphosYIELD phate (ADP)-ribose residue of NAD to Gα subunits, an activity known as ADPLOWitYIELD ribosylation. In humans, some ADP-ribosylation is physiological but may also be pathological:
MEDIUM YIELD
FUNDAMENTALS • Vibrio cholerae exotoxin ADP-ribosylates Gsα, leading to an increase
FUNDAMENTALS
in cAMP and subsequently chloride secretion from intestinal mucosal REINFORCEMENT cells, and causing the diarrhea of cholera.
LOW YIELD
REINFORCEMENT
• Certain strains of Escherichia coli release toxins (heat labile or LT)
similar to cholera toxin, producing traveler’s diarrhea.
• Bordetella pertussis exotoxin ADP-ribosylates Giα, dramatically
reducing its responsiveness to the receptor, thus increasing cAMP. It is not known how this relates to the persistent paroxysmal coughing symptomatic of pertussis (whooping cough).
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Biochemistry
Protein (such as Gαs) O Medical Genetics
O:
O P O
O
NH2
; N
Toxin
Behavioral Science/Social Sciences
O
O P O O:
ADP-ribosylated protein
OH OH
NH2
N
N
O
N
N
O : O
O
O P
O
O P : O
HO O
O
OH N N N
HO
OH OH
NH2 N
OH
Nicotinamide adenine dinucleotide (NAD)
+nicotinamide
FigureI-9-7. I-9-7. ADP-Ribosylation ADP-Ribosylation ofofaaProtein Figure Protein
LIPID-SOLUBLE HORMONES Lipid-soluble hormones diffuse through the cell membrane, where they bind to their respective receptors inside the cell. The receptors have a DNA-binding domain (usually Zn-fingers) and interact with specific response elements in enhancer (or possibly silencer) regions associated with certain genes. For example, the cortisol receptor binds to its response element in the enhancer region of the phosphoenolpyruvate carboxykinase (PEPCK) gene. By increasing the amount of PEPCK in the hepatocyte, cortisol can increase the capacity for gluconeogenesis, one of its mechanisms for responding to chronic stress often associated with injury. The enhancer mechanism was reviewed in Chapter 5.
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●
Hormones
Review Questions 1. A patient with manic depressive disorder is treated with lithium, which slows the turnover of inositol phosphates and the phosphatidyl inositol derivatives in cells. Which of the following protein kinases is most directly affected by this drug? A. Protein kinase C B. Receptor tyrosine kinase C. Protein kinase G D. Protein kinase A E. Protein kinase M Items 2 and 3 Tumor cells from a person with leukemia have been analyzed to determine which oncogene is involved in the transformation. After partial sequencing of the gene, the predicted gene product is identified as a tyrosine kinase. 2. Which of the following proteins would most likely be encoded by an oncogene and exhibit tyrosine kinase activity? A. Nuclear transcriptional activator B. Epidermal growth factor C. Membrane-associated G protein D. Platelet-derived growth factor E. Growth factor receptor 3. A kinetic analysis of the tyrosine kinase activities in normal and transformed cells is shown below.
1/V
Normal cells
Tumor cells 1/[ATP]
Which of the following conclusions is best supported by these results? A. The tumor cell kinase has a higher-than-normal affinity for ATP B. A kinase gene has been deleted from the tumor cell genome C. A noncompetitive inhibitor has been synthesized in the tumor cells D. A kinase gene has been amplified in the tumor cell genome E. The tumor cell kinase has a lower-than-normal affinity for ATP
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Part I Biochemistry
Medical Genetics
●
Biochemistry
4. In a DNA sequencing project, an open reading frame (ORF) has been identified. The nucleotide sequence includes a coding region for an SH2 domain in the protein product. This potential protein is most likely to A. bind to an enhancer region in DNA B. be a transmembrane hormone receptor C. transmit signals from a tyrosine kinase receptor
Behavioral Science/Social Sciences
D. bind to an upstream promoter element E. activate a soluble guanyl cyclase enzyme in vascular smooth muscle
γ
β α
+
Enzyme
Second messenger
Substrate
5. The diagram above represents a signal transduction pathway associated with hormone X. The receptor for hormone X is most likely to be characterized as a(n) A. seven-helix transmembrane domain receptor B. intracellular receptor with a zinc-finger domain C. helix-turn-helix transmembrane domain receptor D. transmembrane receptor with a guanyl cyclase domain E. tyrosine kinase domain receptor 6. A 58-year-old man with a history of angina for which he occasionally takes isosorbide dinitrate is having erectile dysfunction. He confides in a colleague, who suggests that sildenafil might help and gives him 3 tablets from his own prescription. The potentially lethal combination of these drugs relates to Isosorbide Dinitrate
Sildenafil
A.
Activates nitric oxide synthase in vascular endothelium
Inhibits guanyl cyclase in vascular smooth muscle
B.
Activates nitric oxide synthase in vascular endothelium
Inhibits guanyl cyclase in corpora cavernosa smooth muscle
C.
Releases cyanide as a byproduct
Inhibits cGMP phosphodiesterase in corpora cavernosa smooth muscle
D.
Activates guanyl cyclase in vascular smooth muscle
Inhibits cGMP phosphodiesterase in vascular smooth muscle
E.
Activates the ANF receptor in vascular smooth muscle
Inhibits protein kinase G in vascular smooth muscle
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Answers 1. Answer: A. The description best fits the PIP2 system in which protein kinase C is activated. 2. Answer: E. Although any of the listed options might be encoded by an oncogene, the “tyrosine kinase” description suggests it is likely to be a growth factor receptor. 3. Answer: D. Because the y-axis is 1/V, a smaller value for the 1/V means an increase in Vmax. An increase in Vmax (with no change in Km) means an increase in the number of enzymes (a kinase in this problem). Gene amplification (insertion of additional copies of the gene in the chromosome) is a well-known mechanism by which oncogenes are overexpressed and by which resistance to certain drugs is developed. For instance, amplification of the dihydrofolate reductase gene can confer resistance to methotrexate. 4. Answer: C. Proteins with SH2 domains might bind to the insulin receptor substrate-1 (IRS-1) to transmit signals from the insulin receptor, a tyrosine kinase type of receptor. PI-3 kinase is an example of an SH2 domain protein. SH2 domains are not involved in DNA binding (choices A and D). Examples of protein domains that bind DNA include zinc fingers (steroid receptors), leucine zippers (CREB protein), and helixturn-helix proteins (homeodomain proteins). 5. Answer: A. The diagram indicates that the receptor activates a trimeric G-protein associated with the inner face of the membrane and that the G-protein subsequently signals an enzyme catalyzing a reaction producing a second messenger. Receptors that activate trimeric G-proteins have a characteristic seven-helix transmembrane domain. The other categories of receptors do not transmit signals through trimeric G-proteins. 6. Answer: D. Nitrates may be metabolized to nitric oxide (NO) that activates a soluble guanyl cyclase in vascular smooth muscle. The increase in cGMP activates protein kinase G and subsequently leads to vasodilation. Sildenafil inhibits cGMP phosphodiesterase (PDE), potentiating vasodilation that can lead to shock and sudden death. Although sildenafil has much higher potency for the cGMP PDE isozyme in the corpora cavernosa, it can also inhibit the cGMP PDE in vascular smooth muscle. Nitric oxide synthase (choices A and B) is the physiologic source of nitric oxide in response to vasodilators such as acetylcholine, bradykinin, histamine, and serotonin.
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Vitamins
10
Learning Objectives ❏❏ Understand differences between vitamins and coenzymes of watersoluble hormones ❏❏ Know pathologies associated with water-soluble vitamins ❏❏ Know metabolism and functions of the 4 fat-soluble vitamins
VITAMINS Vitamins have historically been classified as water-soluble or lipid-soluble. Water-soluble vitamins are precursors for coenzymes and are reviewed in the context of the reactions for which they are important.
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Biochemistry
Table I-10-1. Water-Soluble Vitamins Vitamin or Coenzyme
Medical Genetics
Biotin
Behavioral Science/Social Sciences
Thiamine (B1)
Niacin (B3)
Enzyme
Pathway
Deficiency
Pyruvate carboxylase A cetyl CoA carboxylase
Gluconeogenesis Fatty acid synthesis
MCC* (rare): excessive consumption of raw eggs (contain avidin, a biotin-binding protein); also caused by biotinidase deficiency
Propionyl CoA carboxylase
Odd-carbon fatty acids, Val, Met, Ile, Thr
Alopecia (hair loss), bowel inflammation, muscle pain
Pyruvate dehydrogenase
PDH
MCC: alcoholism (alcohol interferes with absorption)
α-Ketoglutarate dehydrogenase
TCA cycle
Wernicke (ataxia, nystagmus, ophthal-moplegia)
Transketolase
HMP shunt
Korsakoff (confabulation, psychosis)
Branched chain ketoacid dehydrogenase
Metabolism of valine isoleucine and leucine
Dehydrogenases
Many
NAD(H)
Wet beri-beri (high-output cardiac failure, fluid retention, vascular leak) and dry beri-beri (peripheral neuropathy) Pellagra: diarrhea, dementia, dermatitis, and, if not treated, death Pellagra may also be related to deficiency of tryptophan (corn is low in tryptophan), which supplies a portion of the niacin requirement
NADP(H)
Folic acid
Thymidylate synthase
Thymidine (pyrimidine) synthesis
MCC: alcoholism and pregnancy (body stores depleted in 3 months), hemodialysis
THF
Enzymes in purine synthesis need not be memorized
Purine synthesis
Homocystinemia with risk of deep vein thrombosis and atherosclerosis Megaloblastic (macrocytic) anemia Deficiency in early pregnancy causes neural tube defects in fetus
Cyanocobalamin (B12)
Homocysteine methyltransferase Methylmalonyl CoA mutase
Methionine, SAM Odd-carbon fatty acids, Val, Met, Ile, Thr
MCC: pernicious anemia. Also in aging, especially with poor nutrition, bacterial overgrowth of terminal ileum, resection of the terminal ileum secondary to Crohn disease, chronic pancreatitis, and, rarely, vegans, or infection with D. latum Megaloblastic (macrocytic) anemia Progressive peripheral neuropathy
*MCC, most common cause
(Continued)
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Vitamins
Table I-10-1. Water-Soluble Vitamins (continued ) Vitamin or Coenzyme
Enzyme
Pathway
Deficiency
Pyridoxine (B6)
Aminotransferases (transaminase):
Protein catabolism
MCC: isoniazid therapy
Pyridoxal-P (PLP)
AST (GOT), ALT (GPT) δ-Aminolevulinate synthase
Sideroblastic anemia Heme synthesis
Cheilosis or stomatitis (cracking or scaling of lip borders and corners of the mouth) Convulsions
Riboflavin (B2) FAD(H2)
Dehydrogenases
Many
Corneal neovascularization Cheilosis or stomatitis (cracking or scaling of lip borders and corners of the mouth) Magenta-colored tongue
Ascorbate (C)
Prolyl and lysyl hydroxylases
Collagen synthesis
MCC: diet deficient in citrus fruits and green vegetables
Catecholamine synthesis Absorption of iron in GI tract
Scurvy: poor wound healing, easy bruising (perifollicular hemorrhage), bleeding gums, increased bleeding time, painful glossitis, anemia
Fatty acid metabolism
Rare
Dopamine hydroxylase Dopamine hydroxylase
Pantothenic acid
Fatty acid synthase
CoA
Fatty acyl CoA synthetase Pyruvate dehydrogenase
PDH
α-Ketoglutarate dehydrogenase
TCA cycle
Scurvy A 7-month-old infant presented in a “pithed frog” position, in which he lay on his back and made little attempt to lift the legs and arms because of pain. The infant cried when touched or moved, and there appeared to be numerous areas of swelling and bruising throughout the body. The mother informed the pediatrician that the infant was bottle-fed. However, the mother stated that she always boiled the formula extensively, much longer than the recommended time, to ensure that it was sterile.
Bridge to Pharmacology High-dose niacin can be used to treat hyperlipidemia.
The patient has infantile scurvy, which often occurs in infants 2–10 months of age who are bottle-fed with formula that is overheated for pasteurization and not supplemented with vitamin C. Vitamin C is destroyed by excessive heat. Although bleeding in an infant with scurvy might occur similarly as in an adult, gum bleeding does not unless there are erupted teeth. Biochemically, vitamin C is necessary as a cofactor by proline and lysine hydroxylases in collagen synthesis. In scurvy, because proline and lysine residues are not hydroxylated, hydrogen bonding within the triple helices does not take place. Consequently, collagen fibers are significantly less stable than normal. Vitamin C also has roles as 1) an antioxidant, 2) in reducing iron in the intestine to enable the absorption of iron, and 3) in hepatic synthesis of bile acids.
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Biochemistry
Note
Vitamin D deficiency is caused by insufficient sunlight, inadequate fortified foods (milk), or end-stage Medical Genetics renal disease (renal osteodystrophy). Symptoms: • Bone demineralization
There are 4 important lipid-soluble vitamins: D, A, K, and E. • Two of them (A and D) work through enhancer mechanisms similar to
those for lipid-soluble hormones.
• In addition, all 4 have more specialized mechanisms through which
they act.
Table I-10-2. Lipid-Soluble Vitamins
Behavioral Science/Social Sciences
• Rickets (children)
Vitamin
Important Functions
• Osteomalacia (adults)
D (cholecalciferol)
In response to hypocalcemia, helps normalize serum calcium levels
A (carotene)
Retinoic acid and retinol act as growth regulators, especially in epithelium
Vitamin A deficiency is caused by fat malabsorption or a fat-free diet. Symptoms: • Night blindness • Keratinized squamous epithelia • Xerophthalmia, Bitot spots • Keratomalacia, blindness
Retinal is important in rod and cone cells for vision K (menaquinone, bacteria; phytoquinone, plants)
Carboxylation of glutamic acid residues in many Ca2+-binding proteins, importantly coagulation factors II, VII, IX, and X, as well as protein C and protein S
E (α-tocopherol)
Antioxidant in the lipid phase. Protects membrane lipids from peroxidation
• Follicular hyperkeratosis • Alopecia
VITAMIN D AND CALCIUM HOMEOSTASIS Vitamin E deficiency is caused by fat malabsorption or premature birth. Symptoms: • Hemolytic anemia • Acanthocytosis • Peripheral neuropathy • Ataxia • Retinitis pigmentosum
Hypocalcemia (below-normal blood calcium) stimulates release of parathyroid hormone (PTH), which in turn binds to receptors on cells of the renal proximal tubules. The receptors are coupled through cAMP to activation of a 1α-hydroxylase important for the final, rate-limiting step in the conversion of vitamin D to 1,25-DHCC (dihydroxycholecalciferol or calcitriol). Once formed, 1,25-DHCC acts on duodenal epithelial cells as a lipid-soluble hormone. Its intracellular receptor (a Zn-finger protein) binds to response elements in enhancer regions of DNA to induce the synthesis of calcium-binding proteins thought to play a role in stimulating calcium uptake from the GI tract. 1,25-DHCC also facilitates calcium reabsorption in the kidney and mobilizes calcium from bone when PTH is also present. All these actions help bring blood calcium levels back within the normal range. The relation of vitamin D to calcium homeostasis and its in vivo activation are shown below.
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7-Dehydrocholesterol Skin UV light Cholecalciferol (Vitamin D3) Liver 25-Hydroxylase
Dietary source required if insufficient exposure to UV light. Vitamin D3 is found in saltwater fish (salmon) and egg yolks. Vitamin D3, prepared from animal products and then irradiated with UV light, is added to milk and some fortified cereals. Cirrhosis and liver failure may produce bone demineralization.
25-Hydroxycholecalciferol Kidney
Hypocalcemia
1α-Hydroxylase (induce) 1,25-Dihydroxycholecalciferol (Calcitriol, 1,25-DHCC)
BONE: Osteoclasts; Ca2+ mineralization or demineralization (with PTH)
+ PARATHYROID Parathyroid hormone (PTH)
Patients with end-stage renal disease develop renal osteodystrophy; IV or oral 1,25-DHCC may be given.
INTESTINE (Duodenum): increase calcium uptake from intestine HY
MY
Figure I-10-1. Synthesis Synthesisand andActivation ActivationofofVitamin Vitamin Figure I-10-1. DD
Synthesis of 1, 25-Dihydroxycholecalciferol (Calcitriol)
LY
High-Yield
MEDIUM YIELD
Humans can synthesize calcitriol from 7-dehydrocholesterol derived from choLOW YIELD lesterol in the liver. Three steps are involved, each occurring in a different tissue: Step 1. Activation of 7-dehydrocholesterol by UV light inFUNDAMENTALS the skin produces cholecalciferol (vitamin D3); this step is insufficient for many people in REINFORCEMENT cold, cloudy climates, and vitamin D3 supplementation is necessary.
HY MY LY HIGH Bridge toYIELD Pharmacology Bisphosphonates are a class of drugs MEDIUM YIELD used in the treatment of osteoporosis.
LOW YIELD
• Function by inhibiting osteoclast action and resorption of bone; FUNDAMENTALS results in a modest increase in bone mineral density (BMD) REINFORCEMENT
Step 2. 25-hydroxylation in the liver (patients with severe liver disease may need to be given 25-DHCC or 1,25-DHCC).
• Will lead to strengthening of bone and decrease in fractures
Step 3. 1α-hydroxylation in the proximal renal tubule cells in response to PTH; genetic deficiencies or patients with end-stage renal disease develop renal osteodystrophy because of insufficiency of 1,25-DHCC and must be given 1,25-DHCC or a drug analog that does not require metabolism in the kidney. Such patients include those with:
• Commonly used bisphosphates are ibandronate, risedronate, and alendronate
• End-stage renal disease secondary to diabetes mellitus • Fanconi renal syndrome (renal proximal tubule defect) • Genetic deficiency of the 1α-hydroxylase (vitamin D-resistant
rickets)
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Biochemistry
Vitamin D Toxicity Medical Genetics
Behavioral Science/Social Sciences
A 45-year-old man had a 3-week history of weakness, excessive urination, intense thirst, and staggering walk. For most of his adult life, he took excessive amounts of vitamin C because he was told it would help prevent the common cold. The past month, he took excessive amounts of vitamin D and calcium every day because he learned that he was developing osteoporosis. Recent lab tests revealed greatly elevated serum calcium, and vitamin D toxicity was diagnosed. Vitamin D is highly toxic at consumption levels that continuously exceed 10× RDA, resulting in hypercalcemia. Unlike water-soluble vitamins, which are excreted in excess amounts, vitamin D can be stored in the liver as 25-hydroxycholecalciferol. The excess vitamin D can promote intestinal absorption of calcium and phosphate. The direct effect of vitamin D excess on bone is resorption similar to that seen in vitamin D deficiency. Therefore, the increased intestinal absorption of calcium in vitamin D toxicity contributes to hypercalcemia. Rather than help the man’s osteoporosis, a large amount of vitamin D can contribute to it. Hypercalcemia can impair renal function, and early signs include polyuria, polydipsia, and nocturia. Prolonged hypercalcemia can result in calcium deposition in soft tissues, notably the kidney, producing irreversible HY kidney damage. MY
H
LY
HIGH YIEL
High-Yield
Clinical Correlate
Vitamin D Deficiency
Isotretinoin, a form of retinoic acid, is used in the treatment of acne. It is teratogenic (malformations of the craniofacial, cardiac, thymic, and CNS structures) and is therefore absolutely contraindicated in pregnant women. Use with caution in women of childbearing age.
MEDIUM YIELD Deficiency of vitamin D in childhood produces rickets, a constellation of skeletal abnormalities most strikingly seen as deformities of the legs (although LOW YIELD many other developing bones are affected). Muscle weakness is common.
MEDIUM YIE
Deficiency of vitamin D after epiphyseal fusion causes osteomalacia, which proFUNDAMENTALS duces less deformity than rickets. Osteomalacia may present as bone pain and REINFORCEMENT muscle weakness.
FUNDAMENT
Note What to Know for the Exam Vitamins: • Clinical manifestations of deficiencies
Vitamin A (carotene) is converted to several active forms in the body associated with two important functions, maintenance of healthy epithelium and vision. Biochemically, there are 3 vitamin A structures that differ on the basis of the functional group on C-1: hydroxyl (retinol), carboxyl (retinoic acid), and aldehyde (retinal).
Maintenance of Epithelium
• Pathways
Retinol and retinoic acid are required for the growth, differentiation, and maintenance of epithelial cells. In this capacity they bind intracellular receptors, which are in the family of Zn-finger proteins, and they regulate transcription through specific response elements.
• Treatments of deficiencies
REINFORCEM
VITAMIN A
• Enzymes that accumulate
• Preventions of deficiencies
LOW Y
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Vision When first formed, all the double bonds in the conjugated double bond system in retinal are in the trans configuration. This form, all-trans retinal is not active. The conversion of all-trans retinal to the active form cis-retinal takes place in the pigmented epithelial cells. Cis-retinal is then transferred to opsin in the rod cells forming the light receptor rhodopsin. It functions similarly in rod and cone cells. When exposed to light, cis-retinal is converted all-trans retinal. A diagram of the signal transduction pathway for light-activated rhodopsin in the rod cell is shown in Figure I-10-2, along with the relationship of this pathway to rod cell anatomy and changes in the membrane potential. Note the following points: • Rhodopsin is a 7-pass receptor coupled to the trimeric G protein
transducin (Gt).
• When light is present, the pathway activates cGMP phosphodiesterase,
which lowers cGMP.
• Rhodopsin and transducin are embedded in the disk membranes in the
outer rod segment.
• cGMP-gated Na+ channels in the cell membrane of the outer rod
segment respond to the decrease in cGMP by closing and hyperpolarizing the membrane.
• The rod cell is unusual for an excitable cell in that the membrane is
partially depolarized (~ –30 mV) at rest (in darkness) and hyperpolarizes on stimulation.
Because the membrane is partially depolarized in the dark, its neurotransmitter glutamate is continuously released. Glutamate inhibits the optic nerve bipolar cells with which the rod cells synapse. By hyperpolarizing the rod cell membrane, light stops the release of glutamate, relieving inhibition of the optic nerve bipolar cell and thus initiating a signal into the brain.
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Medical Genetics
Behavioral Science/Social Sciences
Outer rod segment
Intradisk space
Rhodopsin
α Cytoplasm
γ Gt
β
cGMP PDE
cGMP
Light
Light Dark 5´GMP (inactive) + cGMP
Light
Na+
–30
Inner rod segment
Membrane potential (meV)
–35
Cell membrane 3 sec
Bipolar cell Light Figure I-10-2. Light-Activated Signal Transduction in the Retinal Rod Cell Figure I-10-2. Light-Activated Signal Transduction in the Retinal Rod Cell
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Vitamin A Deficiency A severe drought in portions of Kenya wiped out a family’s yam crop, their primary food staple. Within several months, a 3-year-old child in the family began to complain of being unable to see very well, especially at dusk or at night. Also, the child’s eyes were red due to constant rubbing because of dryness. Due to the ability of the liver to store vitamin A, deficiencies which are severe enough to result in clinical manifestations are unlikely to be observed, unless there is an extreme lack of dietary vitamin A over several months. Vitamin A deficiency is the most common cause of blindness and is a serious problem in developing countries. It has a peak incidence at age 3–5. In the United States, vitamin A deficiency is most often due to fat malabsorption or liver cirrhosis. Vitamin A deficiency results in night blindness (rod cells are responsible for vision in low light), metaplasia of the corneal epithelium, xerophthalmia (dry eyes), bronchitis, pneumonia, and follicular hyperkeratosis. The spots or patches noted in the eyes of patients with vitamin A deficiency are known as Bitot spots. Because vitamin A is important for differentiation of immune cells, deficiencies can result in frequent infections. β-carotene is the orange pigment in yams, sweet potatoes, carrots, and yellow squash. Upon ingestion, it can be cleaved relatively slowly to two molecules of retinal by an intestinal enzyme, and each retinal molecule is then converted to all-trans-retinol and then absorbed by interstitial cells. Therefore, it is an excellent source of vitamin A.
Note
Recall Question Resection of the terminal ileum in Crohn’s disease leads to deficiency of which of the following vitamins? A. Biotin B. Cyanocobalamin
If vitamin A is continuously ingested at levels greater than 15× RDA, toxicity develops; symptoms include excessive sweating, brittle nails, diarrhea, hypercalcemia, hepatotoxicity, vertigo, and nausea/vomiting. Unlike vitamin A, beta-carotene is not toxic at high levels.
C. Pyridoxine D. Riboflavin E. Thiamine Answer: B
VITAMIN K Vitamin K is required to introduce Ca2+ binding sites on several calcium- dependent proteins. The modification which introduces the Ca2+ binding site is a γ-carboxylation of glutamyl residue(s) in these proteins, often identified simply as the γ-carboxylation of glutamic acid. Nevertheless, this vitamin Kdependent carboxylation is a cotranslational modification occurring as the proteins are synthesized on ribosomes associated with the rough endoplasmic reticulum (RER) during translation.
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Biochemistry
HEPATOCYTE 5´
5´
3´
mRNA
3´
mRNA
Medical Genetics
Prothrombin
Ribosome on RER
Behavioral Science/Social Sciences
COO
Vitamin K γ-Carboxylation by γ-Glutamyl Carboxylase
–
NH2 Glutamic acid
Prothrombin γ-Carboxy Glutamic Acid (binds Ca2+)
Ribosome on RER COO–
NH2
COO–
COO– COO– Prothrombin
NH2
COO–
Secretion by exocytosis Blood Prothrombin
Figure I-10-3. Vitamin K–Dependent γ-Carboxylation of Prothrombin Figure Vitamin γ-Carboxylation of Prothrombin duringI-10-3. Translation onK–Dependent the Rough Endoplasmic Reticulum (RER) during Translation on the Rough Endoplasmic Reticulum (RER)
Examples of proteins undergoing this vitamin K–dependent carboxylation include the coagulation factors II (prothrombin), VII, IX, and X, as well as the anticoagulant proteins C and S. All these proteins require Ca2+ for their function. Vitamin K deficiency produces prolonged bleeding, easy bruising, and potentially fatal hemorrhagic disease. Conditions predisposing to a vitamin K deficiency include: • Fat malabsorption (bile duct occlusion) • Prolonged treatment with broad-spectrum antibiotics (eliminate
intestinal bacteria that supply vitamin K)
• Breast-fed newborns (little intestinal flora, breast milk very low in
vitamin K), especially in a home-birth where a postnatal injection of vitamin K may not be given
• Infants whose mothers have been treated with certain anticonvulsants
during pregnancy such as phenytoin (Dilantin)
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Vitamin K Deficiency A 79-year-old man living alone called his 72-year-old sister and then arrived at the hospital by ambulance complaining of weakness and having a rapid heartbeat. His sister said that he takes no medications and has a history of poor nutrition and poor hygiene. Physical examination confirmed malnourishment and dehydration. A stool specimen was positive for occult blood. He had a prolonged prothrombin time (PT), but his liver function tests (LFTs) were within normal range. He was given an injection of a vitamin that corrected his PT in 2 days. Poor nutrition and malnourishment, lack of medications, occult blood in the stool specimen, prolonged PT, and normal LFTs are all consistent with vitamin K deficiency. Without vitamin K, several blood clotting factors (prothrombin, X, IX, VII) are not γ-carboxylated on glutamate residues by the γ-glutamyl carboxylase during their synthesis (cotranslational modification) in hepatocytes. The PT returned to normal 2 days after a vitamin K injection.
Vitamin K deficiency should be distinguished from vitamin C deficiency. Table I-10-3. Vitamin K versus Vitamin C Deficiency Vitamin K Deficiency
Vitamin C Deficiency
Easy bruising, bleeding
Easy bruising, bleeding
Normal bleeding time
Increased bleeding time
Increased PT
Normal PT
Hemorrhagic disease with no connective tissue problems
• Gum hyperplasia, inflammation, loss of teeth • Skeletal deformity in children • Poor wound healing • Anemia
Associated with:
Associated with:
• Fat malabsorption
• Diet deficient in citrus fruit, green vegetables
• Long-term antibiotic therapy • Breast-fed newborns • Infant whose mother was taking anticonvulsant therapy during pregnancy
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H
HY Immunology
MY Part I
●
LY
Biochemistry
Biochemistry
Clinical Correlate Relative to the other proteins that undergo γ-carboxylation, protein C has Medical Genetics a short half-life. Thus, initiation of warfarin therapy may cause a transient hypercoagulable state. Behavioral Science/Social Sciences
Clinical Correlate Vitamin K (SC, IM, oral, or IV) is used to reverse bleeding from hypothrombinemia caused by excess warfarin.
Anticoagulant Therapy
HIGH YIEL
High-Yield
MEDIUM Warfarin and dicumarol antagonize the γ-carboxylation activity of YIELD vitamin K and thus act as anticoagulants. They interfere with the cotranslational LOWmodificaYIELD tion during synthesis of the precoagulation factors.
MEDIUM YIE
Once these proteins have been released into the bloodstream, vitamin K is no FUNDAMENTALS longer important for their subsequent activation and function.
FUNDAMENT
Related to this are 2 important points:
REINFORCEMENT
LOW Y
REINFORCEM
• Warfarin and dicoumarol prevent coagulation only in vivo and cannot
prevent coagulation of blood in vitro (drawn from a patient into a test tube).
• When warfarin and dicumarol are given to a patient, 2–3 days are
required to see their full anticoagulant activity. Heparin or low- molecular-weight heparin is often given to provide short-term anticoagulant activity. Heparin is an activator of antithrombin III.
VITAMIN E Vitamin E (α-tocopherol) is an antioxidant. As a lipid-soluble compound, it is especially important for protecting other lipids from oxidative damage. It prevents peroxidation of fatty acids in cell membranes, helping to maintain their normal fluidity. Vitamin E deficiency can lead to hemolysis, neurologic problems, and retinitis pigmentosa. High blood levels of vitamin E can cause hemorrhage in patients given warfarin.
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Chapter 10
●
Vitamins
Review Questions Select the ONE best answer. 1. Retinitis pigmentosa (RP) is a genetically heterogeneous disease characterized by progressive photoreceptor degeneration and ultimately blindness. Mutations in more than 20 different genes have been identified in clinically affected patients. Recent studies have mapped an RP locus to the chromosomal location of a new candidate gene at 5q31. One might expect this gene to encode a polypeptide required for the activity of a(n) A. receptor tyrosine kinase B. cGMP phosphodiesterase C. phospholipase C D. adenyl cyclase E. protein kinase C 2. A 27-year-old woman with epilepsy has been taking phenytoin to control her seizures. She is now pregnant, and her physician is considering changing her medication to prevent potential bleeding episodes in the infant. What biochemical activity might be deficient in the infant if her medication is continued? A. Hydroxylation of proline B. Glucuronidation of bilirubin C. Reduction of glutathione D. γ-Carboxylation of glutamate E. Oxidation of lysine 3. A 75-year-old woman is seen in the emergency room with a fractured arm. Physical examination revealed multiple bruises and perifollicular hemorrhages, periodontitis, and painful gums. Her diet consists predominately of weak coffee, bouillon, rolls, and plain pasta. Lab results indicated mild microcytic anemia. Which of the following enzymes should be less active than normal in this patient? A. Homocysteine methyltransferase B. γ-Glutamyl carboxylase C. Dihydrofolate reductase D. ALA synthase E. Prolyl hydroxylase
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Immunology
Part I Biochemistry
●
Biochemistry
Answers 1. Answer: B. Only phosphodiesterase participates as a signaling molecule in the visual cycle of photoreceptor cells.
Medical Genetics
2. Answer: D. Phenyl hydantoins decrease the activity of vitamin K, which is required for the γ-carboxylation of coagulation factors (II, VII, IX, X), as well as proteins C and S. Behavioral Science/Social Sciences
3. Answer: E. The patient has many signs of scurvy from a vitamin C deficiency. The diet, which contains no fruits or vegetables, provides little vitamin C. Prolyl hydroxylase requires vitamin C, and in the absence of hydroxylation, the collagen α-chains do not form stable, mature collagen. The anemia may be due to poor iron absorption in the absence of a scorbate.
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Energy Metabolism
11
Learning Objectives ❏❏ Explain information related to metabolic sources of energy ❏❏ Interpret scenarios about metabolic energy storage and fuel metabolism ❏❏ Answer questions about patterns of fuel metabolism in tissues
METABOLIC SOURCES OF ENERGY Energy is extracted from food via oxidation, resulting in the end products carbon dioxide and water. This process occurs in 4 stages. In stage 1, metabolic fuels are hydrolyzed in the gastrointestinal (GI) tract to a diverse set of monomeric building blocks (glucose, amino acids, and fatty acids) and absorbed. In stage 2, the building blocks are degraded by various pathways in tissues to a common metabolic intermediate, acetyl-CoA. • Most of the energy contained in metabolic fuels is conserved in the
chemical bonds (electrons) of acetyl-CoA.
• A smaller portion is conserved in reducing nicotinamide adenine
dinucleotide (NAD) to NADH or flavin adenine dinucleotide (FAD) to FADH2.
• Reduction indicates the addition of electrons that may be free, part of a
hydrogen atom (H), or a hydride ion (H–).
In stage 3, the citric acid (Krebs, or tricarboxylic acid [TCA]) cycle oxidizes acetyl-CoA to CO2. The energy released in this process is primarily conserved by reducing NAD to NADH or FAD to FADH2. The final stage is oxidative phosphorylation, in which the energy of NADH and FADH2 is released via the electron transport chain (ETC) and used by an ATP synthase to produce ATP. This process requires O2.
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Immunology
Part I
●
Biochemistry
Biochemistry
Stage Medical Genetics
I II
Carbohydrate
Protein
Fat
Glucose
Amino acids
Fatty acids
Pyruvate
Acetyl-CoA
Behavioral Science/Social Sciences
TCA Cycle
III
2 CO2
3 NADH & FADH2 IV
e–
ETC ATP synthase
ADP + Pi
O2 H 2O
ATP
Figure I-11-1. Figure I-11-1. Energy Energyfrom fromMetabolic MetabolicFuels Fuels
METABOLIC ENERGY STORAGE ATP is a form of circulating energy currency in cells. It is formed in catabolic pathways by phosphorylation of ADP and may provide energy for biosynthesis (anabolic pathways). There is a limited amount of ATP in circulation. Most of the excess energy from the diet is stored as fatty acids (a reduced polymer of acetyl CoA) and glycogen (a polymer of glucose). Although proteins can be mobilized for energy in a prolonged fast, they are normally more important for other functions (contractile elements in muscle, enzymes, intracellular matrix, etc.). In addition to energy reserves, many other types of biochemicals are required to maintain an organism. Cholesterol is required for cell membrane structure, proteins for muscle contraction, and polysaccharides for the intracellular matrix, to name just a few examples. These substances may be produced from transformed dietary components.
REGULATION OF FUEL METABOLISM The pathways that are operational in fuel metabolism depend on the nutritional status of the organism. Shifts between storage and mobilization of a particular fuel, as well as shifts among the types of fuel being used, are very pronounced in going from the well-fed state to an overnight fast, and finally to a prolonged state of starvation. The shifting metabolic patterns are regulated mainly by the insulin/glucagon ratio. Insulin is an anabolic hormone which promotes fuel
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Chapter 11
●
Energy Metabolism
storage. Its action is opposed by a number of hormones, including glucagon, epinephrine, cortisol, and growth hormone. The major function of glucagon is to respond rapidly to decreased blood glucose levels by promoting the synthesis and release of glucose into the circulation. Anabolic and catabolic pathways are controlled at 3 important levels: • Allosteric inhibitors and activators of rate-limiting enzymes • Control of gene expression by insulin and glucagon
• Phosphorylation (glucagon) and dephosphorylation (insulin) of
MY
rate-limiting enzymes
Well-Fed (Absorptive) State
HY
HY LY
High-Yield
Immediately after a meal, the blood glucose level rises MEDIUM and stimulates YIELD the release of insulin. The 3 major target tissues for insulin are liver, muscle, and YIELD adipose tissue. Insulin promotes glycogen synthesis in liver andLOW muscle. After the glycogen stores are filled, the liver converts excess glucose to fatty acids and triglycerides. Insulin promotes triglyceride synthesisFUNDAMENTALS in adipose tissue and protein synthesis in muscle, as well as glucose entry into both tissues. REINFORCEMENT After a meal, most of the energy needs of the liver are met by the oxidation of excess amino acids. Two tissues—brain and red blood cells—are insensitive to insulin (are insulinindependent). The brain and other nerves derive energy from oxidizingHY glucose to CO2 and water in both the well-fed and normal fasting states. OnlyMY in prolonged fasting does this situation change. Under all conditions, red blood cells LY use glucose anaerobically for all their energy needs.
Postabsorptive State
MY
High-Yield
Glucagon and epinephrine levels rise during an overnight fast. TheseYIELD hormones MEDIUM exert their effects on skeletal muscle, adipose tissue, and liver. In liver, glycogen LOW YIELD degradation and the release of glucose into the blood are stimulated. Hepatic gluconeogenesis is also stimulated by glucagon, but the response is slower than that of glycogenolysis. The release of amino acids from skeletal muscle and fatty FUNDAMENTALS acids from adipose tissue are both stimulated by the decrease in insulin and by REINFORCEMENT an increase in epinephrine. The amino acids and fatty acids are taken up by the liver, where the amino acids provide the carbon skeletons and the oxidation of fatty acids provides the ATP necessary for gluconeogenesis.
LY HIGH YIELD MEDIUM YIELD LOW YIELD FUNDAMENTALS REINFORCEMENT
HY MY LY HIGH YIELD MEDIUM YIELD LOW YIELD FUNDAMENTALS REINFORCEMENT
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Immunology
Part I
●
Biochemistry
Biochemistry
Medical Genetics
Behavioral Science/Social Sciences
Pyruvate
RED CELL
Lactate
Bile salts
Cholesterol
Fatty acids
Acetyl CoA
Fat
CO2
Glycerol-P
Lactate Pyruvate
Amino acids
ATP
Amino acids
Fatty acids Acetyl CoA
Pyruvate
Chylomicrons
ATP
Glucose
Glucose
Amino acids
Acetyl CoA Pyruvate
CO2
LIVER Glucose
Glucose
Urea
Glycerol VLDL FAT
Glucose
ATP
Bile
Glycerol-P
Glucose
GLYCOGEN
Blood
PROTEIN
CO2
Pyruvate Acetyl CoA CO2 ATP
ATP
Glucose
Glucose
GLYCOGEN
BRAIN
MUSCLE
ADIPOSE TISSUE Glucose
Figure I-11-2. Metabolic Profile of the Well-Fed (Absorptive) State Figure I-11-2. Metabolic Profile of the Well-Fed (Absorptive) State
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Chapter 11
RED CELL
Pyruvate
LIVER
Lactate
Glycerol-P
CO2 ATP
Glycerol
FAT
Fatty acids
CO2 ATP
ADIPOSE TISSUE
Fatty acids
Glucose
Pyruvate
CORI CYCLE Glycerol-P Glucose
Urea Ketone bodies Ketone bodies
Fatty acid albumins
Acetyl CoA
Acetyl CoA
Ketone bodies
Acetyl CoA
Energy Metabolism
ATP
Lactate
Fatty acids
●
Alanine
GLYCOGEN
Glucose Glucose Pyruvate
Alanine
Amino acids
Blood
Acetyl CoA CO2
PROTEIN
ATP
BRAIN CO2 ATP
MUSCLE
Figure I-11-3. Metabolic Profile of the Postabsorptive State Figure I-11-3. Metabolic Profile of the Postabsorptive State
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H
HY Immunology
MY Part I
●
LY
Biochemistry
Biochemistry
HIGH YIEL
High-Yield
Note
Prolonged Fast (Starvation)
Carbohydrate (4 kcal/gm)
YIELD Levels of glucagon and epinephrine are markedly elevatedMEDIUM during starvation. Lipolysis is rapid, resulting in excess acetyl-CoA that is used for ketone LOW YIELDsynthesis. Levels of both lipids and ketones are therefore increased in the blood. Muscle uses fatty acids as the major fuel, and the brain adapts to using ketones for some of its energy. FUNDAMENTALS
MEDIUM YIE
REINFORCEMENT After several weeks of fasting, the brain derives approximately 2/3 of its energy from ketones and 1/3 from glucose. The shift from glucose to ketones as the major fuel diminishes the amount of protein that must be degraded to support gluconeogenesis. There is no “energy-storage form” for protein because each protein has a specific function in the cell. Therefore, the shift from using glucose to ketones during starvation spares protein, which is essential for these other functions. Red blood cells (and renal medullary cells) that have few, if any, mitochondria continue to be dependent on glucose for their energy.
REINFORCEM
Protein (4 kcal/gm)
Medical Genetics
Fat (9 kcal/gm) Alcohol (7 kcal/gm) Behavioral Science/Social Sciences
Note A recommended 2,100-kcal diet consisting of 58% carbohydrate, 12% protein, and 30% fat content:
FUNDAMENT
PATTERNS OF FUEL METABOLISM IN TISSUES
0.58 × 2,100 kcal = 1,218 kcal
Fats are much more energy-rich than carbohydrates, proteins, or ketones. Complete combustion of fat results in 9 kcal/g compared with 4 kcal/g derived from carbohydrate, protein, and ketones. The storage capacity and pathways for utilization of fuels varies by organ and nutritional status of the organism as a whole.
1,218 kcal/4 kcal/g = 305 g
Table I-11-1. Preferred Fuels in the Well-Fed and Fasting States
305 g of carbohydrate
LOW Y
63 g of protein
Organ
Well-Fed
Fasting
0.12 × 2,100 = 252 kcal
Liver
Glucose and amino acids
Fatty acids
252 kcal/4 kcal/g = 63 g
Resting skeletal muscle
Glucose
Fatty acids, ketones
70 g of fat
Cardiac muscle
Fatty acids
Fatty acids, ketones
0.30 × 2,100 = 630 kcal
Adipose tissue
Glucose
Fatty acids
630 kcal/9 kcal/g = 70 g
Brain
Glucose
Glucose (ketones in prolonged fast)
Red blood cells
Glucose
Glucose
Liver Two major roles of the liver in fuel metabolism are to maintain a constant level of blood glucose under a wide range of conditions and to synthesize ketones when excess fatty acids are being oxidized. • After a meal, the glucose concentration in the portal blood is elevated. • The liver extracts excess glucose and uses it to replenish its glycogen
stores. Any glucose remaining in the liver is then converted to acetyl CoA and used for fatty acid synthesis.
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Energy Metabolism
• The increase in insulin after a meal stimulates both glycogen synthesis
and fatty acid synthesis in liver. The fatty acids are converted to triglycerides and released into the blood as very low-density lipoproteins (VLDLs). In the well-fed state, the liver derives most of its energy from the oxidation of excess amino acids.
• Between meals and during prolonged fasts, the liver releases glucose
into the blood. The increase in glucagon during fasting promotes both glycogen degradation and gluconeogenesis.
• Lactate, glycerol, and amino acids provide carbon skeletons for glucose
synthesis.
Adipose Tissue After a meal, the elevated insulin stimulates glucose uptake by adipose tissue. Insulin also stimulates fatty acid release from VLDL and chylomicron triglyceride (triglyceride is also known as triacylglycerol). • Lipoprotein lipase, an enzyme found in the capillary bed of adipose
tissue, is induced by insulin.
• The fatty acids that are released from lipoproteins are taken up by
adipose tissue and re-esterified to triglyceride for storage.
• The glycerol phosphate required for triglyceride synthesis comes from
glucose metabolized in the adipocyte.
• Insulin is also very effective in suppressing the release of fatty acids
from adipose tissue.
• During the fasting state, the decrease in insulin and the increase in
epinephrine activate hormone-sensitive lipase in fat cells, allowing fatty acids to be released into the circulation.
Recall Question In a prolonged state of starvation, which of the following is the major source of energy for muscles? A. Fatty acids B. Glucose C. Glycogen D. Ketones Answer: A
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Immunology
Part I
●
Biochemistry
Biochemistry
Skeletal Muscle Resting muscle
Medical Genetics
Behavioral Science/Social Sciences
The major fuels of skeletal muscle are glucose and fatty acids. Because of the enormous bulk, skeletal muscle is the body’s major consumer of fuel. After a meal, under the influence of insulin, skeletal muscle takes up glucose to replenish glycogen stores and amino acids that are used for protein synthesis. Both excess glucose and amino acids can also be oxidized for energy. In the fasting state, resting muscle uses fatty acids derived from free fatty acids in the blood. Ketones may be used if the fasting state is prolonged. In exercise, skeletal muscle may convert some pyruvate to lactate, which is transported by blood to be converted to glucose in the liver.
Clinical Correlate
Active muscle
Because insulin is necessary for adipose cells to take up fatty acids from triglycerides, high triglyceride levels in the blood may be an indicator of untreated diabetes.
The primary fuel used to support muscle contraction depends on the magnitude and duration of exercise as well as the major fibers involved. Skeletal muscle has stores of both glycogen and some triglycerides. Blood glucose and free fatty acids also may be used. • Fast-twitch muscle fibers have a high capacity for anaerobic glycolysis
but are quick to fatigue. They are involved primarily in short-term, high-intensity exercise.
• Slow-twitch muscle fibers in arm and leg muscles are well-vascularized
and primarily oxidative. They are used during prolonged, low-to- moderate intensity exercise and resist fatigue. Slow-twitch fibers and the number of their mitochondria increase dramatically in trained endurance athletes.
• Short bursts of high-intensity exercise are supported by anaerobic
glycolysis drawing on stored muscle glycogen.
• During moderately high, continuous exercise, oxidation of glucose and
fatty acids are both important, but after 1–3 hours of sustained continuous exercise muscle glycogen stores become depleted and the intensity of exercise declines to a rate that can be supported by oxidation of fatty acids.
Cardiac Muscle During fetal life, cardiac muscle primarily uses glucose as an energy source, but in the postnatal period there is a major switch to β-oxidation of fatty a cids. Thus, in humans, fatty acids serve as the major fuel for cardiac myocytes. When ketones are present during prolonged fasting, they are also used. Thus, not surprisingly, cardiac myocytes most closely parallel the skeletal muscle during extended periods of exercise. In patients with cardiac hypertrophy, this situation reverses to some extent. In the failing heart, glucose oxidation increases, and β-oxidation falls.
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Energy Metabolism
Brain Although the brain represents 2% of total body weight, it obtains 15% of the cardiac output, uses 20% of total O2, and consumes 25% of the total glucose. Therefore, glucose is the primary fuel for the brain. • Blood glucose levels are tightly regulated to maintain the concentration
levels that enable sufficient glucose uptake into the brain via GLUT 1 and GLUT 3 transporters.
• Because glycogen levels in the brain are minor, normal function
depends upon continuous glucose supply from the bloodstream.
• In hypoglycemic conditions (80 proteins MEDIUM YIELD that comprise the major complexes of oxidative phosphorylation, as well as 22 LOW YIELD tRNAs and 2 rRNAs. Mutations in these genes affect highly aerobic tissues (nerves, muscle), and the diseases exhibit characteristic mitochondrial pedigrees (maternal inheritance). FUNDAMENTALS
MEDIUM YIE
Key characteristics of most mitochondrial DNA (mtDNA) REINFORCEMENT diseases are lactic acidosis and massive proliferation of mitochondria in muscle, resulting in ragged red fibers. Examples of mtDNA diseases are:
REINFORCEM
• Leber hereditary optic neuropathy • Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) • Myoclonic epilepsy with ragged-red muscle fibers
LOW Y
FUNDAMENT
• Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes (MELAS)
• Leber hereditary optic neuropathy • Ragged-red muscle fiber disease
Coordinate Regulation of the Citric Acid Cycle and Oxidative Phosphorylation The rates of oxidative phosphorylation and the citric acid cycle are closely coordinated, and are dependent mainly on the availability of O2 and ADP. • If O2 is limited, the rate of oxidative phosphorylation decreases, and
the concentrations of NADH and FADH2 increase. The accumulation of NADH, in turn, inhibits the citric acid cycle. The coordinated regulation of these pathways is known as “respiratory control.”
• If O2 is adequate, the rate of oxidative phosphorylation depends on the
availability of ADP. The concentrations of ADP and ATP are reciprocally related; an accumulation of ADP is accompanied by a decrease in ATP and the amount of energy available to the cell. –– Therefore, ADP accumulation signals the need for ATP synthesis. –– ADP allosterically activates isocitrate dehydrogenase, thereby increasing the rate of the citric acid cycle and the production of NADH and FADH2. Elevated levels of these reduced coenzymes, in turn, increase the rate of electron transport and ATP synthesis.
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Chapter 13
●
Citric Acid Cycle and Oxidative Phosphorylation
Review Questions Select the ONE best answer. 1. During a myocardial infarction, the oxygen supply to an area of the heart is dramatically reduced, forcing the cardiac myocytes to switch to anaerobic metabolism. Under these conditions, which of the following enzymes would be activated by increasing intracellular AMP? A. Succinate dehydrogenase B. Phosphofructokinase-1 C. Glucokinase D. Pyruvate dehydrogenase E. Lactate dehydrogenase Items 2 and 3 A 40-year-old African American man is seen in the emergency room for a severe headache. His blood pressure is 180/110 mm Hg, and he has evidence of retinal hemorrhage. An infusion of nitroprusside is given. 2. Which of the following enzymes is affected most directly by the active metabolite of this drug? A. Phospholipase A2 B. Cyclic AMP phosphodiesterase C. Guanylate cyclase D. Cyclic GMP phosphodiesterase E. Phospholipase C 3. When nitroprusside is given in higher than usual doses, it may be accompanied by the administration of thiosulfate to reduce potential toxic side effects. Which complex associated with electron transport or oxidative phosphorylation is most sensitive to the toxic byproduct that may accumulate with high doses of nitroprusside? A. NADH dehydrogenase B. Succinate dehydrogenase C. Cytochrome b/c1
D. Cytochrome a/a3
E. F0F1 ATP synthase
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Immunology
Part I Biochemistry
Medical Genetics
●
Biochemistry
4. A patient has been exposed to a toxic compound that increases the permeability of mitochondrial membranes for protons. Which of the following events in liver cells would you expect to occur? A. Increased ATP levels B. Increased F1F0 ATP synthase activity
C. Increased oxygen utilization Behavioral Science/Social Sciences
D. Decreased malate-aspartate shuttle activity E. Decreased pyruvate dehydrogenase activity Items 5 and 6 A. Citrate shuttle B. Glycerolphosphate shuttle C. Malate-aspartate shuttle D. Carnitine shuttle E. Adenine nucleotide shuttle 5. Required for cholesterol and fatty acid synthesis in hepatocytes 6. Required for the hepatic conversion of pyruvate to glucose
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Chapter 13
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Citric Acid Cycle and Oxidative Phosphorylation
Answers 1. Answer: B. Both PFK-1 and LDH participate in extrahepatic anaerobic glycolysis, but only PFK-1 is regulated by allosteric effectors. 2. Answer: C. Nitroprusside is metabolized to produce nitric oxide. NO, normally produced by the vascular endothelium, stimulates the cyclase in vascular smooth muscle to increase cGMP, activate protein kinase G, and cause relaxation. 3. Answer: D. In addition to NO, metabolism of nitroprusside also releases small quantities of cyanide, a potent and potentially lethal inhibitor of cyt a/a3 (complex IV). Thiosulfate is a common antidote for CN poisoning. 4. Answer: C. The toxic agent (example, 2,4-dinitrophenol) would uncouple oxidative phosphorylation, leading to a fall in ATP levels, increased respiration, and increased substrate utilization. 5. Answer: A. Both fatty acids and cholesterol are synthesized from acetylCoA in the cytoplasm. Acetyl-CoA, which is produced in the mitochondria, is delivered to these pathways using the citrate shuttle. 6. Answer: C. Oxaloacetate, produced from pyruvate, exits the mitochondrion after conversion to malate.
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Glycogen, Gluconeogenesis, and the Hexose Monophosphate Shunt
14
Learning Objectives ❏❏ Interpret scenarios about glycogenesis and glycogenolysis ❏❏ Know how glycogen synthesis is regulated ❏❏ Know how glycogenolysis is regulated ❏❏ Know the glycogen storage diseases ❏❏ Solve problems concerning gluconeogenesis ❏❏ Use knowledge of hexose monophosphate shunt
GLYCOGENESIS AND GLYCOGENOLYSIS Glycogen, a branched polymer of glucose, represents a storage form of glucose. Glycogen synthesis and degradation occur primarily in liver and skeletal muscle, although other tissues such as cardiac muscle and the kidney store smaller quantities. Glycogen is stored in the cytoplasm as single granules (skeletal muscle) or as clusters of granules (liver). The granule has a central protein core with polyglucose chains radiating outward to form a sphere. • Glycogen granules composed entirely of linear chains have the highest
density of glucose near the core.
Figure I-14-1. Figure I-14-1. Glycogen Granule A glycogen granule
• If the chains are branched, glucose density is highest at the periphery
of the granule, allowing more rapid release of glucose on demand.
Glycogen stored in the liver is a source of glucose mobilized during hypoglycemia. Muscle glycogen is stored as an energy reserve for muscle contraction. In white (fast-twitch) muscle fibers, the glucose is converted primarily to lactate, whereas in red (slow-twitch) muscle fibers, the glucose is completely oxidized.
GLYCOGEN SYNTHESIS Synthesis of glycogen granules begins with a core protein glycogenin. Glucose addition to a granule begins with glucose 6-phosphate, which is converted to glucose 1-phosphate and activated to UDP-glucose for addition to the glycogen chain by glycogen synthase. Glycogen synthase is the rate-limiting enzyme of glycogen synthesis.
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Immunology
Part I
●
Biochemistry
Biochemistry
Medical Genetics
Behavioral Science/Social Sciences
Insulin (liver muscle) + Glycogen synthase (and branching enzyme)
Epinephrine (liver and muscle) Glucagon AMP (liver) muscle
Glycogen Pi
UDP
UDP-Glucose
+ + + Glycogen phosphorylase (and debranching enzyme)
PPi UTP
Glucose 1-P
Glucose 6-phosphatase (liver)
Glucose 6-P
Glucose
Glycolysis (ATP) (muscle) CO2+H2O
H
HY Lactate
Pyruvate
MY Figure I-14-2. Glycogen Metabolism Figure I-14-2. Glycogen Metabolism
LY
HIGH YIEL
High-Yield
Glycogen Synthase
Glycogen synthase forms the α1,4 glycosidic bond found in the linear glucose MEDIUM YIELD chains of the granule. Note the differences in the control of glycogen synthase in LOW YIELD the liver and skeletal muscle.
MEDIUM YIE
FUNDAMENTALS Table I-14-1. Comparison of Glycogen Synthase in Liver and Muscle REINFORCEMENT
FUNDAMENT
Glycogen Synthase
Liver
Skeletal Muscle
Activated by
Insulin
Insulin
Inhibited by
Glucagon, epinephrine
Epinephrine
LOW Y
REINFORCEM
Branching Enzyme (Glycosyl α1,4: α1,6 Transferase) Branching enzyme is responsible for introducing α1,6-linked branches into the granule as it grows. Branching enzyme: • Hydrolyzes one of the α1,4 bonds to release a block of oligoglucose,
which is then moved and added in a slightly different location
• Forms an α1,6 bond to create a branch
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Chapter 14
●
Glycogen, Gluconeogenesis, and the Hexose Monophosphate Shunt
α1,4 bond Core 1. Glycogen synthase makes a linear α1,4-linked polyglucose chain ( ). 2. Branching enzyme hydrolyzes an α1,4 bond. α1,6 bond Core 3. Transfers the oligoglucose unit and attaches it with an α1,6 bond to create a branch. 4. Glycogen synthase extends both branches. Figure I-14-3.Branching BranchingEnzyme Enzyme Figure I-14-3.
GLYCOGENOLYSIS
HY (in The rate-limiting enzyme of glycogenolysis is glycogen phosphorylase contrast to a hydrolase, a phosphorylase breaks bonds using Pi rather MY than H2O). The glucose 1-phosphate formed is converted to glucose 6-phosphate by LY the same mutase used in glycogen synthesis. High-Yield
Glycogen Phosphorylase
HY MY LY HIGH YIELD
Glycogen phosphorylase breaks α1,4 glycosidic bonds,MEDIUM releasing glucose YIELD 1-phosphate from the periphery of the granule. Control of the enzyme in liver LOW YIELD and muscle is compared below.
MEDIUM YIELD
Table I-14-2. Comparison of Glycogen Phosphorylase in Liver and Muscle FUNDAMENTALS
FUNDAMENTALS
Glycogen Phosphorylase
Liver
Skeletal Muscle REINFORCEMENT
Activated by
Epinephrine Glucagon
Epinephrine AMP Ca2+ (through calmodulin)
Inhibited by
Insulin
Insulin ATP
LOW YIELD
REINFORCEMENT
Glycogen phosphorylase cannot break α1,6 bonds and thus stops when it nears the outermost branch points.
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Immunology
Part I Biochemistry
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Biochemistry α1,4 bond nearest the branch point
Medical Genetics
Behavioral Science/Social Sciences
to core 1. Glycogen phosphorylase releases glucose 1-P from the periphery of the granule until it encounters the first branch points. 2. Debranching enzyme hydrolyzes the α1,4 bond nearest the branch point, as shown. α1,6 bond
to core
3. Transfers the oligoglucose unit to the end of another chain, then 4. Hydrolyzes the α1,6 bond releasing the single glucose from the former branch. Figure I-14-4. Debranching Enzyme Figure I-14-4. Debranching Enzyme
Debranching Enzyme (Glucosyl α1,4: α1,4 Transferase and α1,6 Glucosidase) Debranching enzyme deconstructs the branches in glycogen that have been exposed by glycogen phosphorylase. This is a 2-step process. Debranching enzyme: • Breaks an α1,4 bond adjacent to the branch point and moves the small
oligoglucose chain released to the exposed end of the other chain
• Forms a new α1,4 bond • Hydrolyzes the α1,6 bond, releasing the single residue at the branch
point as free glucose; this represents the only free glucose produced directly in glycogenolysis
GENETIC DEFICIENCIES OF ENZYMES IN GLYCOGEN METABOLISM Important genetic deficiencies are classed as glycogen storage diseases since all are characterized by an accumulation of glycogen.
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Glycogen, Gluconeogenesis, and the Hexose Monophosphate Shunt
Table I-14-3. Glycogen Storage Diseases Type
Deficient Enzyme
Cardinal Clinical Features
Glycogen Structure
I: von Gierke
Glucose-6-phosphatase
Severe hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, hyperuricemia, short stature, doll-like facies, protruding abdomen emaciated extremities
Normal
Lysosomal
Cardiomegaly, muscle weakness, death by 2 years
Glycogen-like material in inclusion bodies
II: Pompe
α1, 4-glucosidase III: Cori
Glycogen debranching enzyme
Mild hypoglycemia, liver enlargement
Short outer branches; single glucose residue at outer branch
IV: Andersen
Branching enzyme
Infantile hypotonia, cirrhosis, death by 2 years
Very few branches, especially toward periphery
V: McArdle
Muscle glycogen phosphorylase
Muscle cramps and weakness on HY exercise, myoglobinuria
Normal
VI: Hers
Hepatic glycogen phosphorylase
Mild fasting hypoglycemia, hepatomegaly, cirrhosis LY
Glucose-6-Phosphatase Deficiency (von Gierke Disease)
MY
High-Yield
MEDIUM YIELD
Deficiency of hepatic glucose-6-phosphatase produces a profound fasting LOW YIELD hypoglycemia, lactic acidosis, and hepatomegaly. Additional symptoms include: • Glycogen deposits in the liver (glucose 6-P stimulates glycogen syntheFUNDAMENTALS
sis, and glycogenolysis is inhibited)
REINFORCEMENT • Hyperuricemia predisposing to gout. Decreased Pi causes increased
AMP, which is degraded to uric acid. Lactate slows uric acid excretion in the kidney.
Normal
HY MY LY
Note HIGH YIELD Glycogen storage diseases are the MEDIUM YIELD favorite biochemistry topic of the exam. LOW YIELD Be sure to know: • Clinical features FUNDAMENTALS • Deficient enzyme REINFORCEMENT • Accumulating by-products
• Hyperlipidemia with skin xanthomas • Fatty liver
In a person with glucose-6-phosphatase deficiency, ingestion of galactose or fructose causes no increase in blood glucose, nor does administration of glucagon or epinephrine.
Lysosomal α1,4 Glucosidase Deficiency (Pompe Disease) Pompe disease is different from the other diseases described here because the enzyme missing is not one in the normal process of glycogenolysis. The deficient enzyme normally resides in the lysosome and is responsible for digesting glycogen-like material accumulating in endosomes. In this respect, it is more similar to diseases like Tay-Sachs or even I-cell disease in which indigestible substrates accumulate in inclusion bodies. In Pompe disease, the tissues most severely affected are those that normally have glycogen stores. With infantile onset, massive cardiomegaly is usually the cause of death, typically age 400 different mutations in the G6PDH gene are known). The disease is X-linked recessive. FUNDAMENTALS • Major symptom is an acute episodic or chronic hemolysis REINFORCEMENT (rare)
LOW Y
FUNDAMENT
REINFORCEM
• Female heterozygous for G6PDH deficiency have increased resistance
to malaria; consequently, the deficiency is often seen in families where malaria is endemic
Because red blood cells contain a large amount of oxygen, they are prone to spontaneously generate ROS that damage protein and lipid in the cell. In the presence of ROS, hemoglobin may precipitate (Heinz bodies) and membrane lipids may undergo peroxidation, weakening the membrane and causing hemolysis. As peroxides form, they are rapidly destroyed by the glutathione peroxidase/glutathione reductase system in the red blood cell, thus avoiding these complications. NADPH required by glutathione reductase is supplied by the HMP shunt in the erythrocyte. Persons with mutations that partially destroy G6PDH activity may develop an acute, episodic hemolysis. Certain mutations affect the stability of G6PDH, and, because erythrocytes cannot synthesize proteins, the enzyme is gradually lost over time and older red blood cells lyse. This process is accelerated by certain drugs and, in a subset of patients, ingestion of fava beans. In the United States, the most likely cause of a hemolytic episode in these patients is overwhelming infection, often pneumonia (viral and bacterial) or infectious hepatitis. In rare instances, a mutation may decrease the activity of G6PDH sufficiently to cause chronic nonspherocytic hemolytic anemia. Symptoms of CGD may also develop if there is insufficient activity of G6PDH (100 femtoliters (fL)
●●
PMN nucleus more than 5 lobes
●●
PMN nucleus more than 5 lobes
Homocysteinemia with risk for cardiovascular disease
●
Amino Acid Metabolism
Bridge to Pathology Vitamin B12 deficiency causes demyelination of the posterior columns and lateral corticospinal tracts in the spinal cord.
Homocysteinemia with risk for cardiovascular disease Methylmalonic aciduria Progressive peripheral neuropathy
Deficiency develops in 3–4 months Risk factors for deficiency: ●●
Pregnancy (neural tube defects in fetus may result)
Deficiency develops in years Risk factors for deficiency: ●●
Pernicious anemia
●●
Gastric resection
●●
Alcoholism
●●
Chronic pancreatitis
●●
Severe malnutrition
●●
Severe malnutrition
●●
Gastric or terminal ileum resection
●●
Vegan
●●
Infection with D. latum
●●
Aging
●●
●●
Bacterial overgrowth of the terminal ileum H. pylori infection
SPECIALIZED PRODUCTS DERIVED FROM AMINO ACIDS Table I-17-3. Products of Amino Acids Amino Acid
Products
Tyrosine
Thyroid hormones T3 and T4 Melanin Catecholamines
Tryptophan
Serotonin NAD, NADP
Arginine
Nitric oxide (NO)
Glutamate
γ-Aminobutyric acid (GABA)
Histidine
Histamine
HEME SYNTHESIS Heme synthesis occurs in almost all tissues because heme proteins include not only hemoglobin and myoglobin but all the cytochromes (electron transport chain, cytochrome P-450, cytochrome b5), as well as the enzymes catalase, peroxidase, and the soluble guanylate cyclase stimulated by nitric oxide. The pathway producing heme, as shown below, is controlled independently in different tissues. In liver, the rate-limiting enzyme δ-aminolevulinate synthase (ALA) is repressed by heme.
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Biochemistry
Biochemistry
Glycine + Succinyl-CoA ALA synthase B6 (mitochondria)
Medical Genetics
Repressed by heme
δ-Aminolevulinic acid Behavioral Science/Social Sciences
ALA dehydratase Porphobilinogen Porphobilinogen deaminase aka hydroxymethylbilane synthase
Note Compounds with an “-ogen” suffix, such as urobilinogen, are colorless substances. In the presence of oxygen, they spontaneously oxidize, forming a conjugated double-bond network in the compounds. These oxidized compounds are highly colored substances and have an “-in” suffix (e.g., porphobilin, urobilin).
Hydroxymethylbilane Uroporphyrinogen III synthase Uroporphyrinogen-III Uroporphyrinogen decarboxylase Coproporphyrinogen III
Protoporphyrin IX Fe2+
Ferrochelatase
Inhibited by lead (Pb)
Acute intermittent porphyria • Autosomal dominant, late onset • Episodic, variable expression • Anxiety, confusion, paranoia • Acute abdominal pain • No photosensitivity • Port-wine urine in some patients • Never give barbiturates
Porphyria cutanea tarda • Most common porphyria • Autosomal dominant late onset • Photosensitivity • Inflammation, blistering, shearing of skin in areas exposed to sunlight • Hyperpigmentation • Exacerbated by alcohol • Red-brown to deep-red urine Inhibited by lead (Pb)
H
HY
Heme Figure I-17-6. Heme Synthesis Figure I-17-5. Heme Synthesis
MY LY
High-Yield Acute Intermittent Porphyria: Porphobilinogen Deaminase (Hydroxymethylbilane MEDIUM YIELD Synthase) Deficiency LOW YIELD
HIGH YIEL
MEDIUM YIE
This late-onset autosomal dominant disease exhibits variable expression. Many heterozygotes remain symptom-free throughout their lives. Signs and sympFUNDAMENTALS toms, when present, include: • Abdominal pain, often resulting in multiple laparoscopies (scars on REINFORCEMENT abdomen)
LOW Y
FUNDAMENT
REINFORCEM
• Anxiety, paranoia, and depression
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• Paralysis • Motor, sensory or autonomic neuropathy • Weakness • Excretion of ALA (δ-aminolevulinic) and PBG (porphobilinogen)
during episodes
• In severe cases, dark port-wine color to urine on standing
HY
HY
Some of these individuals are incorrectly diagnosed and placed in psychiatric MY institutions. Episodes may be induced by hormonal changes and by many drugs, LY including barbiturates.
Other Porphyrias
MY LY HIGH YIELD
High-Yield
Deficiencies of other enzymes in the heme pathway produce porphyrias MEDIUM YIELD in which photosensitivity is a common finding. Chronic inflammation to overt LOW YIELD blistering and shearing in exposed areas of the skin characterize these porphyrias. The most common is porphyria cutanea tarda (deficiency of uroporphyrinogen decarboxylase), an autosomal dominant condition with late onset. FUNDAMENTALS β-Carotene is often administered to porphryia patients with photosensitivity to REINFORCEMENT reduce the production of reactive oxygen species.
MEDIUM YIELD LOW YIELD FUNDAMENTALS REINFORCEMENT
Porphyria cutanea tarda A 35-year-old man was becoming very sensitive to sunlight and often detected persistent rashes and blisters throughout areas of his body that were exposed to the sun. He also observed that drinking excessive alcohol with his friends after softball games worsened the incidence of the recurrent blisters and sunburns. He became even more concerned after he noticed his urine became a red-brown tint if he did not flush the toilet. Porphyria cutanea tarda is an adult-onset hepatic porphyria in which hepatocytes are unable to decarboxylate uroporphyrinogen in heme synthesis. The uroporphyrin spills out of the liver and eventually into urine, giving rise to the characteristic red-wine urine if it is allowed to stand, a HY or hallmark of porphyrias. Hepatotoxic substances, such as excessive alcohol iron deposits, can exacerbate the disease. Skin lesions are related to high MY circulating levels of porphyrins.
LY
Vitamin B6 Deficiency
High-Yield HY
ALA synthase, the rate-limiting enzyme, requires pyridoxine (vitamin MEDIUM YIELD MY B6). Deficiency of pyridoxine is associated with isoniazid therapy for tuberculosis LOW YIELD LY and may cause sideroblastic anemia with ringed sideroblasts.
Iron Deficiency
FUNDAMENTALS High-Yield
REINFORCEMENT The last enzyme in the pathway, heme synthase (ferrochelatase), introduces MEDIUM YIELD the 2+ Fe into the heme ring. Deficiency of iron produces a microcytic hypochromic LOW YIELD anemia. FUNDAMENTALS REINFORCEMENT
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Bridge to Pharmacology MY
Barbiturates are hydroxylated by the microsomal cytochrome LY P-450 system in the liver to facilitate their efficient elimination from the body. HIGH YIELD HYthe barbiturates Administration of results in stimulation of cytochrome MEDIUM YIELD MY P-450 synthesis, which in turn reduces LOW YIELD heme levels. The reduction in heme LY lessens the repression of ALA synthase, causing more porphyrin FUNDAMENTALS HIGH YIELD In porphyrias, the precursor synthesis. REINFORCEMENT indirect production MEDIUM YIELDof more precursors by the barbiturates exacerbates the disease. LOW YIELD
FUNDAMENTALS REINFORCEMENT
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Biochemistry
Medical Genetics
Lead inactivates many enzymes including ALA dehydraseMEDIUM and ferrochelatase YIELD (heme synthase), and can produce a microcytic sideroblastic anemia with ringed sideroblasts in the bone marrow. Other symptoms include:LOW YIELD • Coarse basophilic stippling of erythrocytes • Headache, nausea, memory loss
Behavioral Science/Social Sciences
HIGH YIEL
High-Yield
Lead Poisoning
• Abdominal pain, diarrhea (lead colic)
FUNDAMENTALS
REINFORCEMENT
MEDIUM YIE
LOW Y
FUNDAMENT
REINFORCEM
• Lead lines in gums • Lead deposits in abdomen and epiphyses of bone seen on radiograph • Neuropathy (claw hand, wrist-drop) • Increased urinary ALA • Increased free erythrocyte protoporphyrin
Clinical Correlate The failure of ferrochelatase to insert Fe2+ into protoporphyrin IX to form heme, such as in lead poisoning or iron deficiency anemia, results in the nonenzymatic insertion of Zn2+ to form zinc-protoporphyrin. This complex is extremely fluorescent and is easily detected.
Note Anemia is an important topic on the exam. Compare and contrast all anemias (differential diagnosis).
Vitamin B6 deficiency, iron deficiency, and lead poisoning all can cause anemia. Table I-17-4. Vitamin B6 Deficiency, Iron Deficiency, and Lead Poisoning Vitamin B6 (Pyridoxine) Deficiency
Iron Deficiency
Lead Poisoning
Microcytic
Microcytic
Microcytic Coarse basophilic stippling in erythrocyte
Ringed side roblasts in bone marrow
Ringed sideroblasts in bone marrow
Protoporphyrin: ↓
Protoporphyrin: ↑
Protoporphyrin: ↑
δ-ALA: ↓
δ-ALA: Normal
δ-ALA: ↑
Bridge to Pathology
Ferritin: ↑
Ferritin: ↓
Ferritin: ↑
Hemochromatosis is an i nherited, autosomal recessive disease (prevalence 1/200) generally seen in men age >40 and in older women. The disease is characterized by a daily intestinal absorption of 2–3 mg of iron compared with the normal 1 mg. Over 20–30 years, the disease results in levels of 20–30 grams of iron in the body (normal 4 grams). Hemosiderin deposits are found in the liver, pancreas, skin, and joints.
Serum iron: ↑
Serum iron: ↓
Serum iron: ↑
Isoniazid for tuberculosis
Dietary iron insufficient to compensate for normal loss
Lead paint Pottery glaze Batteries (Diagnose by measuring blood lead level)
IRON TRANSPORT AND STORAGE Iron (Fe3+) released from hemoglobin in the histiocytes is bound to ferritin and then transported in the blood by transferrin, which can deliver it to tissues for synthesis of heme. Important proteins in this context are: • Ferroxidase (also known as ceruloplasmin, a Cu2+ protein) oxidizes Fe2+ to Fe3+ for transport and storage. • Transferrin carries Fe3+ in blood.
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• Ferritin itself oxidizes Fe2+ to Fe3+ for storage of normal amounts of
Fe3+ in tissues. Loss of iron from the body is accomplished by bleeding and shedding epithelial cells of the mucosa and skin. The body has no mechanism for excreting iron, so controlling its absorption into the mucosal cells is crucial. No other nutrient is regulated in this manner.
• Hemosiderin binds excess Fe3+ to prevent escape of free Fe3+ into the
blood, where it is toxic.
Dietary Fe3+ Ferritin (Fe3+)
Vitamin C Fe2+
Mucosa
Fe2+
Fe2+
Ferritin (Fe3+)
Transferrin Fe3+
Fe2+ Most tissues Bone Erythropoiesis
= Transferrin receptor
Hb RBC
Many enzymes and cytochromes
Transferrin
RES cells Fe2+
RBC turnover
Figure I-17-7. Iron Metabolism Figure I-17-6. Iron Metabolism
BILIRUBIN METABOLISM Subsequent to lysis of older erythrocytes in the spleen, heme released from hemoglobin is converted to bilirubin in the histiocytes. • Bilirubin is not water-soluble and is therefore transported in the blood attached to serum albumin. • Hepatocytes conjugate bilirubin with glucuronic acid, increasing its
water solubility.
• Conjugated bilirubin is secreted into the bile. • Intestinal bacteria convert conjugated bilirubin into urobilinogen. • A portion of the urobilinogen is further converted to bile pigments
(stercobilin) and excreted in the feces, producing their characteristic red-brown color. Bile duct obstruction results in clay-colored stools.
• Some of the urobilinogen is converted to urobilin (yellow) and excreted
in urine.
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Clinical Correlate
Excessive RBC destruction in hemolytic anemia results in excessive conversion of bilirubin to urobilinogen in the Medical Genetics intestine. Higher-than-normal absorption of the urobilinogen and its subsequent excretion in the urine results in a deeper-colored urine. Behavioral Science/Social Sciences
Spleen
Heme Biliverdin Bilirubin Albumin
Blood
Bilirubin-albumin
Clinical Correlate At very high levels, lipid-soluble bilirubin may cross the blood-brain barrier and precipitate in the basal ganglia, causing irreversible brain damage (kernicterus).
Hemolysis of older RBC releases hemoglobin • Heme metabolized in histiocytes • Production of biliverdin releases carbon monoxide (CO)
Bilirubin
Liver
Conditions that increase indirect bilirubin • Hemolysis • Crigler-Najjar syndromes • Gilbert syndrome • Low levels of conjugation enzymes in newborn • Hepatic damage
UDP-Glucuronate UDP-glucuronyl transferase Bilirubin diglucuronide Intestine Urobilinogen Bile pigments (stercobilin)
Feces
Conditions that increase direct bilirubin • Hepatic damage • Bile duct obstruction (clay-colored stools) • Dubin-Johnson (black pigmentation in liver) • Rotor syndrome
Figure I-17-8. Heme Catabolism and Bilirubin Figure I-17-7. Heme Catabolism and Bilirubin
Recall Question Which substance is the human body unable to excrete? A. Biotin B. Cobalamine C. Iron D. Niacin Answer: C
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HY MY LY
Bilirubin and Jaundice
High-Yield
MY Chapter 17
●
AminoLYAcid Metabolism
HIGH YIELD
Jaundice (yellow color of skin, whites of the eyes) may occur MEDIUM when blood levels of YIELD bilirubin exceed normal (icterus). It may be characterized by an increase in unconLOW YIELD of jugated (indirect) bilirubin, conjugated (direct) bilirubin, or both. Accumulation bilirubin (usually unconjugated) in the brain (kernicterus) may result in death.
MEDIUM YIELD
FUNDAMENTALS When conjugated bilirubin increases, it may be excreted, giving a deep yellowred color to the urine. REINFORCEMENT
FUNDAMENTALS
LOW YIELD
REINFORCEMENT
Examples of conditions associated with increased bilirubin and jaundice include hemolytic crisis, UDP-glucuronyl transferase deficiency, hepatic damage, and bile duct occlusion.
Hemolytic crisis With severe hemolysis, more bilirubin is released into the blood than can be transported on albumin and conjugated in the liver. Unconjugated and total bilirubin increase and may produce jaundice and kernicterus. Examples i nclude: • Episode of hemolysis in G6PDH deficiency • Sickle cell crisis • Rh disease of newborn
Hemolytic crisis may be confirmed by low hemoglobin and elevated r eticulocyte counts.
UDP-glucuronyl transferase deficiency When bilirubin conjugation is low because of genetic or functional deficiency of the glucuronyl transferase system, unconjugated and total bilirubin increase. Examples include: • Crigler-Najjar syndromes (types I and II) • Gilbert syndrome • Physiologic jaundice in the newborn, especially premature infants
(enzymes may not be fully induced)
Hepatic damage Viral hepatitis or cirrhosis produces an increase in both direct and indirect bilirubin. Aminotransferase levels will also be elevated. • Alcoholic liver disease, AST increases more than ALT • Viral hepatitis, ALT increases more than AST
Bile duct occlusion Occlusion of the bile duct (gallstone, primary biliary cirrhosis, pancreatic cancer) prevents conjugated bilirubin from leaving the liver. Conjugated bilirubin increases in blood and may also appear in urine. Feces are light-colored.
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Biochemistry
Review Questions Select the ONE best answer.
Medical Genetics
Behavioral Science/Social Sciences
1. Which enzymes are responsible for producing the direct donors of nitrogen into the pathway producing urea? A. B. C. D. E.
Arginase and argininosuccinate lyase Xanthine oxidase and guanine deaminase Glutamate dehydrogenase and glutaminase Argininosuccinate synthetase and ornithine transcarbamoylase Aspartate aminotransferase and carbamoyl phosphate synthetase
2. Two days after a full-term normal delivery, a neonate begins to hyperventilate, develops hypothermia and cerebral edema, and becomes comatose. Urinalysis reveals high levels of glutamine and orotic acid. BUN is below normal. Which enzyme is most likely to be deficient in this child? A. B. C. D. E.
Cytoplasmic glutaminase Cytoplasmic carbamoyl phosphate synthetase Cytoplasmic orotidylate decarboxylase Mitochondrial carbamoyl phosphate synthetase Mitochondrial ornithine transcarbamoylase
Items 3 and 4 A 49-year-old man with a rare recessive condition is at high risk for deep vein thrombosis and stroke and has had replacement of ectopic lenses. He has a normal hematocrit and no evidence of megaloblastic anemia. 3. A mutation in the gene encoding which of the following is most likely to cause this disease? A. B. C. D. E.
Cystathionine synthase Homocysteine methyltransferase Fibrillin Lysyl oxidase Branched chain α-ketoacid dehydrogenase
4. Amino acid analysis of this patient’s plasma would most likely reveal an abnormally elevated level of A. B. C. D. E.
lysine leucine methionine ornithine cysteine
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5. A 56-year-old man with a history of genetic disease undergoes hip replacement surgery for arthritis. During the operation the surgeon notes a dark pigmentation (ochronosis) in the cartilage. His ochronotic arthritis is most likely caused by oxidation and polymerization of excess tissue A. B. C. D. E.
homogentisic acid orotic acid methylmalonic acid uric acid ascorbic acid
Items 6–8 Valine Isoleucine
C.
Propionyl-CoA F. Methylmalonyl-CoA
Glutamate
B.
G.
H. Succinate Isocitrate Maleylacetoacetate D. Homogentisate Malate Acetyl-CoA
Tyrosine
A.
E.
Pyruvate
Phenylalanine
I. Alanine
Figure SQ-XVII-2
For each of the conditions below, link the missing substrate or enzyme. 6. A 9-week-old boy, healthy at birth, begins to develop symptoms of ketoacidosis, vomiting, lethargy, seizures and hypertonia. Urine has characteristic odor of maple syrup. 7. A child with white-blond hair, blue eyes, and pale complexion is on a special diet in which one of the essential amino acids is severely restricted. He has been told to avoid foods artificially sweetened with aspartame. 8. A chronically ill patient on long-term (home) parenteral nutrition develops metabolic acidosis, a grayish pallor, scaly dermatitis, and alopecia (hair loss). These symptoms subside upon addition of the B vitamin biotin to the alimentation fluid.
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Biochemistry
9. A woman 7 months pregnant with her first child develops anemia. Laboratory evaluation indicates an increased mean cell volume (MVC), hypersegmented neutrophils, and altered morphology of several other cell types. The most likely underlying cause of this woman’s anemia is A. B. C. D. E.
folate deficiency iron deficiency glucose 6-phosphate dehydrogenase deficiency cyanocobalamin (B12) deficiency lead poisoning
Items 10 and 11 A 64-year-old woman is seen by a hematologist for evaluation of a macrocytic anemia. The woman was severely malnourished. Both homocysteine and methylmalonate were elevated in her blood and urine, and the transketolase level in her erythrocytes was below normal. 10. What is the best evidence cited that the anemia is due to a primary deficiency of cyanocobalamin (B12)? A. B. C. D. E.
Macrocytic anemia Elevated methylmalonate Low transketolase activity Elevated homocysteine Severe malnutrition
11. In response to a B12 deficiency, which of the additional conditions may develop in this patient if she is not treated? A. B. C. D. E.
Progressive peripheral neuropathy Gout Wernicke-Korsakoff Destruction of parietal cells Bleeding gums and loose teeth
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Items 12–15 B
citrate
C
D
A
E G malate
F
succinate
Link the following to the letters in the cycle. 12. Obligate activator of hepatic Figure pyruvateSQ-XVII-3 carboxylase in the postabsorptive state. 13. Product formed by argininosuccinate lyase during urea synthesis. 14. Substrate and energy source for synthesis of δ-aminolevulinate in the heme pathway. 15. Converted to glutamate in a reaction requiring the coenzyme form of pyridoxine (B6) 16. A 62-year-old man being treated for tuberculosis develops a microcytic, hypochromic anemia. Ferritin levels are increased, and marked sideroblastosis is present. A decrease in which of the following enzyme activities is most directly responsible for the anemia in this man? A. B. C. D. E.
Cytochrome oxidase Cytochrome P450 oxidase Pyruvate kinase δ-Aminolevulinate synthase Lysyl oxidase
17. A 48-year-old man developed abdominal colic, muscle pain, and fatigue. Following a 3-week hospitalization, acute intermittent porphyria was initially diagnosed based on a high level of urinary δ-aminolevulinic acid. Subsequent analysis of the patient’s circulating red blood cells revealed that 70% contained elevated levels of zinc protoporphyrin, and the diagnosis was corrected. The correct diagnosis is most likely to be A. B. C. D. E.
protoporphyria congenital erythropoietic porphyria lead poisoning barbiturate addiction iron deficiency
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18. A 3-week-old infant has been having intermittent vomiting and convulsions. She also has had episodes of screaming and hyperventilation. The infant has been lethargic between episodes. Tests reveal an expanded abdomen, and blood values show decreased citrulline amounts as well as a decreased BUN. What other clinical outcomes would be expected in this infant? A. B. C. D. E.
Decreased blood pH and uric acid crystals in urine Decreased blood pH and increased lactic acid in blood Increased blood glutamine and increased orotic acid in urine Increased blood ammonia and increased urea in urine Megaloblastic anemia and increased methylmalonic acid in blood
19. A 69-year-old male presents to his family physician with a complaint of recent onset difficulty in performing activities of daily living. He is a retired factory worker who last worked 4 years ago. Upon questioning, his spouse reveals that he “hasn’t been able to get around the way he used to.” Physical examination reveals a well-nourished 69-year-old man who walks with an exaggerated kyphosis. His gait appears to be quite slow and wide-based. He also appears to have a resting tremor. The appropriate management of his case would target which of the following? A. B. C. D. E.
Amino acid degradation Catecholamine synthesis Ganglioside degradation Prostaglandin synthesis Sphingolipid degradation
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Answers 1. Answer: E. Aspartate is produced by AST and carbamoyl phosphate by CPS-I. 2. Answer: E. Given these symptoms, the defect is in the urea cycle and the elevated orotate suggests deficiency of ornithine transcarbamoylase. 3. Answer: A. Homocysteine, the substrate for the enzyme, accumulates increasing the risk of deep vein thrombosis and disrupting the normal crosslinking of fibrillin. Deficiency of homocysteine methyltransferase would cause homocystinuria, but would also predispose to megaloblastic anemia. 4. Answer: C. Only methionine is degraded via the homocysteine/ cystathionine pathway and would be elevated in the plasma of a cystathionine synthase–deficient patient via activation of homocysteine methyltransferase by excess substrate. 5. Answer: A. Adults with alcaptonuria show a high prevalence of ochronotic arthritis due to deficiency of homogentisate oxidase. 6. Answer: C. Maple syrup urine disease; substrates are branched chain α-ketoacids derived from the branched chain amino acids. 7. Answer: E. The child has PKU; aspartame contains phenylalanine. These children may be blond, blue-eyed, and pale complected because of deficient melanin production from tyrosine. 8. Answer: F. The only biotin-dependent reaction in the diagram. The enzyme is propionyl-CoA carboxylase. 9. Answer: A. Pregnant woman with megaloblastic anemia and elevated serum homocysteine strongly suggests folate deficiency. Iron deficiency presents as microcytic, hypochromic anemia and would not elevate homocysteine. B12 deficiency is not most likely in this presentation. 10. Answer: B. Methylmalonyl-CoA mutase requires B12 but not folate for activity. Macrocytic anemia, elevated homocysteine, and macrocytic anemia can be caused by B12 or folate deficiency. 11. Answer: A. Progressive peripheral neuropathy. A distractor may be D, but this would be the cause of a B12 deficiency, not a result of it. 12. Answer: B. Acetyl-CoA activates pyruvate carboxylase and gluconeogenesis during fasting. 13. Answer: F. Fumarate. 14. Answer: E. Succinyl-CoA. 15. Answer: D. Glutamate is produced by B6-dependent transamination of α-ketoglutarate. 16. Answer: D. Sideroblastic anemia in a person being treated for tuberculosis (with isoniazid) is most likely due to vitamin B6 deficiency. δ-Aminolevulinate synthase, the first enzyme in heme synthesis, requires vitamin B6 (pyridoxine).
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Biochemistry
17. Answer: C. Lead inhibits both ferrochelatase (increasing the zinc protoporphyrin) and ALA dehydrase (increasing δ-ALA). 18. Answer: C. The infant has a defect in the urea cycle, resulting from ornithine transcarbamylase (OTC) deficiency. OTC deficiency would result in decreased intermediates of the urea cycle, including decreased urea formation as indicated by the decreased BUN. OTC can be diagnosed by elevated orotic acid since carbamyl phosphate accumulates in the liver mitochondria and spills into the cytoplasm entering the pyrimidinesynthesis pathway. Methylmalonic acid in blood (choice E) is seen in vitamin B12 disorders. A decreased BUN would result in elevated ammonia in blood, raising the pH (choices A and B). Decreased BUN means decreased blood urea, hence, decreased urea in urine (choice D). 19. Answer: B. The above case describes a patient with Parkinson’s disease, which is caused by degeneration of the substantia nigra. This leads to dopamine deficiency in the brain and results in resting tremors, bradykinesia, cog-wheeling of the hand joints, and rigidity of musculature. In addition, patients are often described as having “mask-like facies.” Dopamine is one of the catecholamines synthesized in a common pathway with norepinephrine and epinephrine. The diseases involving amino acid degradation (choice A), ganglioside degradation (choice C), and sphingolipid degradation (choice E) do not match the presentation seen in the case.
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18
Learning Objectives ❏❏ Explain information related to pyrimidine synthesis ❏❏ Explain information related to purine synthesis ❏❏ Demonstrate understanding of purine catabolism and the salvage enzyme HGPRT
OVERVIEW Nucleotides are needed for DNA and RNA synthesis (DNA replication and transcription) and for energy transfer. Nucleoside triphosphates (ATP and GTP) provide energy for reactions that would otherwise be extremely unfavorable in the cell. Ribose 5-phosphate for nucleotide synthesis is derived from the hexose monophosphate shunt and is activated by the addition of pyrophosphate from ATP, forming phosphoribosyl pyrophosphate (PRPP) using PRPP synthetase. Cells synthesize nucleotides in 2 ways: de novo synthesis and salvage pathways. • In de novo synthesis, which occurs predominantly in the liver, purines
and pyrimidines are synthesized from smaller precursors, and PRPP is added to the pathway at some point.
• In the salvage pathways, preformed purine and pyrimidine bases can
be converted into nucleotides by salvage enzymes distinct from those of de novo synthesis. Purine and pyrimidine bases for salvage enzymes may arise from: –– Synthesis in the liver and transport to other tissues –– Digestion of endogenous nucleic acids (cell death, RNA turnover)
In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis. In Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent or deficient. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation. Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. Patients also all have hyperuricemia because purines cannot be salvaged, causing gout.
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Immunology
Part I
●
Biochemistry
Biochemistry
HMP shunt
Medical Genetics
Ribose 5-P ATP
Behavioral Science/Social Sciences
P
O R
OH
PRPP synthetase
Phosphoribosylpyrophosphate (PRPP)
P
O R
P P
Purines Pyrimidines De novo synthesis
Salvage pathways
Nucleotides
P
Base O R
DNA, RNA Figure I-18-1. Nucleotide Synthesis Figure I-18-1. Nucleotide Synthesis and De Novo Pathways by Salvage and by DeSalvage Novo Pathways
PYRIMIDINE SYNTHESIS Pyrimidines are synthesized de novo in the cytoplasm from aspartate, CO2, and glutamine. Synthesis involves a cytoplasmic carbamoyl phosphate synthetase that differs from the mitochondrial enzyme with the same name used in the urea cycle.
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Chapter 18
Orotic Aciduria Several days after birth, an infant was observed to have severe anemia, which was found to be megaloblastic. There was no evidence of hepatomegaly or splenomegaly. The newborn was started on a bottle-fed regimen containing folate, vitamin B12, vitamin B6, and iron. One week later the infant’s condition did not improve. The pediatrician noted that the infant’s urine contained a crystalline residue, which was analyzed and determined to be orotic acid. Lab tests indicated no evidence of hyperammonemia. The infant was given a formula which contained uridine. Shortly thereafter, the infant’s condition improved significantly. Orotic aciduria is an autosomal recessive disorder caused by a defect in uridine monophosphate (UMP) synthase. This enzyme contains two activities, orotate phosphoribosyltransferase and orotidine decarboxylase. The lack of pyrimidines impairs nucleic acid synthesis needed for hematopoiesis, explaining the megaloblastic anemia in this infant. Orotic acid accumulates and spills into the urine, resulting in orotic acid crystals and orotic acid urinary obstruction. The presence of orotic acid in urine might suggest that the defect could be ornithine transcarbamylase (OTC) deficiency, but the lack of hyperammonemia rules out a defect in the urea cycle. Uridine administration relieves the symptoms by bypassing the defect in the pyrimidine pathway. Uridine is salvaged to UMP, which feedback-inhibits carbamoyl phosphate synthase-2, preventing orotic acid formation.
●
Purine and Pyrimidine Metabolism
Note Two Orotic Acidurias • Hyperammonemia (no megaloblastic anemia) –– Pathway: urea cycle –– Enzyme deficient: OTC • Megaloblastic anemia (no hyperammonemia) –– Pathway: pyrimidine synthesis –– Enzyme deficient: UMP synthase Folate and B12 deficiency (megaloblastic anemia but no orotic aciduria)
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Part I
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Biochemistry
Biochemistry
Carbamoyl phosphate CO2 + glutamine synthetase-2 +ATP (Cytoplasm)
Medical Genetics
Aspartate
Carbamoyl phosphate
Orotic acid PRPP
UMP synthase CO2
Behavioral Science/Social Sciences
UMP UDP
Bridge to Pharmacology
Hydroxyurea
Cotrimoxazole contains the synergistic antibiotics sulfamethoxazole and trimethoprim, which inhibit different steps in the prokaryotic synthesis of tetrahydrofolate.
sulfamethoxazole
Ribonucleotide reductase dUDP
CTP
dUMP N5N10 methylene THF THF
PABA
–
Dihydrofolate reductase –
DHF
Thymidylate synthase – dTMP
5-Fluorouracil
Methotrexate (eukaryotic) Trimethoprim (prokaryotic) Pyrimethamine (protozoal)
folic acid
Figure I-18-2. De Novo Pyrimidine Synthesis Figure I-18-2. De Novo Pyrimidine Synthesis DHF
trimethoprim THF
The primary end product of pyrimidine synthesis is UMP. In the conversion of UMP to dTMP, 3 important enzymes are ribonucleotide reductase, thymidylate synthase, and dihydrofolate reductase; all are targets of antineoplastic drugs.
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Chapter 18
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Purine and Pyrimidine Metabolism
Table I-18-1. Important Enzymes of Pyrimidine Synthesis Enzyme
Function
Drug
Ribonucleotide reductase
Reduces all NDPs to dNDPs for DNA synthesis
Hydroxyurea (S phase)
Thymidylate synthase
Methylates dUMP to dTMP
5-Fluorouracil (S phase)
Dihydrofolate reductase (DHFR)
Converts DHF to THF Without DHFR, thymidylate synthesis will eventually stop
Requires THF Methotrexate (eukaryotic) (S phase)
HY
Trimethoprim (prokaryotic)
MY
Pyrimethamine (protozoal)
HY MY
LY High-Yield
Ribonucleotide Reductase
Ribonucleotide reductase is required for the formation of the deoxyribonucleoMEDIUM YIELD tides for DNA synthesis. • All 4 nucleotide substrates must be diphosphates.
LOW YIELD
• dADP and dATP strongly inhibit ribonucleotide reductase. FUNDAMENTALS • Hydroxyurea, an anticancer drug, blocks DNA synthesis indirectly by REINFORCEMENT
inhibiting ribonucleotide reductase. UDP CDP ADP GDP
Ribonucleotide reductase –
Hydroxyurea
dUDP dCDP dADP dGDP
dUMP
LY HIGH YIELD MEDIUM YIELD LOW YIELD FUNDAMENTALS REINFORCEMENT
dTMP
dADP, dATP
Figure I-18-3. Ribonucleotide Reductase Figure I-18-3. Ribonucleotide Reductase
PYRIMIDINE CATABOLISM Pyrimidines may be completely catabolized (NH4+ is produced) or recycled by pyrimidine salvage enzymes.
PURINE SYNTHESIS Purines are synthesized de novo beginning with PRPP. The most important enzyme is PRPP amidotransferase, which catalyzes the first and rate-limiting reaction of the pathway. It is inhibited by the 3 purine nucleotide end products AMP, GMP, and IMP.
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Immunology
Part I
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Biochemistry
Biochemistry
Medical Genetics
The drugs allopurinol (used for gout) and 6-mercaptopurine (antineoplastic) also inhibit PRPP amidotransferase. These drugs are purine analogs which must be converted to their respective nucleotides by HGPRT within cells. • The amino acids glycine, aspartate, and glutamine are used in purine
synthesis.
• Tetrahydrofolate is required for synthesis of all the purines. Behavioral Science/Social Sciences
• Inosine monophosphate (contains the purine base hypoxanthine) is the
precursor for AMP and GMP.
Ribose 5-Phosphate
Bridge to Microbiology
PRPP synthetase
Protozoan and multicellular parasites and many obligate parasites, such as Chlamydia, cannot synthesize purines de novo because they lack the necessary genes in the purine pathway. However, they have elaborate salvage mechanisms for acquiring purines from the host to synthesize their own nucleic acids to grow.
PRPP AMP IMP
GMP
P
_
O R
P P
Allopurinol nucleotide
_ PRPP amidotransferase
5-Phosphoribosylamine
P
6-Mercaptopurine nucleotide
NH2 O R
Glycine, aspartate, glutamine THF as carbon donor Inosine P monophosphate (IMP) Amino from glutamine
O R
Hypoxanthine
Amino from aspartate
GMP
AMP
Allopurinol 6-mercaptopurine
HGPRT
Allopurinol nucleotide 6-Mercaptopurine nucleotide
PRPP Figure I-18-4. DeDeNovo Figure I-18-4. NovoPurine Purine Synthesis Synthesis
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Purine and Pyrimidine Metabolism
PURINE CATABOLISM AND THE SALVAGE ENZYME HGPRT Excess purine nucleotides or those released from DNA and RNA by nucleases are catabolized first to nucleosides (loss of Pi) and then to free purine bases (release of ribose or deoxyribose). Excess nucleoside monophosphates may accumulate when: • RNA is normally digested by nucleases (mRNAs and other types of
RNAs are continuously turned over in normal cells).
• Dying cells release DNA and RNA, which is digested by nucleases. • The concentration of free Pi decreases as it may in galactosemia,
hereditary fructose intolerance, and glucose-6-phosphatase deficiency.
Salvage enzymes recycle normally about 90% of these purines, and 10% are converted to uric acid and excreted in urine. When purine catabolism is increased significantly, a person is at risk for developing hyperuricemia and potentially gout. Purine catabolism to uric acid and salvage of the purine bases hypoxanthine (derived from adenosine) and guanine are shown below.
AMP
ATP, GTP High-energy compounds DNA and RNA
IMP GMP
Pi AMP
HGPRT deficiency (Lesch-Nyhan syndrome) • Spastic cerebral palsy • Self-mutilation (hands, lips) • Hyperuricemia and gout • Early death • X-linked (recessive)
Ribose-P
NH3 Adenosine
Adenosine deaminase
Inosine
Hypoxanthine Purine nucleoside phosphorylase and or
Pi
Xanthine
Ribose-P
Allopurinol Adenosine deaminase (ADA) deficiency • Severe combined immunodeficiency • Autosomal recessive
90%
Guanine
Guanosine
GMP
Salvage pathway HGPRT (HPRT)
Dietary purines converted to uric acid by enterocytes and added to the blood for excretion in the urine
–
Excretion pathway Xanthine oxidase 10%
Uric acid
FigureI-18-5. I-18-5.Purine PurineExcretion Excretionand andSalvage SalvagePathways Pathways Figure
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H
HY Immunology
MY Part I
●
LY
Biochemistry
Biochemistry
Medical Genetics
Bridge to Pharmacology
HIGH YIEL
High-Yield
Adenosine Deaminase Deficiency
Adenosine deaminase (ADA) deficiency, an autosomal MEDIUM recessiveYIELD disorder, causes a type of severe combined immunodeficiency (SCID). Lacking both LOWorganisms YIELD B-cell and T-cell function, children are multiply infected with many (Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. ExperiFUNDAMENTALS mental gene therapy trials have not yet yielded completely successful cures. REINFORCEMENT
Thiazide diuretics (hydrochlorothiazide and chlorthalidone) may cause hyperuricemia.
High levels of dATP accumulate in red cells of ADA patients and inhibit ribonucleotide reductase, thereby inhibiting the production of other HY essential deoxynucleotide precursors for DNA synthesis (see Figure I-18-3). Although MY it is believed that the impaired DNA synthesis contributes to dysfunction of T cells LY and B cells, it is not known why the main effects are limited to these cell types.
Bridge to Pathology
Hyperuricemia and Gout
Treatment of large tumors with chemotherapeutic regimens or radiation may cause “turnor lysis syndrome” and excessive excretion of uric acid, resulting in gout. The cause of the excessive uric acid is the destruction of the cancer cell’s nucleic acid into purines undergoing turnover.
Hyperuricemia may be produced by overproduction of uric acid or underexcretion MEDIUM YIELD of uric acid by the kidneys. Hyperuricemia may progress to acute and chronic gouty LOW YIELD arthritis if uric acid (monosodium urate) is deposited in joints and surrounding soft tissue, where it causes inflammation. Uric acid is produced from excess endogenous purines as shown in Figure I-18-5, and is also produced from dietary purines FUNDAMENTALS (digestion of nucleic acid in the intestine) by intestinal epithelia. Both sources of REINFORCEMENT uric acid are transported in the blood to the kidneys for excretion in urine.
Behavioral Science/Social Sciences
Clinical Correlate Gout Acute gouty arthritis, seen most commonly in males, results from precipitation of monosodium urate crystals in joints. The crystals, identified as negatively birefringent and needle-shaped, initiate neutrophil-mediated and acute inflammation, often first affecting the big toe. Chronic gout may manifest over time as tophi (deposits of monosodium urate) in soft tissue around joints, leading to chronic inflammation involving granulomas. • Acute attacks of gout are treated with colchicine or indomethacin to reduce the inflammation.
MEDIUM YIE
LOW Y
FUNDAMENT
REINFORCEM
H
HIGH YIEL
High-Yield
MEDIUM YIE
LOW Y
FUNDAMENT
REINFORCEM
Allopurinol inhibits xanthine oxidase and also can reduce purine synthesis by inhibiting PRPP amidotransferase, provided HGPRT is active (see Figure I-18-4). Hyperuricemia and gout often accompany the following conditions: • Lesch-Nyhan syndrome (no purine salvage) • Partial deficiency of HGPRT • Alcoholism (lactate and urate compete for same transport system in
the kidney)
• Glucose 6-phosphatase deficiency • Hereditary fructose intolerance (aldolase B deficiency) • Galactose 1-phosphate uridyl transferase deficiency (galactosemia) • Mutations in PRPP synthetase that lower Km
H
HY
In the last 2 diseases, phosphorylated sugars accumulate, decreasing the MYavailable Pi and increasing AMP (which cannot be phosphorylated to ADP and LY ATP). The excess AMP is converted to uric acid.
Lesch-Nyhan Syndrome
High-Yield
Lesch-Nyhan syndrome is an X-linked recessive condition involving: MEDIUM YIELD
• Chronic hyperuricemia, because of underexcretion, is treated with a uricosuric drug (probenecid).
• Near-complete deficiency of HGPRT activity
• Overproduction of uric acid and chronic gout are treated with allopurinol.
• Hyperuricemia
HIGH YIEL
MEDIUM YIE
LOW YIELD
LOW Y
• Mental retardation FUNDAMENTALS • Spastic cerebral palsy with compulsive biting of hands and lips REINFORCEMENT
FUNDAMENT
REINFORCEM
• Death often in first decade
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Purine and Pyrimidine Metabolism
Over 100 distinct mutations of the HGPRT gene located on the X chromosome have been reported to give rise to Lesch-Nyhan syndrome. These mutations include complete deletions of the gene, point mutations that result in an increased Km for hypoxanthine and guanine for the enzyme, and mutations that cause the encoded enzyme to have a short half-life.
Lesch-Nyhan Syndrome The parents of a 9-month-old infant were concerned that their son appeared generally weak, had difficulty moving his arms and legs, repeatedly bit his lips, and frequently seemed to be in pain. The infant was brought to the pediatrician. The parents mentioned that since the baby was born, they often noticed tiny, orange-colored particles when they changed the infant’s diapers. Lab analysis of uric acid in urine was normalized to the urinary creatinine in the infant, and it was found that the amount was 3 times greater than the normal range. One of the earliest signs of Lesch-Nyhan syndrome is the appearance of orange crystals in diapers. They are needle-shaped sodium urate crystals. Without the salvaging of hypoxanthine and guanine by HGPRT, the purines are shunted toward the excretion pathway. This is compounded by the lack of regulatory control of the PRPP amidotransferase in the purine synthesis pathway, resulting in the synthesis of even more purines in the body. The large amounts of urate will cause crippling, gouty arthritis and urate nephropathy. Renal failure is usually the cause of death. Treatment with allopurinol will ease the amount of urate deposits formed.
Bridge to Pharmacology Febuxostat is a nonpurine inhibitor of xanthine oxidase.
Bridge to Medical Genetics There are a large number of known mutations in the HGPRT gene. These have varying effects on the Km for the enzyme product, generating varying degrees of severity. This concept is known as allelic heterogeneity.
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Immunology
Part I Biochemistry
●
Biochemistry
Review Questions Select the ONE best answer.
Medical Genetics
Behavioral Science/Social Sciences
1. A 6-month-old boy becomes progressively lethargic and pale and shows delayed motor development. Laboratory evaluation reveals normal blood urea nitrogen (BUN), low serum iron, hemoglobin 4.6 g/dL, and leukopenia. His bone marrow shows marked megaloblastosis, which did not respond to treatment with iron, folic acid, vitamin B12, or pyridoxine. His urine developed abundant white precipitate identified as orotic acid. The underlying defect causing the megaloblastic anemia in this child is most likely in which of the following pathways? A. Homocysteine metabolism B. Pyrimidine synthesis C. Urea synthesis D. Uric acid synthesis E. Heme synthesis 2. Patients with Lesch-Nyhan syndrome have hyperuricemia, indicating an increased biosynthesis of purine nucleotides, and markedly decreased levels of hypoxanthine phosphoribosyl transferase (HPRT). The hyperuricemia can be explained on the basis of a decrease in which regulator of purine biosynthesis? A. ATP B. GDP C. Glutamine D. IMP E. PRPP 3. A 12-week-old infant with a history of persistent diarrhea and candidiasis is seen for a respiratory tract infection with Pneumocystis jiroveci. A chest x-ray confirms pneumonia and reveals absence of a thymic shadow. Trace IgG is present in his serum, but IgA and IgM are absent. His red blood cells completely lack an essential enzyme in purine degradation. The product normally formed by this enzyme is A. guanine monophosphate B. hypoxanthine C. inosine D. xanthine E. xanthine monophosphate
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Purine and Pyrimidine Metabolism
Items 4 and 5 The anticancer drug 6-mercaptopurine is deactivated by the enzyme xanthine oxidase. A cancer patient being treated with 6-mercaptopurine develops hyperuricemia, and the physician decides to give the patient allopurinol. 4. What effect will allopurinol have on the activity of 6-mercaptopurine? A. Enhanced deactivation of 6-mercaptopurine B. Enhanced elimination of 6-mercaptopurine as uric acid C. Enhanced retention and potentiation of activity D. Decreased inhibition of PRPP glutamylamidotransferase 5. Resistance of neoplastic cells to the chemotherapeutic effect of 6-mercaptopurine would most likely involve loss or inactivation of a gene encoding A. thymidylate synthase B. hypoxanthine phosphoribosyltransferase C. purine nucleoside pyrophosphorylase D. orotic acid phosphoribosyltransferase E. adenosine deaminase
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Part I Biochemistry
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Biochemistry
Answers 1. Answer: B. Accumulation of orotic acid indicates megaloblastic anemia arises because pyrimidines are required for DNA synthesis.
Medical Genetics
Behavioral Science/Social Sciences
2. Answer: D. IMP is a feedback inhibitor of PRPP amidophosphoribosyl transferase, the first reaction in the biosynthesis of purines. IMP is formed by the HPRT reaction in the salvage of hypoxanthine. 3. Answer: C. The child most likely has severe combined immunodeficiency caused by adenosine deaminase deficiency. This enzyme deaminates adenosine (a nucleoside) to form inosine (another nucleoside). Hypoxanthine and xanthine are both purine bases, and the monophosphates are nucleotides. 4. Answer: C. Because allopurinol inhibits xanthine oxidase, the 6-mercaptopurine will not be deactivated as rapidly. 5. Answer: B. HPRT is required for activation of 6-mercaptopurine to its ribonucleotide and inhibition of purine synthesis. The other enzymes listed are not targets for this drug.
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PART II
Medical Genetics
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Single-Gene Disorders
1
Learning Objectives ❏❏ Interpret scenarios about basic definitions ❏❏ Use knowledge of major modes of inheritance ❏❏ Understand important principles that can characterize single-gene diseases
BASIC DEFINITIONS Chromosomes Humans are composed of 2 groups of cells: • Gametes. Ova and sperm cells, which are haploid, have one copy of each
type of chromosome (1–22, X or Y). This DNA is transmitted to offspring.
• Somatic cells (cells other than gametes). Nearly all somatic cells are diploid,
having 2 copies of each type of autosome (1–22) and either XX or XY.
Diploid cells • Homologous chromosomes. The 2 chromosomes in each diploid pair
are said to be homologs, or homologous chromosomes. They contain the same genes, but because one is of paternal origin and one is of maternal origin, they may have different alleles at some loci.
• X and Y chromosomes, or the sex chromosomes, have some homolo-
gous regions but the majority of genes are different. The regions that are homologous are sometimes referred to as pseudoautosomal regions. During meiosis-1 of male spermatogenesis, the X and Y chromosomes pair in the pseudoautosomal regions, allowing the chromosomes to segregate into different cells.
Genes • Gene. Physically a gene consists of a sequence of DNA that encodes a
Note • Gene: basic unit of inheritance • Locus: location of a gene on a chromosome • Allele: different forms of a gene • Genotype: alleles found at a locus • Phenotype: physically observable features • Homozygote: alleles at a locus are the same • Heterozygote: alleles at a locus are different • Dominant: requires only one copy of the mutation to produce disease • Recessive: requires 2 copies of the mutation to produce disease
specific protein (or a nontranslated RNA; for example: tRNA, rRNA, or snRNA).
• Locus. The physical location of a gene on a chromosome is termed a locus. • Alleles. Variation (mutation) in the DNA sequence of a gene produces
a new allele at that locus. Many genes have multiple alleles.
• Polymorphism. When a specific site on a chromosome has multiple
alleles in the population, it is said to be polymorphic (many forms).
Note Although the term alleles is used most frequently with genes, noncoding DNA can also have alleles of specific sequences.
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Medical Genetics
For example, the β-globin gene encodes a protein (β-globin). It has been mapped to chromosome 11p15.5 indicating its locus, a specific location on chromosome 11. Throughout human history there have been many mutations in the β-globin gene, and each mutation has created a new allele in the population. The β-globin locus is therefore polymorphic. Some alleles cause no clinical disease, but others, like the sickle cell allele, are associated with significant disease. Included among the disease-causing alleles are those associated with sickle cell anemia and several associated with β-thalassemia.
Genotype The specific DNA sequence at a locus is termed a genotype. In diploid somatic cells a genotype may be: • Homozygous if the individual has the same allele on both homologs
(homologous chromosomes) at that locus.
• Heterozygous if the individual has different alleles on the two
homologs (homologous chromosomes) at that locus.
Note
Phenotype
Major types of single-gene mutations:
The phenotype is generally understood as the expression of the genotype in terms of observable characteristics.
• Missense • Nonsense • Deletion • Insertion • Frameshift
Mutations A mutation is an alteration in DNA sequence (thus, mutations produce new alleles). When mutations occur in cells giving rise to gametes, the mutations can be transmitted to future generations. Missense mutations result in the substitution of a single amino acid in the polypeptide chain (e.g., sickle cell disease is caused by a missense mutation that produces a substitution of valine for glutamic acid in the β-globin polypeptide). Nonsense mutations produce a stop codon, resulting in premature termination of translation and a truncated protein. Nucleotide bases may be inserted or deleted. When the number of inserted or deleted bases is a multiple of 3, the mutation is said to be in-frame. If not a multiple of 3, the mutation is a frameshift, which alters all codons downstream of the m utation, typically producing a truncated or severely altered protein product. Mutations can occur in promoter and other regulatory regions or in genes for transcription factors that bind to these regions. This can decrease or increase the amount of gene product produced in the cell. (For a complete description of these and other mutations, see Section I, Chapter 4: Translation; Mutations.) Mutations can also be classified according to their phenotypic effects. Mutations that cause a missing protein product or cause decreased activity of the protein are termed loss-of-function. Those that produce a protein product with a new function or increased activity are termed gain-of-function.
Recurrence risk The recurrence risk is the probability that the offspring of a couple will express a genetic disease. For example, in the mating of a normal homozygote with a heterozygote who has a dominant disease-causing allele, the recurrence risk for each offspring is 1/2, or 50%. It is important to remember that each reproductive event is statistically independent of all previous events. Therefore, the recurrence risk remains the same regardless of the number of previously affected or unaffected offspring. Determining the mode of inheritance of a disease
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Single-Gene Disorders
(e.g., autosomal dominant versus autosomal recessive) enables one to assign an appropriate recurrence risk for a family.
Pedigrees A patient’s family history is diagrammed in a pedigree. The first affected individual to be identified in the family is termed the proband. Generation I II III
1
2
1
2
IV
1
2
3
4
5
6
3
4
5
6
1
2
SB
3
Male
Dead
Female
Mating
Unknown sex
Consanguineous or incestuous mating
Affected
Sibship
Carrier of an autosomal recessive (Optional)
Dizygotic twins
Carrier of an X-linked recessive (Optional) SB
7
Stillborn
Monozygotic twins
Figure II-1-1. Pedigree PedigreeNomenclature Nomenclature Figure II-1-1.
MY
MY
LY
MAJOR MODES OF INHERITANCE Autosomal Dominant Inheritance
HY
HY
High-Yield
A number of features in a pedigree help identify autosomal dominant MEDIUM YIELD inheritance:
LOW YIELD
• Because affected individuals must receive a disease-causing gene from
an affected parent, the disease is typically observed in multiple generaFUNDAMENTALS tions of a pedigree.
REINFORCEMENT • Skipped generations are not typically seen because two unaffected
LY HIGH YIELD MEDIUM YIELD LOW YIELD FUNDAMENTALS REINFORCEMENT
parents cannot transmit a disease-causing allele to their offspring (an exception occurs when there is reduced penetrance).
• Because these genes are located on autosomes, males and females are
affected in roughly equal frequencies.
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Medical Genetics
Autosomal dominant alleles are relatively rare in populations, so the typical mating pattern is a heterozygous affected individual (Aa genotype) mating with a homozygous normal individual (aa genotype). Note that, by convention, the dominant allele is shown in uppercase (A) and the recessive allele is shown in lowercase (a). The recurrence risk is thus 50%, and half the children, on average, will be affected with the disease. If both parents are heterozygous, the recurrence risk is 75%.
Note Autosomal Dominant Diseases • Familial hypercholesterolemia (LDL receptor deficiency)
Figure DominantInheritance Inheritance Figure II-1-2. II-1-2. Autosomal Autosomal Dominant A
a
a
Aa
aa
a
Aa
aa
• Huntington disease • Neurofibromatosis type 1 • Marfan syndrome • Acute intermittent porphyria
H
A Punnett square: Affected offspring (Aa) are shaded. HY
MY
Figure II-1-3. Recurrence forMating the Mating of Affected Individual (Aa) Figure II-1-3. Recurrence RiskRisk for the of Affected Individual (Aa) with LY with a Homozygous Unaffected Individual (aa) using a Punnett Square a Homozygous Unaffected Individual (aa) using a Punnett Square
Autosomal Recessive Inheritance
HIGH YIEL
High-Yield
Important features that distinguish autosomal recessive inheritance: MEDIUM YIELD
MEDIUM YIE
• Because autosomal recessive alleles are clinically expressedLOW onlyYIELD in the
LOW Y
homozygous state, the offspring must inherit one copy of the diseasecausing allele from each parent.
FUNDAMENTALS • In contrast to autosomal dominant diseases, autosomal recessive diseases are typically seen in only one generation of a REINFORCEMENT pedigree.
FUNDAMENT
REINFORCEM
• Because these genes are located on autosomes, males and females are
affected in roughly equal frequencies.
Most commonly, a homozygote is produced by the union of two heterozygous (carrier) parents. The recurrence risk for offspring of such matings is 25%.
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Consanguinity (the mating of related individuals) is sometimes seen in recessive pedigrees because individuals who share common ancestors are more likely to carry the same recessive disease-causing alleles.
A consanguineous mating has produced two affected offspring. Figure foran anAutosomal AutosomalRecessive Recessive Disease FigureII-1-4. II-1-4. Pedigree Pedigree for Disease
Determining the Recurrence Risk for an Individual Whose Phenotype Is Known. In Figure II-1-4, individual IV-1 may wish to know his risk of being a carrier. Because his phenotype is known, there are only 3 possible genotypes he can have, assuming complete penetrance of the disease-producing allele. He cannot be homozygous for the recessive allele (aa). Two of the remaining 3 possibilities are carriers (Aa and aA), and one is homozygous normal (AA). Thus, his risk of being a carrier is 2/3, or 0.67 (67%).
Note Autosomal Recessive Diseases • Sickle cell anemia • Cystic fibrosis • Phenylketonuria (PKU) • Tay-Sachs disease (hexosaminidase A deficiency)
A
a
A
AA
Aa
Note
a
Aa
aa
Cystic fibrosis is an important topic on the exam.
The affected genotype (aa) is shaded.
HY
HY
Figure Riskfor forthe theMating Matingofof MY FigureII-1-5. II-1-5.Recurrence Recurrence Risk Two (Aa)ofofaaRecessive Recessive Mutation TwoHeterozygous HeterozygousCarriers Carriers (Aa) Mutation
MY
LY
X-Linked Recessive Inheritance Properties of X-linked recessive inheritance
LY
High-Yield
HIGH YIELD
MEDIUM YIELD
MEDIUM YIELD
YIELD Because males have only one copy of the X chromosome, they LOW are said to be hemizygous (hemi = “half ”) for the X chromosome. If a recessive disease- causing mutation occurs on the X chromosome, a male will be affected with the FUNDAMENTALS disease. REINFORCEMENT • Because males require only one copy of the mutation to express the
LOW YIELD FUNDAMENTALS REINFORCEMENT
disease and females require 2 copies, X-linked recessive diseases are seen much more commonly in males than in females.
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transmit the disease-causing mutation to a heterozygous daughter, who is unaffected but who can transmit the disease-causing allele to her sons.
• Male-to-male transmission is not seen in X-linked inheritance; this
helps distinguish it from autosomal inheritance.
Note X-Linked Recessive Diseases • Duchenne muscular dystrophy • Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase [HGPRT] deficiency) • Glucose-6-phosphate dehydrogenase deficiency • Hemophilia A and B
Figure II-1-6. X-Linked Recessive Inheritance Figure II-1-6. X-Linked Recessive Inheritance
• Red-green color blindness • Menkes disease • Ornithine transcarbamoylase (OTC) deficiency • SCID (IL-receptor γ-chain deficiency)
Recurrence risks Figure II-1-7 shows the recurrence risks for X-linked recessive diseases. • Affected male–homozygous normal female: All of the daughters will be
heterozygous carriers; all of the sons will be homozygous normal.
• Normal male–carrier female: On average, half of the sons will be
affected and half of the daughters will be carriers. Note that in this case, the recurrence rate is different depending on the sex of the child. If the fetal sex is known, the recurrence rate for a daughter is 0, and that for a son is 50%. If the sex of the fetus is not known, then the recurrence rate is multiplied by 1/2, the probability that the fetus is a male versus a female. Therefore if the sex is unknown, the recurrence risk is 25%. x
Y
X
Xx
XY
X
Xx
XY
X
Y
X
XX
XY
x
Xx
xY
A
B
A. Affected male–homozygous normal female (X chromosome with mutation is in lower case) B. Normal male–carrier female
Figure II-1-7. RecurrenceRisks Risksfor forX-Linked X-Linked Recessive Figure II-1-7. Recurrence RecessiveDiseases Diseases
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X inactivation
Note
Normal males inherit an X chromosome from their mother and a Y chromosome from their father, whereas normal females inherit an X chromosome from each parent. Because the Y chromosome carries only about 50 protein-coding genes and the X chromosome carries hundreds of protein-coding genes, a mechanism must exist to equalize the amount of protein encoded by X chromosomes in males and females. This mechanism, termed X inactivation, occurs in the blastocyst (~100 cells) during the development of female embryos. When an X chromosome is inactivated, its DNA is not transcribed into mRNA, and the chromosome is visualized under the microscope as a highly condensed Barr body in the nuclei of interphase cells. X inactivation has several important characteristics:
X inactivation occurs early in the female embryo and is random, fixed, and incomplete. In a cell, all X chromosomes but one are inactivated.
• It is random—in some cells of the female embryo, the X chromosome
inherited from the father is inactivated, and in others the X chromosome inherited from the mother is inactivated. Like coin tossing, this is a random process. As shown in Figure II-1-6, most women have their paternal X chromosome active in approximately 50% of their cells and the maternal X chromosome active in approximately 50% of their cells. Thus, females are said to be mosaics with respect to the active X chromosome.
Note Genetic mosaicism is the presence of 2 or more cell lines with different karyotypes in an individual. It arises from mitotic nondisjunction. The number of cell lines that develop and their relative proportions are influenced by the timing of nondisjunction during embryogenesis and the viability of the aneuploid cells produced.
• It is fixed—once inactivation of an X chromosome occurs in a cell, the
same X chromosome is inactivated in all descendants of the cell.
• It is incomplete—there are regions throughout the X chromosome,
including the tips of both the long and short arms, that are not inactivated.
• X-chromosome inactivation is permanent in somatic cells and
r eversible in developing germ line cells. Both X chromosomes are active during oogenesis.
• All X chromosomes in a cell are inactivated except one. For example,
females with 3 X chromosomes in each cell (see Chapter 3) have two X chromosomes inactivated in each cell (thus, two Barr bodies can be visualized in an interphase cell). X-chromosome inactivation is thought to be mediated by >1 mechanism.
• A gene called XIST has been identified as the primary gene that causes
X inactivation. XIST produces an RNA product that coats the chromosome, helping produce its inactivation.
• Condensation into heterochromatin • Methylation of gene regions on the X chromosome
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Maternal X active Number of Females
Paternal X Barr body
Blastocyst ~100 cells
5/95 50/50 95/5 Percentage of cells with paternal/maternal X active Paternal X active
Maternal X Barr body
Figure II-1-8. Inactivation of the X Chromosome during Figure II-1-8. InactivationIsofa the X Chromosome during Embryogenesis Random Process Embryogenesis Is a Random Process
Manifesting (female) heterozygotes Normal females have two copies of the X chromosome, so they usually require two copies of the mutation to express the disease. However, because X inactivation is a random process, a heterozygous female will occasionally express an X-linked recessive mutation because, by random chance, most of the X chromosomes carrying the normal allele have been inactivated. Such females are termed manifesting heterozygotes. Because they usually have at least a small population of active X chromosomes carrying the normal allele, their disease expression is typically milder than that of hemizygous males.
Recall Question Which of the following is an X-linked recessive disease? A. Acute intermittent porphyria B. Duchenne muscular dystrophy C. Huntington disease D. Marfan syndrome Answer: B
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Y Chromosome Highlights • The SRY (sex determining region) gene is a transcription factor that
HY
HY
initiates male development.
MY • The q arm of Y chromosomes contains a large block of heterochromatin.
MY
• Microdeletions of Yq in males result in nonobstructive azoospermia. LY
X-Linked Dominant Inheritance
High-Yield
LY HIGHCorrelate YIELD Clinical
There are relatively few diseases whose inheritance is classified X-linked MEDIUMasYIELD dominant. Fragile X syndrome is an important example. In this condition, females LOW YIELDthat are differently affected than males, and whereas penetrance in males is 100%, in females is approximately 60%. The typical fragile X patient described is male.
Fragile X Syndrome MEDIUM YIELD
FUNDAMENTALS As in X-linked recessive inheritance, male–male transmission of the diseasecausing mutation is not seen. REINFORCEMENT
FUNDAMENTALS • Large ears
• Heterozygous females are affected. Because females have 2 X
chromosomes (and thus 2 chances to inherit an X-linked diseasecausing mutation) and males have only one, X-linked dominant diseases are seen about twice as often in females as in males.
• As in autosomal dominant inheritance, the disease phenotype is seen
Males: 100% penetrance
LOW YIELD
• Mental retardation
• Prominent jaw REINFORCEMENT • Macro-orchidism (usually postpubertal) Females: 60% penetrance • Mental retardation
in multiple generations of a pedigree; skipped generations are relatively unusual.
• Examine the children of an affected male (II-1 in the figure below).
None of his sons will be affected, but all of his daughters have the disease (assuming complete penetrance).
Note The penetrance of a disease-causing mutation is the percentage of individuals who are known to have the disease-causing genotype who display the disease phenotype (develop symptoms).
Figure II-1-9. X-Linked Dominant Inheritance Figure II-1-9. X-Linked Dominant Inheritance
Recurrence Risks Figure II-1-10 shows the recurrence risks for X-linked dominant inheritance. • Affected male–homozygous normal female: None of the sons are
affected; all of the daughters are affected. Note that in this case, the recurrence rate is different depending on the sex of the child. If the fetal sex is known, the recurrence rate for a daughter is 100%, and that for a son is 0%. If the sex of the fetus is not known, then the recurrence rate is multiplied by 1/2, the probability that the fetus is a male versus a female. Therefore if the sex is unknown, the recurrence risk is 50%.
• Normal male–heterozygous affected female: on average, 50% of sons
are affected and 50% of daughters are affected.
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Note X-Linked Dominant Diseases • Hypophosphatemic rickets
Affected male–homozygous normal female (the mutation-carrying chromosome is upper case) X
Y
x
Xx
xY
x
Xx
xY
• Fragile X syndrome
Normal male–heterozygous affected female x
Y
X
Xx
XY
x
xx
xY
Figure II-1-10. II-1-10. Recurrence Recurrence Risks Figure Risksfor forX-Linked X-LinkedDominant DominantInheritance Inheritance
Affected individuals have an affected parent? (Multiple generations affected?) Yes
No
Dominant
Recessive
Male-male transmission?
All (or almost all) affected are males?
Yes
No
Autosomal dominant No
Yes
May be Xdominant
X-linked recessive
No Autosomal recessive
Are all daughters of an affected male also affected? Yes X-dominant
Note: If transmission occurs only through affected mothers and never through affected sons, the pedigree is likely to reflect mitochondrial inheritance.
Figure II-I-11. II-1-11.AABasic BasicDecision DecisionTree Tree for for Determining Determining Figure theMode Mode of of Inheritance Inheritance in in aa Pedigree Pedigree the
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HY
HY MY LY
MY Chapter 1
Mitochondria, which are cytoplasmic organelles involved inMEDIUM cellular respiration, YIELD have their own chromosomes, each of which contains 16,569 DNA base pairs LOW YIELD (bp) arranged in a circular molecule. This DNA encodes 13 proteins that are subunits of complexes in the electron transport and oxidative phosphorylation processes (see Part I, Chapter 13). In addition, mitochondrial DNA encodes 22 FUNDAMENTALS transfer RNAs and 2 ribosomal RNAs. REINFORCEMENT
Because a sperm cell contributes no mitochondria to the egg cell during fertilization, mitochondrial DNA is inherited exclusively through females. Pedigrees for mitochondrial diseases thus display a distinct mode of inheritance: Diseases are transmitted only from affected females to their offspring.
LY Single-Gene Disorders
HIGH YIELD
High-Yield
Mitochondrial Inheritance
●
MEDIUM YIELD LOW YIELD FUNDAMENTALS REINFORCEMENT
• Both males and females are affected. • Transmission of the disease is only from a female. • All offspring of an affected female are affected. • None of the offspring of an affected male is affected. • Diseases are typically neuropathies and/or myopathies.
Heteroplasmy A typical cell contains hundreds of mitochondria in its cytoplasm, and each mitochondrion has its own copy of the mitochondrial genome. When a specific mutation occurs in some of the mitochondria, this mutation can be unevenly distributed into daughter cells during cell division: Some cells may inherit more mitochondria in which the normal DNA sequence predominates, while others inherit mostly mitochondria with the mutated, disease-causing gene. This condition is known as heteroplasmy. Variations in heteroplasmy account for substantial variation in the severity of expression of mitochondrial diseases.
Note Mitochondrial Diseases • Leber hereditary optic neuropathy • MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Figure II-1-12. Disease Figure II-1-12. Pedigree Pedigreefor fora aMitochondrial Mitochondrial Disease
• Myoclonic epilepsy with ragged red muscle fibers
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IMPORTANT PRINCIPLES THAT CAN CHARACTERIZE SINGLE-GENE DISEASES Variable Expression Hemochromatosis Mary B. is a 45-year-old white female with hip pain of 2 years’ duration. She also experiences moderate chronic fatigue. Routine blood work shows that liver function tests (LFTs) are slightly elevated. She does not drink alcohol. She takes no prescription drugs although she does use aspirin for the hip pain. She takes no vitamin or mineral supplements. Mary B.’s 48-year-old brother has recently been diagnosed with hereditary hemochromatosis. Her brother’s symptoms include arthritis for which he takes Tylenol (acetaminophen), significant hepatomegaly, diabetes, and “bronze” skin. His transferrin saturation is 75% and ferritin 1300 ng/mL. A liver biopsy revealed stainable iron in all hepatocytes and initial indications of hepatic cirrhosis. He was found to be homozygous for the most common mutation (C282Y) causing hemochromatosis. Subsequently Mary was tested and also proved to be homozygous for the C282Y mutation. Following diagnosis, both individuals were treated with periodic phlebotomy to satisfactorily reduce iron load.
Most genetic diseases vary in the degree of phenotypic expression: Some individuals may be severely affected, whereas others are more mildly affected. This can be the result of several factors. Environmental Influences. In the case of hemochromatosis described above, Mary’s less-severe phenotype may in part be attributable to loss of blood during regular menses throughout adulthood. Her brother’s use of Tylenol may contribute to his liver problems. The autosomal recessive disease xeroderma pigmentosum will be expressed more severely in individuals who are exposed more frequently to ultraviolet radiation. Allelic Heterogeneity. Different mutations in the disease-causing locus may cause more- or less-severe expression. Most genetic diseases show some degree of allelic heterogeneity. For example, missense mutations in the factor VIII gene tend to produce less severe hemophilia than do nonsense mutations, which result in a truncated protein product and little, if any, expression of factor VIII. Allelic heterogeneity usually results in phenotypic variation between families, not within a single family. Generally the same mutation is responsible for all cases of the disease within a family. In the example of hemochromatosis above, both Mary and her brother have inherited the same mutation; thus, allelic heterogeneity is not responsible for the variable expression in this case. It is relatively uncommon to see a genetic disease in which there is no allelic heterogeneity. Heteroplasmy in mitochondrial pedigrees. Modifier Loci. Disease expression may be affected by the action of other loci, termed modifier loci. Often these may not be identified.
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HY MY LY
Incomplete Penetrance
High-Yield
A disease-causing mutation is said to have incomplete penetrance MEDIUMwhen YIELDsome individuals who have the disease genotype (e.g., one copy of the mutation for an LOW YIELD autosomal dominant disease or two copies for an autosomal recessive disease) do not display the disease phenotype. Incomplete penetrance is distinguished from variable expression in that the nonpenetrant gene has no phenotypic FUNDAMENTALS expression at all. In the pedigree shown below, individual II-4 must have the REINFORCEMENT disease-causing allele (he passed it from his father to his son) but shows no symptoms. He is an example of nonpenetrance.
MY Chapter 1
●
LY Single-Gene Disorders
HIGH YIELD MEDIUM YIELD LOW YIELD FUNDAMENTALS REINFORCEMENT
I II III The unaffected male in generation II (II-4) has an affected father and two affected sons. He must have the disease-causing mutation, although it shows incomplete penetrance.
FigureII-1-13. II-1-13.Incomplete Incomplete Penetrance Penetrance for Disease Figure foran anAutosomal AutosomalDominant Dominant Disease
The penetrance of a disease-causing mutation is quantified by examining a large number of families and calculating the percentage of individuals who are known to have the disease-causing genotype who display the disease phenotype. Suppose that we had data from several different family studies of the disease affecting the family above and had identified 50 individuals with the diseaseproducing genotype. Of these individuals only 40 had any symptom(s). Penetrance would be calculated as: 40/50 = 0.80, or 80% Penetrance must be taken into account when predicting recurrence risks. For instance, if II-1 and II-2 have another child, the recurrence risk is: 0.50 × 0.80 = 0.40, or 40% Both dominant diseases and recessive diseases can show incomplete (reduced) penetrance. • Although 1 in 300 whites inherits the homozygous genotype for
hemochromatosis, a much smaller percentage of individuals develop the disease (approximately 1 in 1,000–2,000). Penetrance for this autosomal recessive disease is only about 15%.
Notice that hereditary hemochromatosis is an example of incomplete penetrance and also an example of variable expression. Expression of the disease phenotype in individuals homozygous for the disease-causing mutation can run the gamut from severe symptoms to none at all. Among the 15% of individuals with at least some phenotypic expression, that expression can be more or less
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severe (variable expression). However, 85% of individuals homozygous for the disease-causing mutation never have any symptoms (nonpenetrance). The same factors that contribute to variable expression in hemochromatosis can also contribute to incomplete penetrance. It is necessary to be able to: • Define incomplete (reduced) penetrance. • Identify an example of incomplete penetrance in an autosomal domi-
nant pedigree as shown in Figure II-1-13.
• Include penetrance in a simple recurrence risk calculation.
Incomplete Penetrance in Familial Cancer. Retinoblastoma is an autosomal dominant condition caused by an inherited loss-of-function mutation in the Rb tumor suppressor gene. In 10% of individuals who inherit this mutation, there is no additional somatic mutation in the normal copy and retinoblastoma does not develop, although they can pass the mutation to their offspring. Penetrance of retinoblastoma is therefore 90%.
Pleiotropy Pleiotropy exists when a single disease-causing mutation affects multiple organ systems. Pleiotropy is a common feature of genetic diseases.
Pleiotropy in Marfan Syndrome Marfan syndrome is an autosomal dominant disease that affects approximately 1 in 10,000 individuals. It is characterized by skeletal abnormalities (thin, elongated limbs; pectus excavatum; pectus carinatum), hypermobile joints, ocular abnormalities (frequent myopia and detached lens), and most importantly, cardiovascular disease (mitral valve prolapse and aortic aneurysm). Dilatation of the ascending aorta is seen in 90% of patients and frequently leads to aortic rupture or congestive heart failure. Although the features of this disease seem rather disparate, they are all caused by a mutation in the gene that encodes fibrillin, a key component of connective tissue. Fibrillin is expressed in the periosteum and perichondrium, the suspensory ligament of the eye, and the aorta. Defective fibrillin causes the connective tissue to be “stretchy” and leads to all of the observed disease features. Marfan syndrome thus provides a good example of the principle of pleiotropy.
Locus Heterogeneity Locus heterogeneity exists when the same disease phenotype can be caused by mutations in different loci. Locus heterogeneity becomes especially important when genetic testing is performed by testing for mutations at specific loci.
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Locus Heterogeneity in Osteogenesis Imperfecta Type 2 Osteogenesis imperfecta (OI) is a disease of bone development that affects approximately 1 in 10,000 individuals. It results from a defect in the collagen protein, a major component of the bone matrix. Four types of OI have been identified. Type 2, the severe perinatal type, is the result of a defect in type 1 collagen, a trimeric molecule that has a triple helix structure. Two members of the trimer are encoded by a gene on chromosome 17, and the third is encoded by a gene on chromosome 7. Mutations in either of these genes give rise to a faulty collagen molecule, causing type 2 OI. Often, patients with chromosome 17 mutations are clinically indistinguishable from those with chromosome 7 mutations. This exemplifies the principle of locus heterogeneity.
New Mutations In many genetic diseases, particularly those in which the mortality rate is high or the fertility rate is low, a large proportion of cases are caused by a new mutation transmitted from an unaffected parent to an affected offspring. There is thus no family history of the disease (for example, 100% of individuals with osteogenesis imperfecta type 2, discussed above, are the result of a new mutation in the family). A pedigree in which there has been a new mutation is shown in Figure II-I-14. Because the mutation occurred in only one parental gamete, the recurrence risk for other offspring of the parents remains very low. However, the recurrence risk for future offspring of the affected individual would be the same as that of any individual who has inherited the disease-causing mutation.
New mutation Figure II-1-14. Pedigree witha aNew NewMutation Mutation Figure II-1-14. Pedigree with
Delayed Age of Onset Many individuals who carry a disease-causing mutation do not manifest the phenotype until later in life. This can complicate the interpretation of a pedigree because it may be difficult to distinguish genetically normal individuals from those who have inherited the mutation but have not yet displayed the phenotype.
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Clinical Correlate Diseases with Delayed Age of Onset • Acute intermittent porphyria (peri- or postpubertal) • Huntington disease • Hemochromatosis • Familial breast cancer
Delayed Age of Onset in Huntington Disease Huntington disease, an autosomal dominant condition, affects approximately 1 in 20,000 individuals. Features of the disease include progressive dementia, loss of motor control, and affective disorder. This is a slowly progressing disease, with an average duration of approximately 15 years. Common causes of death include aspiration pneumonia, head trauma (resulting from loss of motor control), and suicide. Most patients first develop symptoms in their 30s or 40s, so this is a good example of a disease with delayed age of onset. The mutation produces a buildup of toxic protein aggregates in neurons, eventually resulting in neuronal death.
Anticipation Anticipation refers to a pattern of inheritance in which individuals in the most recent generations of a pedigree develop a disease at an earlier age or with greater severity than do those in earlier generations. For a number of genetic diseases, this phenomenon can be attributed to the gradual expansion of trinucleotide repeat polymorphisms within or near a coding gene. Huntington disease was cited above as an example of delayed age of onset; it is also a good example of anticipation. The condition results from a gain-of-function mutation on chromosome 4 and is an example of a trinucleotide repeat expansion disorder. Normal huntingin genes have fewer than 27 CAG repeats in the 5′ coding region, and the number is stable from generation to generation. In families who eventually present with Huntington disease, premutations of 27–35 repeats are seen, although these individuals do not have Huntington disease. Some of these individuals (generally males) may then transmit an expanded number of repeats to their offspring. Individuals with more than 39 repeats are then seen, and these individuals develop symptoms. Within this group, age of onset is correlated with the n umber of repeats and ranges from a median age 66 (39 repeats) to age 1/100, e.g., q >1/10, the complete Hardy-Weinberg equation should be used to obtain an accurate answer. In this case, p = 1 - q. Although the Hardy-Weinberg equation applies equally well to autosomal dominant and recessive alleles, genotypes, and diseases, the equation is most HYa large frequently used with autosomal recessive conditions. In these instances, percentage of the disease-producing allele is “hidden” in heterozygous MY carriers who cannot be distinguished phenotypically (clinically) from homozygous LY normal individuals.
HY MY LY
Practical Application of Hardy-Weinberg
High-Yield
HIGH YIELD
A simple example is illustrated by the following case.
MEDIUM YIELD
MEDIUM YIELD
LOWShe YIELD A 20-year-old college student is taking a course in human genetics. is aware that she has an autosomal recessive genetic disease that has required her lifelong adherence to a diet low in natural protein with supplements of FUNDAMENTALS tyrosine and restricted amounts of phenylalanine. She also must avoid foods artificially sweetened with aspartame (Nutrasweet™). She asks her genetics REINFORCEMENT professor about the chances that she would marry a man with the diseaseproducing allele. The geneticist tells her that the known prevalence of PKU in the population is 1/10,000 live births, but the frequency of carriers is much higher, approximately 1/50. Her greatest risk comes from marrying a carrier for two reasons. First, the frequency of carriers for this condition is much higher than the frequency of affected homozygotes, and second, an affected person would be identifiable clinically. The geneticist used the Hardy-Weinberg equation to estimate the carrier frequency from the known prevalence of the disease in the following way:
LOW YIELD FUNDAMENTALS REINFORCEMENT
Note
Hardy-Weinberg Equilibrium in Phenylketonuria (PKU) • Prevalence of PKU is 1/10,000 live births • Allele frequency = (1/10,000) = 1/100 = 0.01 • Carrier frequency = 2(1/100) = 1/50
Disease prevalence = q2 = 1/10,000 live births Carrier frequency = 2q (to be calculated) q = square root of 1/10,000, which is 1/100 2q = 2/100, or 1/50, the carrier frequency The woman now asks a second question: “Knowing that I have a 1/50 chance of marrying a carrier of this allele, what is the probability that I will have a child with PKU?”
The geneticist answers, “The chance of you having a child with PKU is 1/100.” This answer is based on the joint occurrence of two nonindependent events: • The probability that she will marry a heterozygous carrier (1/50), and • If he is a carrier, the probability that he will pass his PKU allele versus
the normal allele to the child (1/2).
These probabilities would be multiplied to give: • 1/50 × 1/2 = 1/100, the probability that she will have a child with PKU.
Bridge to Statistics If events are nonindependent, multiply the probability of one event by the probability of the second event, assuming that the first has occurred. For example, what is the probability that the student’s husband will pass the disease-producing allele to the child? It is the probability that he will be a carrier (1/50, event 1) multiplied by the probability that he will pass the disease-causing gene along (1/2, event 2), assuming he is a carrier.
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Medical Genetics
Note Assuming random mating, the HardyWeinberg principle specifies a Behavioral Science/Social Sciences predictable relationship between allele frequencies and genotype frequencies in populations. This principle can be applied to estimate the frequency of heterozygous carriers of an autosomal recessive mutation.
In summary, there are 3 major terms one usually works with in the HardyWeinberg equation applied to autosomal recessive conditions: • q2, the disease prevalence • 2q, the carrier frequency • q, the frequency of the disease-causing allele
When answering questions involving Hardy-Weinberg calculations, it is important to identify which of these terms has been given in the stem of the question and which term you are asked to calculate. This exercise demonstrates two important points: • The Hardy-Weinberg principle can be applied to estimate the
revalence of heterozygous carriers in populations when we know p only the prevalence of the recessive disease.
• For autosomal recessive diseases, such as PKU, the prevalence of
heterozygous carriers is much higher than the prevalence of affected homozygotes. In effect, the vast majority of recessive genes are hidden in the heterozygotes.
Hardy-Weinberg Equilibrium for Dominant Diseases The calculations for dominant diseases must acknowledge that most of the affected individuals will be heterozygous. In this case, the prevalence is 2q. (One can again use the assumption that p ~ 1.) The term q2 represents the prevalence of homozygous affected individuals who, although much less commonly seen, may have more severe symptoms. For example, • 1/500 people in the United States have a form of LDL-receptor deficiency
and are at increased risk for cardiovascular disease and myocardial infarction.
• Taking 2q = 1/500, one can calculate that q2 = 1/106, or one in a
million live births are homozygous for the condition. These individuals have greatly elevated LDL-cholesterol levels, a much-higher risk for cardiovascular disease than heterozygotes, and are more likely to present with characteristic xanthomas, xanthelasmas, and corneal arcus.
In contrast, in Huntington disease (autosomal dominant), the number of triplet repeats correlates much more strongly with disease severity than does heterozygous or homozygous status.
Sex Chromosomes and Allele Frequencies When considering X-linked recessive conditions, one must acknowledge that most cases occur in hemizygous males (xY). Therefore, q = disease-producing allele frequency but, paradoxically, it also equals the prevalence of affected males. Thus, the statement “1/10,000 males has hemophilia A” also gives the allele frequency for the disease-producing allele: 1/10,000. • q2 = prevalence of disease in females (1/108, or 1/100,000,000) • 2q = prevalence of female carriers (1/5,000)
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This exercise demonstrates that: • As with autosomal recessive traits, the majority of X-linked recessive
genes are hidden in female heterozygous carriers (although a considerable number of these genes are seen in affected males).
• X-linked recessive traits are seen much more commonly in males than
in females.
FACTORS RESPONSIBLE FOR GENETIC VARIATION IN/AMONG POPULATIONS Although human populations are typically in Hardy-Weinberg equilibrium for most loci, deviations from equilibrium can be produced by new mutations, the introduction of a new mutation into a population from outside (founder effect), nonrandom mating (for example, consanguinity), the action of natural selection, genetic drift, and gene flow. Although these factors are discussed independently, often more than one effect contributes to allele frequencies in a population.
Mutation
Note
Mutation, discussed previously, is ultimately the source of all new genetic variation in populations. In general, mutation rates do not differ very much from population to population.
The 4 evolutionary factors responsible for genetic variation in populations are:
In some cases, a new mutation can be introduced into a population when someone carrying the mutation is one of the early founders of the community. This is referred to as a founder effect. As the community rapidly expands through generations, the frequency of the mutation can be affected by natural selection, by genetic drift (see below), and by consanguinity.
• Mutation • Natural selection • Genetic drift • Gene flow
Branched Chain Ketoacid Dehydrogenase Deficiency Branched chain ketoacid dehydrogenase deficiency (maple syrup urine disease) occurs in 1/176 live births in the Mennonite community of Lancastershire, Pennsylvania. In the U.S. population at large, the disease occurs in only 1/180,000 live births. The predominance of a single mutation (allele) in the branched chain dehydrogenase gene in this group suggests a common origin of the mutation. This may be due to a founder effect.
Natural Selection Natural selection acts upon genetic variation, increasing the frequencies of alleles that promote survival or fertility (referred to as fitness) and decreasing the frequencies of alleles that reduce fitness. The reduced fitness of most disease-producing alleles helps explain why most genetic diseases are relatively rare. Dominant diseases, in which the disease-causing allele is more readily exposed to the effects of natural selection, tend to have lower allele frequencies than do recessive diseases, where the allele is typically hidden in heterozygotes.
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Medical Genetics
Sickle Cell Disease and Malaria Behavioral Science/Social Sciences
Sickle cell disease affects 1/600 African Americans and up to 1/50 individuals in some parts of Africa. How could this highly deleterious disease-causing mutation become so frequent, especially in Africa? The answer lies in the fact that the falciparum malaria parasite, which has been common in much of Africa, does not survive well in the erythrocytes of sickle cell heterozygotes. These individuals, who have no clinical signs of sickle cell disease, are thus protected against the lethal effects of malaria. Consequently, there is a heterozygote advantage for the sickle cell mutation, and it maintains a relatively high frequency in some African populations.
There is now evidence for heterozygote advantages for several other recessive diseases that are relatively common in some populations. Examples include: • Cystic fibrosis (heterozygote resistance to typhoid fever) • Hemochromatosis (heterozygote advantage in iron-poor environments) • Glucose-6-phosphate dehydrogenase deficiency, hemolytic anemia
(heterozygote resistance to malaria)
Genetic Drift Mutation rates do not vary significantly from population to population, a lthough they can result in significant differences in allele frequencies when they occur in small populations or are introduced by a founder effect. Mutation rates and founder effects act along with genetic drift to make certain genetic diseases more common (or rarer) in small, isolated populations than in the world at large. Consider the pedigrees (very small populations) shown in Figure II-2-1.
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Affected person who either founds or moves into the small population (founder effect)
I II
III
I
New mutation in a family
II
III Genetic drift begins. In both examples the frequency of affected persons in generation III is 2/3, higher than the 1/2 predicted by statistics. Figure II-2-1. Genetic Drift in Two Small Populations Figure II-2-1. Genetic Drift in Two Small Populations (Illustrated with a Dominant Disease) (Illustrated with a Dominant Disease)
If the woman and the affected man (II-5) in the top panel had 1,000 children rather than 6, the prevalence of the disease in their offspring (Generation III) would be closer to 1/2, the statistical mean. Although genetic drift affects populations larger than a single family, this example illustrates two points: • When a new mutation or a founder effect occurs in a small population,
genetic drift can make the allele more or less prevalent than statistics alone would predict.
• A relatively large population in Hardy-Weinberg equilibrium for an
allele or many alleles can be affected by population “bottlenecks” in which natural disaster or large-scale genocide dramatically reduces the size of the population. Genetic drift may then change allele frequencies and a new Hardy-Weinberg equilibrium is reached.
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Gene Flow Gene flow refers to the exchange of genes among populations. Because of gene flow, populations located close to one another often tend to have similar gene frequencies. Gene flow can also cause gene frequencies to change through time: The frequency of sickle cell disease is lower in African Americans in part because of gene flow from other sectors of the U.S. population that do not carry the disease-causing mutation; in addition, the heterozygote advantage for the sickle cell mutation (see text box) has disappeared because malaria has become rare in North America.
Note
Consanguinity and Its Health Consequences
Consanguineous matings are more likely to produce offspring affected with recessive diseases because individuals who share common ancestors are more liable to share disease-causing mutations.
Consanguinity refers to the mating of individuals who are related to one another (typically, a union is considered to be consanguineous if it occurs between individuals related at the second-cousin level or closer). Figure II-2-2 illustrates a pedigree for a consanguineous union. Because of their mutual descent from common ancestors, relatives are more likely to share the same disease-causing genes. Statistically, • Siblings (II-2 and II-3 or II-4) share 1/2 of their genes. • First cousins (III-3 and III-4) share 1/8 of their genes (1/2 × 1/2 × 1/2). • Second cousins (IV-1 and IV-2) share 1/32 of their genes (1/8 × 1/2 × 1/2).
These numbers are referred to as the coefficients of relationship. Thus, if i ndividual III-1 carries a disease-causing allele, there is a 1/2 chance that individual III-3 (his brother) has it and a 1/8 chance that individual III-4 (his first cousin) has it. I
II
III IV Figure II-2-2. A Pedigree Illustrating Consanguinity Figure II-2-2. A Pedigree Illustrating Consanguinity
Consequently, there is an increased risk of genetic disease in the offspring of consanguineous matings. Dozens of empirical studies have examined the health consequences of consanguinity, particularly first-cousin matings. These studies show that the offspring of first-cousin matings are approximately twice as likely to present with a genetic disease as are the offspring of unrelated matings. The frequency of genetic disease increases further in the offspring of closer unions (e.g., uncle/niece or brother/sister matings).
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Review Questions 1. A population has been assayed for a 4-allele polymorphism, and the following genotype counts have been obtained: Genotype
Count
1,1
4
1,3
8
1,4
3
2,3
5
2,4
9
3,3
4
3,4
6
4,4
11
On the basis of these genotype counts, what are the gene frequencies of alleles 1 and 2? A. 0.38, 0.28 B. 0.19, 0.14 C. 0.095, 0.07 D. 0.25, 0.25 E. 0.38, 0.20 2. Which of the following best characterizes Hardy-Weinberg equilibrium? A. Consanguinity has no effect on Hardy-Weinberg equilibrium. B. Genotype frequencies can be estimated from allele frequencies, but the reverse is not true. C. Natural selection has no effect on Hardy-Weinberg equilibrium. D. Once a population deviates from Hardy-Weinberg equilibrium, it takes many generations to return to equilibrium. E. The frequency of heterozygous carriers of an autosomal recessive mutation can be estimated if one knows the incidence of affected homozygotes in the population.
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3. In a genetic counseling session, a healthy couple has revealed that they are first cousins and that they are concerned about health risks for their offspring. Which of the following best characterizes these risks? A. Because the couple shares approximately half of their genes, most of the offspring are likely to be affected with some type of genetic disorder. B. The couple has an increased risk of producing a child with an autosomal dominant disease. C. The couple has an increased risk of producing a child with an autosomal recessive disease. D. The couple has an increased risk of producing a child with Down syndrome. E. There is no known increase in risk for the offspring. 4. An African American couple has produced two children with sickle cell disease. They have asked why this disease seems to be more common in the African American population than in other U.S. populations. Which of the following factors provides the best explanation? A. Consanguinity B. Genetic drift C. Increased gene flow in this population D. Increased mutation rate in this population E. Natural selection 5. If the incidence of cystic fibrosis is 1/2,500 among a population of Europeans, what is the predicted incidence of heterozygous carriers of a cystic fibrosis mutation in this population? A. 1/25 B. 1/50 C. 2/2,500 D. 1/2,500 E. (1/2,500)2 6. A man is a known heterozygous carrier of a mutation causing hyperprolinemia, an autosomal recessive condition. Phenotypic expression is variable and ranges from high urinary excretion of proline to neurologic manifestations including seizures. Suppose that 0.0025% (1/40,000) of the population is homozygous for the mutation causing this condition. If the man mates with somebody from the general population, what is the probability that he and his mate will produce a child who is homozygous for the mutation involved? A. 1% (1/100) B. 0.5% (1/200) C. 0.25% (1/400) D. 0.1% (1/1,000) E. 0.05% (1/2,000)
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7. The incidence of Duchenne muscular dystrophy in North America is about 1/3,000 males. On the basis for this figure, what is the gene frequency of this X-linked recessive mutation? A. 1/3,000 B. 2/3,000 C. (1/3,000)2 D. 1/6,000 E. 1/9,000
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Answers 1. Answer: B. The denominator of the gene frequency is 100, which is obtained by adding the number of genotyped individuals (50) and multiplying by 2 (because each individual has two alleles at the locus). The numerator is obtained by counting the number of alleles of each type: the 4 homozygotes with the 1,1 genotype contribute 8 copies of allele 1; the 1,3 heterozygotes contribute another 8 alleles; and the 1,4 heterozygotes contribute 3 alleles. Adding these together, we obtain 19 copies of allele 1. Dividing by 100, this yields a gene frequency of 0.19 for allele 1. For allele 2, there are two classes of heterozygotes that have a copy of the allele: those with the 2,3 and 2,4 genotypes. These 2 genotypes yield 5 and 9 copies of allele 2, respectively, for a frequency of 14/100 = 0.14. 2. Answer: E. The incidence of affected homozygotes permits the estimation of the frequency of the recessive mutation in the population. Using the Hardy-Weinberg equilibrium relationship between gene frequency and genotype frequency, the gene frequency can then be used to estimate the frequency of the heterozygous genotype in the population. Consanguinity (choice A) affects Hardy-Weinberg equilibrium by increasing the number of homozygotes in the population above the equilibrium expectation (i.e., consanguinity results in a violation of the assumption of random mating). Genotype frequencies can be estimated from gene frequencies (choice B), but gene frequencies can also be estimated from genotype frequencies (as in choice A). By eliminating a specific genotype from the population (e.g., affected homozygotes), natural selection can cause deviations from equilibrium (choice C). Only one generation of random mating is required to return a population to equilibrium (choice D). 3. Answer: C. Because the couple shares common ancestors (i.e., one set of grandparents), they are more likely to be heterozygous carriers of the same autosomal recessive disease-causing mutations. Thus, their risk of producing a child with an autosomal recessive disease is elevated above that of the general population. First cousins share approximately 1/8 of their genes, not 1/2 (choice A). Because both members of the couple are healthy, neither one is likely to harbor a dominant disease-causing mutation (choice B). In addition, consanguinity itself does not elevate the probability of producing a child with a dominant disease because only one copy of the diseasecausing allele is needed to cause the disease. Down syndrome (choice D) typically is the result of a new mutation. When it is transmitted by an affected female, it acts like a dominant mutation and thus would not be affected by consanguinity. Empirical studies indicate that the risk of genetic disease in the offspring of first cousin couples is approximately double that of the general population (choice E).
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4. Answer: E. The frequency of sickle cell disease is elevated in many African populations because heterozygous carriers of the sickle cell mutation are resistant to malarial infection but do not develop sickle cell disease, which is autosomal recessive. Thus, there is a selective advantage for the mutation in heterozygous carriers, elevating its frequency in the population. Consanguinity (choice A) could elevate the incidence of this autosomal recessive disease in a specific family, but it does not account for the elevated incidence of this specific disease in the African American population in general. The African American population is large and consequently would not be expected to have experienced elevated levels of genetic drift (choice B). Although there has been gene flow (choice C) from other populations into the African American population, this would be expected to decrease, rather than increase, the frequency of sickle cell disease because the frequency of this disease is highest in some African populations. There is no evidence that the mutation rate (choice D) is elevated in this population. In contrast, the evidence for natural selection is very strong. 5. Answer: A. This answer is obtained by taking the square root of the incidence (i.e., the frequency of affected homozygotes) to get a gene frequency for the disease-causing mutation (q) of 1/50 (0.02). The carrier frequency is given by 2pq, or approximately 2q, or 1/25. 6. Answer: C. One must first determine the probability that the man’s mate will also be a heterozygous carrier. If the frequency of affected homozygotes (q2) is 1/40,000, then the allele frequency, q, is 1/200. The carrier frequency in the population (approximately 2q) is 1/100. Three independent events must happen for their child to be homozygous for the mutation. The mate must be a carrier (probability 1/100), the mate must pass along the mutant allele (probability 1/2), and the man must also pass along the mutant allele (probability 1/2). Multiplying the 3 probabilities to determine the probability of their joint occurrence gives 1/100 × 1/2 × 1/2 = 1/400. 7. Answer: A. Because males have only a single X chromosome, each affected male has one copy of the disease-causing recessive mutation. Thus, the incidence of an X-linked recessive disease in the male portion of a population is a direct estimate of the gene frequency in the population.
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3
Learning Objectives ❏❏ Interpret scenarios about basic definitions and terminology ❏❏ Solve problems concerning numerical chromosome abnormalities ❏❏ Demonstrate understanding of structural chromosome abnormalities ❏❏ Solve problems concerning advances in molecular cytogenetics
OVERVIEW This chapter reviews diseases that are caused by microscopically observable alterations in chromosomes. These alterations may involve the presence of extra chromosomes or the loss of chromosomes. They may also consist of structural alterations of chromosomes. Chromosome abnormalities are seen in approximately 1 in 150 live births and are the leading known cause of mental retardation. The vast majority of fetuses with chromosome abnormalities are lost prenatally: Chromosome abnormalities are seen in 50% of spontaneous fetal losses during the first trimester of pregnancy, and they are seen in 20% of fetuses lost during the second trimester. Thus, chromosome abnormalities are the leading known cause of pregnancy loss.
Note X chromosome contains ~1,200 genes Y chromosome contains ~50 genes
BASIC DEFINITIONS AND TERMINOLOGY Karyotype Chromosomes are most easily visualized during the metaphase stage of mitosis, when they are maximally condensed. They are photographed under the microscope to create a karyotype, an ordered display of the 23 pairs of human chromosomes in a typical somatic cell (Figure II-3-1). In Figure II-3-1A, a karyogram represents a drawing of each type of chromosome; the presentation is haploid (only one copy of each chromosome is shown). Figure II-3-1B is a karyotype of an individual male. It is diploid, showing both copies of each autosome, the X and the Y chromosome. Chromosomes are ordered according to size, with the sex chromosomes (X and Y) placed in the lower right portion of the karyotype. Metaphase chromosomes can be grouped according to size and to the position of the centromere, but accurate identification requires staining with one of a variety of dyes to reveal characteristic banding patterns.
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Chromosome banding To visualize chromosomes in a karyotype unambiguously, various stains are applied so that banding is evident. • G-banding. Mitotic chromosomes are partially digested with trypsin (to digest some associated protein) and then stained with Giemsa, a dye that binds DNA. G-banding reveals a pattern of light and dark (G-bands) regions that allow chromosomes to be accurately identified in a karyotype. There are several other stains that can be used in a similar manner. The chromosomes depicted in Figure II-3-1 have been stained with Giemsa.
p
3
2
2 1 1
1
q2 3 4
1
1 q2 3
1
2 1 1
2
2
14
1
4 1
5
16
6 1 1 2
17
2 1 1
1 q2 3
2
1 1 2
1 2
2
p1
1
2 4
3
15
2 1
1
2
3
1 1 3
13
1 2
3
p1
1
1
2
1
2
2
7 1
8 1
2
1
18
2 1 1 2 3
19
20
1
1
1
1
1
1
2
2
2
9 1 1 2
10 1 1
11
12 2 1 1
1 1
2
21
22
Y
X
Negative or pale staining 'Q' and 'G' bands Positive 'R' bands Positive 'Q' and 'G' bands Negative 'R' bands Variable bands A
B Figure Idealized Drawing Drawing FigureII-3-1. II-3-1.Human HumanMetaphase MetaphaseChromosomes. Chromosomes. (A) (A) Idealized (Karyogram) and (B) Photograph of Metaphase Chromosomes (Karyotype) (Karyogram) and (B) Photograph of Metaphase Chromosomes (Karyotype)
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Chromosome abnormalities in some cases can be identified visually by looking at the banding pattern, but this technique reveals differences (for instance, larger deletions) only to a resolution of about 4 Mb. Smaller abnormalities (microdeletions) must be identified in other ways (FISH), discussed at the end of the chapter.
Chromosome nomenclature Each mitotic chromosome contains a centromere and two sister chromatids because the cell has gone through interphase and has entered mitosis when the karyotype analysis is performed (metaphase). The long arm of the chromosome is labeled q, and the short arm is labeled p. One of the characteristics described is the relative position of the centromere. • Metacentric chromosomes (for instance, chromosome 1) have the centromere near the middle. The p and q arms are of roughly equal length. • Submetacentric chromosomes have the centromere displaced toward
one end (for example, chromosome 4). The p and q arms are evident.
• Acrocentric chromosomes have the centromere far toward one end. In
these chromosomes, the p arm contains little genetic information, most of it residing on the q arm. Chromosomes 13, 14, 15, 21, and 22 are the acrocentric chromosomes. Only the acrocentric chromosomes are involved in
• Robertsonian translocations, which will be discussed in this chapter.
The tips of the chromosomes are called telomeres. Table II-3-1 contains some standard nomenclature applied to chromosomes. Table II-3-1. Common Symbols Used in Karyotype Nomenclature 1-22
Autosome number
X, Y
Sex chromosomes
(+) or (-)
When placed before an autosomal number, indicates that chromosome is extra or missing
p
Short arm of the chromosome
q
Long arm of the chromosome
t
Translocation
del
Deletion
Note
HY MY LY
NUMERICAL CHROMOSOME ABNORMALITIES Euploidy
High-Yield
When a cell has a multiple of 23 chromosomes, it is said to be euploid. Gametes MEDIUM YIELD (sperm and egg cells) are euploid cells that have 23 chromosomes (one member of LOWcontaining YIELD each pair); they are said to be haploid. Most somatic cells are diploid, both members of each pair, or 46 chromosomes. FUNDAMENTALS REINFORCEMENT
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HY
Euploid Cells (multiple MY of 23 chromosomes)
LY
• Haploid (23 chromosomes): gametes • Diploid (46 chromosomes): most HIGH YIELD somatic cells
MEDIUM • Triploid (69YIELD chromosomes): rare lethal condition LOW YIELD • Tetraploid (92 chromosomes): very rare lethal condition FUNDAMENTALS
REINFORCEMENT
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Two types of euploid cells with abnormal numbers of chromosomes are seen in humans: triploidy and tetraploidy. Triploidy refers to cells that contain 3 copies of each chromosome (69 total). Triploidy, which usually occurs as a result of the fertilization of an ovum by 2 sperm cells, is common at conception, but the vast majority of these conceptions are lost prenatally. However, about 1 in 10,000 live births is a triploid. These babies have multiple defects of the heart and central nervous system, and they do not survive. HY
H
Tetraploidy refers to cells that contain 4 copies of each chromosome (92 MYtotal). This lethal condition is much rarer than triploidy among live births: Only a few LY cases have been described.
HIGH YIEL
High-Yield
Aneuploidy
Aneuploidy, a deviation from the euploid number, represents the gain (+) or MEDIUM YIELD loss (-) of a specific chromosome. Two major forms of aneuploidy are observed: LOW YIELD • Monosomy (loss of a chromosome) • Trisomy (gain of a chromosome)
Autosomal aneuploidy
FUNDAMENTALS
MEDIUM YIE
LOW Y
FUNDAMENT
REINFORCEMENT
REINFORCEM
Two generalizations are helpful: • All autosomal monosomies are inconsistent with a live birth. • Only 3 autosomal trisomies (trisomy 13, 18, and 21) are consistent with
a live birth.
Trisomy 21 (47,XY,+21 or 47,XX,+21); Down Syndrome • Most common autosomal trisomy • Mental retardation • Short stature • Hypotonia • Depressed nasal bridge, upslanting palpebral fissures, epicanthal fold • Congenital heart defects in approximately 40% of cases • Increased risk of acute lymphoblastic leukemia • Alzheimer disease by fifth or sixth decade (amyloid precursor protein,
APP gene on chromosome 21)
• Reduced fertility • Risk increases with increased maternal age
Trisomy 18 (47,XY,+18 or 47,XX,+18); Edward Syndrome • Clenched fist with overlapping fingers • Inward turning, “rocker-bottom” feet • Congenital heart defects • Low-set ears, micrognathia (small lower jaw) • Mental retardation • Very poor prognosis
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Trisomy 13 (47,XY,+13 or 47,XX,+13); Patau Syndrome • Polydactyly (extra fingers and toes) • Cleft lip, palate • Microphthalmia (small eyes) • Microcephaly, mental retardation • Cardiac and renal defects • Very poor prognosis
Sex chromosome aneuploidy
Note
Aneuploidy involving the sex chromosomes is relatively common and tends to have less severe consequences than does autosomal aneuploidy. Some generalizations are helpful: • At least one X chromosome is required for survival.
Trisomy is the most common genetic cause of spontaneous loss of pregnancy.
• If a Y chromosome is present, the phenotype is male (with minor
exceptions).
• If more than one X chromosome is present, all but one will become a
Barr body in each cell.
The two important sex chromosome aneuploidies are Turner syndrome and Klinefelter syndrome. Klinefelter Syndrome (47,XXY) • Testicular atrophy • Infertility • Gynecomastia
Note
• Female distribution of hair
Genetic Mosaicism in Turner Syndrome
• Low testosterone • Elevated FSH and LH • High-pitched voice
Turner Syndrome (45,X or 45,XO) • Only monosomy consistent with life • 50% are 45,X • Majority of others are mosaics for 45,X and one other cell lineage
(46,XX, 47,XXX, 46,XY)
• Females with 45,X;46,XY are at increased risk for gonadal blastoma.
Genetic mosaicism is defined as a condition in which there are cells of different genotypes or chromosome constitutions within a single individual. Some women with Turner syndrome have somatic cells that are 45,X and others that are 46,XX or 47,XXX. Mosaicism in Turner syndrome is thought to arise in early embryogenesis by mechanisms that are not completely understood.
• Short stature • Edema of wrists and ankles in newborn • Cystic hygroma in utero resulting in excess nuchal skin and “webbed” neck • Primary amenorrhea • Coarctation of the aorta or other congenital heart defect in some cases • Infertility • Gonadal dysgenesis
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Nondisjunction is the usual cause of aneuploidies Germ cells undergo meiosis to produce the haploid egg or sperm. Normal meiosis is illustrated in Figure II-3-2A. The original cell is diploid for all chromosomes, although only one homologous pair is shown in the figure for simplicity. The same events would occur for each pair of homologs within the cell. Figure II-3-2B shows the result of nondisjunction of one homologous pair (for example, chromosome 21) during meiosis 1. All other homologs segregate (disjoin) normally in the cell. Two of the gametes are diploid for chromosome 21. When fertilization occurs, the conception will be a trisomy 21 with Down syndrome. The other gametes with no copy of chromosome 21 will result in conceptions that are monosomy 21, a condition incompatible with a live birth. Figure II-3-2C shows the result of nondisjunction during meiosis 2. In this case, the sister chromatids of a chromosome (for example, chromosome 21) fail to segregate (disjoin). The sister chromatids of all other chromosomes segregate normally. One of the gametes is diploid for chromosome 21. When fertilization occurs, the conception will be a trisomy 21 with Down syndrome. One gamete has no copy of chromosome 21 and will result in a conception that is a monosomy 21. The remaining two gametes are normal haploid ones. Some important points to remember: • Nondisjunction is the usual cause of aneuploidies including Down, Edward, Patau, Turner, and Klinefelter syndromes. • Nondisjunction is more likely to occur during oogenesis than during
spermatogenesis.
• Nondisjunction is more likely with increasing maternal age. Environ-
mental agents (e.g., radiation, alcohol) appear to have no measurable influence.
• Nondisjunction is more likely in meiosis I than meiosis II.
Clinical Correlate: Maternal Age and Risk of Down Syndrome Surveys of babies with trisomy 21 show that 90–95% of the time, the extra copy of the chromosome is contributed by the mother (similar figures are obtained for trisomies of the 18th and 13th chromosomes). The increased risk of Down syndrome with maternal age is well documented. • F or women age 3 indicates linkage, while score 3 is the estimate of the recombination frequency. • Then examine the row of recombination frequencies. The value directly above the LOD score >3 is the recombination frequency.
Table II-4-1. LOD Scores for a Gene and a Marker Recombination frequency (θ)
0.01
0.05
0.10
0.20
0.30
0.40
LOD score
0.58
1.89
3.47
2.03
–0.44
–1.20
When interpreting LOD scores, the following rules apply: • LOD score >3.00 shows statistical evidence of linkage. (It is 1,000
times more likely that the gene and the marker are linked at that distance than unlinked.)
• LOD score 3.00, the data may be suggestive of linkage, but results from additional families with the disease would need to be gathered. Gene mapping by linkage analysis serves several important functions: • It can define the approximate location of a disease-causing gene. • Linked markers can be used along with family pedigree information
for genetic testing (see Chapter 5). In practice, markers that are useful for genetic testing must show less than 1% recombination with the gene involved (be 55 with high alcohol intake; immunosuppressed patients such as renal transplant patients Pathogenesis: facultative intracellular pathogen; endotoxin
Disease(s) • Legionnaires disease (“atypical pneumonia”): associated with air-
conditioning systems (now routinely decontaminated); pneumonia; hyponatremia; mental confusion; diarrhea (no Legionella in GI tract)
• Pontiac fever: pneumonitis; no fatalities
Diagnosis • Urinary antigen test (serogroup 1) • DFA (direct fluorescent antibody) on biopsy, (+) by Dieterle silver stain • Fourfold increase in antibody
Treatment: fluoroquinolone (levofloxacin) or macrolide (azithromycin) with rifampin (immunocompromised patients); drug must penetrate human cells. Prevention: routine decontamination of air-conditioner cooling tanks
GENUS: FRANCISELLA Francisella tularensis Distinguishing Features • Small gram-negative rod • Potential biowarfare agent • Zoonosis
Key Vignette Clues Francisella tularensis • Hunter with ulceroglandular disease, atypical pneumonia, or GI disease • Arkansas/Missouri • Exposure to rabbits, ticks
Reservoir: many species of wild animals, especially rabbits, deer, and rodents; endemic in every state of the U.S. but highest in Arkansas and Missouri
Transmission • Tick bite (Dermacentor) → ulceroglandular disease, characterized
by fever, ulcer at bite site, and regional lymph node enlargement and necrosis
• Traumatic implantation while skinning rabbits → ulceroglandular
disease
• Aerosols (skinning rabbits) → pneumonia • Ingestion (of undercooked, infected meat or contaminated water) pro-
duces typhoidal tularemia.
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Part II l Microbiology Microbiology
Pathogenesis: facultative intracellular pathogen (localizes in reticuloendothelial cells); granulomatous response Disease: ulceroglandular tularemia (open wound contact with rabbit blood; tick bite); pneumonic tularemia (bioterrorism; atypical pneumonia) Diagnosis: serodiagnosis (culture is hazardous); DFA; grows on BCYE Treatment: streptomycin Prevention: protection against tick bites; glove use while butchering rabbits; live, attenuated vaccine (for those at high risk)
Key Vignette Clues Bordetella pertussis • Unvaccinated child (immigrant family or religious objections) • Cough with inspiratory “whoop”
GENUS: BORDETELLA Genus Features • Gram-negative small rods • Strict aerobes
Species of Medical Importance: Bordetella pertussis
Note
Bordetella pertussis
B. pertussis Immunity
Distinguishing Features: small gram-negative, aerobic rods; encapsulated organism
• Vaccine immunity lasts 5–10 yrs (and is primarily IgA)
Reservoir: human (vaccinated)
• Babies born with little immunity
Transmission: respiratory droplets
• Vaccinated humans >10 yrs serve as reservoir
Pathogenesis
• 12–20% of afebrile adults with cough >2 wks have pertussis • Vaccine (DTaP) • Acellular • Components: immunogens vary by manufacturer; pertussis toxoid; filamentous hemagglutinin; pertactin (OMP); one other
• B. pertussis is mucosal surface pathogen • Attachment to nasopharyngeal ciliated epithelial cells is via fila-
mentous hemagglutinin; pertussis toxin (on outer membrane) aids in attachment
• Toxins damage respiratory epithelium.
–– Adenylate cyclase toxin: impairs leukocyte chemotaxis → inhibits phagocytosis and causes local edema –– Tracheal cytotoxin: interferes with ciliary action; kills ciliated cells –– Endotoxin –– Pertussis toxin (A and B component, OM protein toxin): ADP ribosylation of Gi (inhibiting negative regulator of adenylate cyclase) interferes with transfer of signals from cell surface to intracellular mediator system: lymphocytosis; islet-activation leading to hypoglycemia; blocking of immune effector cells (decreased chemotaxis); increased histamine sensitivity
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Table II-2-18. Stages of Whooping Cough (Pertussis) vs. Results of Bacterial Culture Incubation
Catarrhal
Paroxysmal
Convalescent
Duration
7–10 days
1–2 weeks
2–4 weeks
3–4 weeks (or longer)
Symptoms
None
Rhinorrhea, malaise, sneezing, anorexia
Repetitive cough with whoops, vomiting, leukocytosis
Diminished paroxysmal cough, development of secondary complications (pneumonia, seizures, encephalopathy)
Bacterial Culture
Diagnosis • Fastidious/delicate: Regan-Lowe or Bordet-Gengou media; either direct
cough plates or nasopharyngeal cultures
• Difficult to culture from middle of paroxysmal stage on • Direct immunofluorescence (DFA) on nasopharyngeal smear • PCR and serologic tests available
Treatment: supportive care, i.e., hospitalization if age 1:160 considered positive Treatment: rifampin and doxycycline minimum 6 weeks (adults); rifampin and cotrimoxazole (children) Prevention: vaccinate cattle; pasteurize milk (especially goat milk)
GENUS: HAEMOPHILUS Key Vignette Clues Haemophilus influenzae • Unvaccinated child 3 mo−2 y: meningitis, pneumonia, epiglottitis • Smokers with COPD: bronchitis, pneumonia • Gram (−) rod, requires factors X and V
Haemophilus influenzae Distinguishing Features • Encapsulated, gram-negative rod; 95% of invasive disease caused by capsular type b • Requires growth factors X (hemin) and V (NAD) for growth on
nutrient or blood agar (BA)
• Grows near S. aureus on BA = “satellite” phenomenon • Chocolate agar provides both X and V factors
Reservoir: human nasopharynx Transmission: respiratory droplets, shared toys
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Pathogenesis • Polysaccharide capsule (type b capsule is polyribitol phosphate) most
important virulence factor
• Capsule important in diagnosis; antigen screen on CSF (e.g., latex
particle agglutination); serotype all isolates by quellung.
• IgA protease is a mucosal colonizing factor.
Diseases • Meningitis
–– Epidemic in unvaccinated children ages 3 months to 2 years –– After maternal antibody has waned and before immune response of child is adequate –– Up to 1990, H. influenzae was most common cause of meningitis age 1–5 (mainly 2,400 serotypes of Salmonella. • S. typhi • S. enteritidis • S. typhimurium
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• S. choleraesuis • S. paratyphi • S. dublin
Salmonella enterica typhi Distinguishing Features • Gram-negative rods, highly motile with the Vi capsule • Facultative anaerobe, non–lactose fermenting • Produces H2S • Species identification with biochemical reactions • Sensitive to acid
Reservoir: humans only; no animal reservoirs
Key Vignette Clues Salmonella typhi • Patient with fever, abdominal pain • Travel to endemic area • Gram (−), encapsulated, nonlactose fermenter, produces H2S gas • Widal test
Transmission: fecal-oral route from human carriers (gall bladder); decreased stomach acid or impairment of mononuclear cells as in sickle cell disease predisposes to Salmonella infection Pathogenesis and Disease: typhoid fever (enteric fever), S. typhi (milder form: paratyphoid fever; S. paratyphi) • Infection begins in ileocecal region; constipation common • Host cell membranes “ruffle” from Salmonella contact. • Salmonella reach basolateral side of M cells, then mesenteric lymph
nodes and blood (transient 19 septicemia)
• At 1 week: patients have 80% positive blood cultures; 25% have rose
spots (trunk/abdomen), signs of septicemia (mainly fever)
• S. typhi survives intracellularly and replicates in macrophages;
resistant to macrophage killing because of decreased fusion of lysosomes with phagosomes and defensins (proteins) allow it to withstand oxygen-dependent and oxygen-independent killing
• By week 3: 85% of stool cultures are positive • Symptoms: fever, headache, abdominal pain, constipation more com-
mon than diarrhea
• Complications if untreated: necrosis of Peyer patches with perforation
(local endotoxin triggered damage), thrombophlebitis, cholecystitis, pneumonia, abscess formation, etc.
Diagnosis: organisms can be isolated from blood, bone marrow, urine, and tissue biopsy from the rose spots if present; antibodies to O, Vi, and H antigens in patient’s serum can be detected by agglutination (Widal test) Treatment: fluoroquinolones or third-generation cephalosporins Prevention: sanitation; 3 vaccines (attenuated oral vaccine of S. typhi strain 21 (Ty21a), parenteral heat-killed S. typhi (no longer used in U.S.), and parenteral ViCPS polysaccharide capsular vaccine)
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Salmonella Subspecies other than typhi (S. enteritidis, S. typhimurium) Distinguishing Features
Key Vignette Clues Salmonella enterica Subspecies Other Than typhi • Enterocolitis—inflammatory, follows ingestion of poultry products or handling pet reptiles • Septicemia—very young or elderly • Osteomyelitis—sickle cell disease • Gram (−) bacillus, motile, non− lactose fermenter, produces H2S
• Facultative gram-negative rods, non–lactose-fermenting on EMB,
MacConkey medium
• Produces H2S, motile (unlike Shigella) • Speciated with biochemical reactions and serotyped with O, H, and Vi
antigens
Reservoir: enteric tracts of humans and domestic animals, e.g., chickens and turtles Transmission: raw chicken and eggs in kitchen; food-borne outbreaks (peanut butter, produce, eggs); reptile pets (snakes, turtles)
Pathogenesis • Sensitive to stomach acid (infectious dose 105 organisms) • Lowered stomach acidity (antacids or gastrectomy) increases risk • Endotoxin in cell wall; no exotoxin • Invades mucosa in ileocecal region, invasive to lamina propria →
inflammation → increased PG → increased cAMP → loose diarrhea; shallow ulceration
• Spread to septicemia not common with S. enterica subsp. enteritidis
(the most common) but may occur with others
Disease(s) • Enterocolitis/gastroenteritis (second most common bacterial cause
after Campylobacter): 6–48 hour incubation; nausea; vomiting; only occasionally bloody, loose stools; fever; abdominal pain; myalgia; headache
• Septicemia (S. enterica subsp. choleraesuis, S. enterica subsp. paratyphi,
and S. enterica subsp. dublin): usually in very young or elderly when it occurs; endocarditis or arthritis complicates 10% of cases
• Osteomyelitis: sickle cell disease predisposes to osteomyelitis; Salmo-
nella is most common causal agent of osteomyelitis in sickle cell disease (not trait) patients (>80%)
Diagnosis: culture on Hektoen agar, H2S production Treatment: antibiotics are contraindicated for self-limiting gastroenteritis; ampicillin, third-generation cephalosporin, fluoroquinolone, or TMP-SMX for invasive disease Prevention: properly cook foods and wash hands, particularly food handlers
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GENUS: GARDNERELLA
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Key Vignette Clues Gardnerella
Gardnerella vaginalis
• Female patient with thin vaginal discharge
Distinguishing Features • Gram-variable rod; has Gram-positive cell envelope
• Post antibiotic or menses
• Facultative anaerobe
• Clue cells
• Catalase-negative and oxidase-negative
• Whiff test
Reservoir: human vagina Transmission: endogenous (normal flora gets disturbed, increased pH)
Pathogenesis • Polymicrobial infections • Works synergistically with other normal flora organisms including
Lactobacillus, Mobiluncus, Bacteroides, Peptostreptococcus
• Thought to flourish when the vaginal pH increases, reduction of vagi-
nal Lactobacillus
• Follows menses or antibiotic therapy
Disease: bacterial vaginosis (vaginal odor, increased discharge (thin, gray, adherent fluid) Diagnosis: pH >4.5, clue cells (epithelial cells covered with bacteria) on vaginal saline smear; for Whiff test, add KOH to sample and assess for “fishy” amine odor Treatment: metronidazole or clindamycin
Recall Question Ulcers caused by Shigella species have which of the following characteristics? A. Are deep B. Have granulomatous borders C. Invade the vascular structures D. Are shallow Answer: D
GENUS: BACTEROIDES Bacteroides fragilis Distinguishing Features: anaerobic gram-negative rods; modified LPS with reduced activity
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Key Vignette Clues
Reservoir: human colon; the genus Bacteroides is predominant anaerobe
Bacteroides fragilis
Transmission: endogenous from bowel defects (e.g., cytotoxic drug use, cancer), surgery, or trauma
• Patient with abdominal trauma, emergency abdominal surgery • Septicemia, peritonitis, abscess • Gram (−) bacilli, anaerobic
Pathogenesis: modified LPS (missing heptose and 2-keto-3 deoxyoctonate) has reduced endotoxin activity; capsule is antiphagocytic Diseases: septicemia, peritonitis (often mixed infections), and abdominal abscess Diagnosis: anaerobes are identified by biochemical tests and gas chromatography
Treatment • Metronidazole, clindamycin, or cefoxitin; abscesses should be surgi-
cally drained
• Antibiotic resistance common (penicillin G, some cephalosporins, and
aminoglycosides); 7−10% of all strains now clindamycin-resistant
Prevention: prophylactic antibiotics for GI or biliary tract surgery
Porphyromonas, Prevotella, Fusobacterium spp. Distinguishing Features: Gram-negative rods, anaerobic, normal oral flora Transmission: endogenous Pathogenesis: Porphyromonas has gingipains: act as proteases, adhesins, degrades IgG antibodies and inflammatory cytokines Disease: periodontal disease Diagnosis: anaerobic, gram-negative rods isolated from abscess
Key Vignette Clues
Treatment: metronidazole
Treponema pallidum • Sexually active patient or neonate of IV drug-using female
SPIROCHETES
• Primary: nontender, indurated genital chancre
GENUS: TREPONEMA
• Secondary: maculopapular, copper-colored rash, condylomata lata
Treponema pallidum Distinguishing Features
• Tertiary: gummas in CNS and cardiovascular system
• Thin spirochete, not reliably seen on Gram stain (basically a gram-
• Spirillar, gram (−) bacteria visualized by dark-field or fluorescent antibody
• Outer membrane has endotoxin-like lipids
• Specific and nonspecific serologic tests
negative cell envelope)
• Axial filaments = endoflagella = periplasmic flagella • Cannot culture in clinical lab; serodiagnosis • Is an obligate pathogen (but not intracellular)
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Reservoir: human genital tract Transmission: transmitted sexually or across the placenta Pathogenesis: disease characterized by endarteritis resulting in lesions; strong tendency to chronicity
Table II-2-22. Stages of Syphilis Stage
Clinical
Diagnosis
Primary (10 d to 3 mo post-exposure)
Nontender chancre; clean, indurated edge; contagious; heals spontaneously 3−6 weeks
Fluorescent microscopy of lesion 50% of patients will be negative by nonspecific serology
Secondary (1 to 3 mo later)
Maculopapular (copper-colored) rash, diffuse, includes palms and soles, patchy alopecia
Serology nonspecific and specific; both positive
Condylomata lata: flat, wartlike perianal and mucous membrane lesions; highly infectious Latent
None
Positive serology
Tertiary (30% of untreated, years later)
Gummas (syphilitic granulomas), aortitis, CNS inflammation (tabes dorsalis)
Serology: specific tests Nonspecific may be negative
Congenital (babies of IV drug-users)
Stillbirth, keratitis, 8th nerve damage, notched teeth; most born asymptomatic or with rhinitis → widespread desquamating maculopapular rash
Serology: should revert to negative within 3 mo of birth if uninfected
Diagnosis • Visualize organisms by immunofluorescence or microscopy (dark
field microscopy was standard but no longer used)
• Serology important: 2 types of antibody:
–– Nontreponemal antibody (= reagin) screening tests ºº Ab binds to cardiolipin: antigen found in mammalian mitochondrial membranes and treponemes; cheap source of antigen is cow heart, used in screening tests (VDRL, RPR, ART); very sensitive in primary (except early) and secondary syphilis; titer may decline in tertiary and with treatment; not specific so confirm with FTA-ABS ºº Examples: venereal disease research lab (VDRL), rapid plasma reagin (RPR), automated reagin test (ART), recombinant antigen test (ICE)
–– Specific tests for treponemal antibody (more expensive)
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ºº Earliest antibodies; bind to spirochetes: these tests are more specific and positive earlier; usually remain positive for life, but positive in those with other treponemal diseases (bejel) and may be positive in Lyme disease; fluorescent treponemal antibody-absorption (FTAABS; most widely used test); Treponema pallidum microhemagglutination (MHA-TP)
Treatment • Benzathine penicillin (long-acting form) for primary and secondary
syphilis (no resistance to penicillin); penicillin G for congenital and late syphilis
• Jarisch-Herxheimer reaction: starts during first 24 hours of antibiotic
treatment; increased temperature and decreased BP; rigors, leukopenia; may occur during treatment of any spirochete disease
Prevention: benzathine penicillin given to contacts; no vaccine available
GENUS: BORRELIA Genus Features • Larger spirochetes • Gram negative • Microaerophilic • Difficult to culture
Key Vignette Clues Borrelia burgdorferi • Patient with influenza-like symptoms and erythema migrans • Spring/summer seasons
Borrelia burgdorferi Reservoir: white-footed mice (nymphs) and white-tailed deer (adult ticks) Transmission: Ixodes (deer) ticks and nymphs; worldwide but in 3 main areas of U.S.: • Ixodes scapularis (I. dammini) in Northeast (e.g., Connecticut), Mid-
west (e.g., Wisconsin, Minnesota)
• Northeast, Midwest, West Coast
• Ixodes pacificus on West Coast (e.g., California)
• Later: neurologic, cardiac, arthritis/arthralgias
• Late spring/early summer incidence
Pathogenesis: B. burgdorferi invades skin and spreads via bloodstream to involve primarily the heart, joints, and CNS; arthritis is caused by immune complexes Disease: Lyme disease (#1 vector-borne disease in U.S.)
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Target rash Flu-like symptoms
Stage 2: early disseminated (days to weeks)
Swollen lymph nodes
(organism spreads hematogenously)
Secondary annular skin lesions Bell palsy, headache, meningitis, extreme fatigue, conjunctivitis Palpitations, arrhythmias, myocarditis, pericarditis
Stage 3: late persistent (months to years)
Arthritis (mostly knees), immune complex-mediated
Diagnosis: serodiagnosis by ELISA (negative early); Western blot for confirmation Treatment: doxycycline, amoxicillin, or azithromycin/clarithromycin for primary; ceftriaxone for secondary; doxycycline or ceftriaxone for arthritis Prevention: DEET; avoid tick bites; vaccine (OspA flagellar antigen) not used in U.S.
Borrelia recurrentis and B. hermsii Distinguishing Features: spirochetes, cause relapsing fever Transmission: human body louse for B. recurrentis; soft ticks from mice for B. hermsii (and 13 other species of Borrelia) Pathogenesis: antigenic variation leads to return of fever/chills Disease(s): relapsing fever (tick-borne relapsing fever in U.S. is caused mainly by B. hermsii); associated with camping in rural areas of Colorado Diagnosis: spirochetes seen on dark-field microscopy of blood smear when patient is febrile Treatment: doxycycline; Jarisch-Herxheimer reaction possible
Recall Question Which of the following bacteria is the most common cause of osteomyelitis in sickle cell disease? A. Escherichia coli B. Salmonella enterica C. Staphylococcus aureus D. Yersinia enterocolitica Answer: B
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GENUS: LEPTOSPIRA
Key Vignette Clues
Leptospira interrogans
Leptospira interrogans
Distinguishing Features: spirochetes with tight terminal hooks or coils (seen on dark-field microscopy but not light; can be cultured in vitro; aerobic); generally diagnosed by serology
• Patients with influenza-like symptoms ± GI symptoms
Reservoir: wild and domestic animals (zoonosis)
• Occupational or recreational exposure to water aerosols
Transmission
• Hawaii
• Contact with animal urine in water; organism penetrates mucous
membranes or enters small breaks in epidermis
• Spirochetes with terminal hook
• In U.S., via dog, livestock, and rat urine through contaminated
recreational waters (jet skiers) or occupational exposure (sewer workers)
• Hawaii highest incidence state
Pathogenesis: no toxins or virulence factors known Disease: leptospirosis (swineherd’s disease, swamp or mud fever); influenzalike disease ± GI tract symptoms (Weil disease); if not treated, can progress to hepatitis and renal failure Diagnosis: serodiagnosis (agglutination test); culture (blood, CSF, urine) available in few labs; dark-field microscopy insensitive Treatment: penicillin G or doxycycline Prevention: doxycycline for short-term exposure; vaccination of domestic livestock and pets; rat control
UNUSUAL BACTERIA Table II-2-23. Comparison of Chlamydiaceae, Rickettsiaceae, and Mycoplasmataceae with Typical Bacteria Typical Bacteria (S. aureus)
Chlamydiaceae
Rickettsiaceae
Mycoplasmataceae
Obligate intracellular parasite?
Mostly no
Yes
Yes
No
Make ATP?
Normal ATP
No ATP
Limited ATP
Normal ATP
Peptidoglycan layer in cell envelope?
Normal peptidoglycan
Modified* peptidoglycan
Normal peptidoglycan
No peptidoglycan
*Chlamydial peptidoglycan lacks muramic acid and is considered by some as modified, by others as absent.
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FAMILY: CHLAMYDIACEAE Family Features • Obligate intracellular bacteria • Elementary body/reticulate body • Not seen on Gram stain • Cannot make ATP • Cell wall lacks muramic acid
Genera of Medical Importance • Chlamydia trachomatis • Chlamydophila pneumoniae • Chlamydophila psittaci
Chlamydia trachomatis Distinguishing Features • Obligate intracellular bacterium; cannot make ATP • Found in cells as metabolically active, replicating reticulate bodies • Infective form: inactive, extracellular elementary body • Not seen on Gram stain; peptidoglycan layer lacks muramic acid
Key Vignette Clues Chlamydia trachomatis • Sexually active patient or neonate • Adult: urethritis, cervicitis, PID, inclusion •
conjunctivitis
Reservoir: human genital tract and eyes
• Neonate: inclusion conjunctivitis/ pneumonia
Transmission: sexual contact and at birth; trachoma is transmitted by handto-eye contact and flies.
• Immigrant from Africa/Asia, genital lymphadenopathy
Pathogenesis: infection of nonciliated columnar or cuboidal epithelial cells of mucosal surfaces leads to granulomatous response and damage
• Cytoplasmic inclusion bodies in scrapings
Diseases • STDs in U.S.
–– Serotypes D-K (most common bacterial STD in U.S., though overall herpes and HPV are more common in prevalence) –– Nongonococcal urethritis, cervicitis, PID, and major portion of infertility (no resistance to reinfection) –– Inclusion conjunctivitis in adults (with NGU and reactive arthritis) –– Inclusion conjunctivitis and/or pneumonia in neonates/infants (staccato cough) with eosinophilic infiltrate • Lymphogranuloma venereum
–– Serotypes L1, 2, 3 (prevalent in Africa, Asia, South America); painless ulcer at site of contact; swollen lymph nodes (buboes) around inguinal ligament (groove sign); tertiary includes ulcers, fistulas, genital elephantiasis
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• Trachoma
–– Leading cause of preventable infectious blindness: serotypes A, B, Ba, and C –– Follicular conjunctivitis leading to conjunctival scarring, and inturned eyelashes leading to corneal scarring and blindness
Diagnosis • NAAT; DNA probes in U.S. (rRNA) and PCR • Cytoplasmic inclusions seen on Giemsa-, iodine-, or fluorescent-
antibody-stained smear or scrapings
• Cannot be cultured on inert media • Is cultured in tissue cultures or embryonated eggs • Serodiagnosis: DFA, ELISA
Treatment: azithromycin or doxycycline Prevention: erythromycin for infected mothers to prevent neonatal disease; systemic erythromycin for neonatal conjunctivitis to prevent pneumonia
Key Vignette Clues Chlamydophila • C. pneumoniae: atypical pneumonia: sputum with intracytoplasmic inclusions • C. psittaci: atypical pneumonia: exposure to parrots
GENUS: CHLAMYDOPHILA Table II-2-24. Diseases Caused by Chlamydophila Species Organism
C. pneumoniae
C. psittaci
Distinguishing characteristics
Potential association with atherosclerosis
No glycogen in inclusion bodies
Reservoir
Human respiratory tract
Birds, parrots, turkeys (major U.S. reservoir)
Transmission
Respiratory droplets
Dust of dried bird secretions and feces
Pathogenesis
Intracellular growth; infects smooth muscle, endothelial cells, or coronary artery and macrophages
Intracellular growth
Disease
Atypical “walking” pneumonia; single lobe; bronchitis; scant sputum, prominent dry cough and hoarseness; sinusitis
Psittacosis (ornithosis); atypical pneumonia with hepatitis, possible CNS and GI symptoms
Diagnosis
Serology (complement fixation or microimmunofluorescence)
Serology, complement fixation Cold-agglutinin negative
Cold-agglutinin negative Treatment
Macrolides and tetracycline
Doxycycline
Prevention
None
Avoid birds
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Recall Question Diagnosis of Lyme disease is done with which of the following? A. Doxycycline treatment challenge B. Skin biopsy C. Skin inspection for tick bite D. Serodiagnosis by ELISA followed by Western blot Answer: D
GENUS: RICKETTSIA Table II-2-25. Infections Caused by Rickettsiae and Close Relatives Group Disease
Bacterium
Arthropod Vector
Reservoir Host
Rocky Mountain Spotted Fever
R. rickettsii
Ticks
Ticks, dogs, rodents
Epidemic Typhus
R. prowazekii
Human louse
Humans
Endemic Typhus
R. typhi
Fleas
Rodents
Scrub Typhus
Orientia tsutsugamushi
Mites
Rodents
Ehrlichiosis
E. chaffeensis
Tick
Small mammals
A. phagocytophilum
Genus Features • Aerobic, gram-negative bacilli (too small to stain well with Gram stain) • Obligate intracellular bacteria (do not make sufficient ATP for
independent life)
Species of Medical Importance • Rickettsia rickettsii • Rickettsia prowazekii • Rickettsia typhi • Orientia tsutsugamushi (formerly R. tsutsugamushi) • Ehrlichia spp. • Coxiella burnetii
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Key Vignette Clues
Rickettsia rickettsii
Rickettsia rickettsii
Reservoir: small wild rodents and larger wild and domestic animals (dogs)
• Patient with influenza-like symptoms and petechial rash that begins on ankles and wrists and moves to trunk • East Coast mountainous areas • Spring/summer seasons • Outdoor exposure • Weil-Felix (+)
Transmission: hard ticks: Dermacentor (also reservoir hosts because of transovarian transmission) Pathogenesis: invade endothelial cells lining capillaries, causing vasculitis in many organs including brain, liver, skin, lungs, kidney, and GI tract Disease: Rocky Mountain spotted fever (RMSF) • Prevalent on East Coast (OK, TN, NC, SC); 2–12 day incubation • Headache, fever (38.8 C [102.0 F]), malaise, myalgias, toxicity,
vomiting, and confusion
• Rash (maculopapular → petechial) starts (by day 6 of illness) on
ankles and wrists and then spreads to the trunk, palms, soles, and face (centripetal rash)
• Ankle and wrist swelling also occur • Diagnosis may be confused by GI symptoms, periorbital swelling, stiff
neck, conjunctivitis, and arthralgias
Diagnosis • Clinical symptoms (above) and tick bite • Start treatment without laboratory confirmation • Serological IFA test most widely used; fourfold increase in titer is
diagnostic
• Weil-Felix test (cross-reaction of Rickettsia antigens with OX strains of
Proteus vulgaris) is no longer used (but may still be asked!)
Treatment: doxycycline, even in children age 6 cm in diameter will rupture within 10 years. Those >5 cm are treated surgically. Syphilitic aneurysms involve the ascending aorta in tertiary syphilis (late stage). Syphilitic (luetic) aortitis causes an obliterative endarteritis of the vasa vasorum, leading to ischemia and smooth-muscle atrophy of the aortic media. Syphilitic aneurysms may dilate the aortic valve ring, causing aortic insufficiency. Aortic dissecting aneurysm occurs when blood from the vessel lumen enters an intimal tear and dissects through the layers of the media. The etiology usually involves degeneration (cystic medial degeneration) of the tunica media. Aortic dissecting aneurysm presents with severe tearing pain. The dissecting aneurysm may compress and obstruct the aortic branches (e.g., renal or coronary arteries). Hypertension and Marfan syndrome are predisposing factors. Berry aneurysm is a congenital aneurysm of the circle of Willis. Microaneurysms are small aneurysms commonly seen in hypertension and diabetes. Mycotic aneurysms are aneurysms usually due to bacterial or fungal infections.
Arteriovenous (AV) Fistulas Arteriovenous (AV) fistulas are a direct communication between a vein and an artery without an intervening capillary bed. They may be congenital or acquired (e.g., trauma). Potential complications include shunting of blood which may lead to high-output heart failure and risk of rupture and hemorrhage.
VENOUS DISEASE Deep Vein Thrombosis Deep vein thrombosis (DVT) usually affects deep leg veins (90%), with iliac, femoral, and popliteal veins being particularly commonly affected. It is often asymptomatic and is consequently a commonly missed diagnosis. When symptomatic, it can produce unilateral leg swelling with warmth, erythema, and positive Homan sign (increased resistance to passive dorsiflexion of the ankle by the examiner). The diagnosis can be established with Doppler “duplex” ultrasound. The major complication is pulmonary embolus.
Varicose Veins Varicose veins are dilated, tortuous veins caused by increased intraluminal pressure. A variety of veins can be affected. • Superficial veins of the lower extremities are particularly vulnerable due
to a lack of structural support from superficial fat and/or incompetent valve(s). Varicosities of these superficial veins are very common (15% of the U.S. population); occur more frequently in females than males; and are common in pregnancy.
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• Esophageal varices are due to portal hypertension (usually caused by cir-
rhosis) and may be a source of life-threatening hemorrhage.
• Varices of the anal region are commonly called hemorrhoids; are associMicrobiology
ated with constipation and pregnancy; and may be complicated by either bleeding (streaks of red blood on hard stools) or thrombosis (painful).
Venous Insufficiency Venous insufficiency is more common in women than men, and the incidence increases with age. Lower extremities demonstrate edema, hyperpigmentation and ulceration due to venous hypertension and incompetent valves.
VASCULAR ECTASIAS A vascular ectasia is a dilatation of a vessel; it is not a neoplasm. Examples include: • Nevus flammeus nuchae is a neck “birthmark” or “stork bite” that
regresses.
• Port wine stain is a vascular birthmark that does not regress. • Spider telangiectasias occur on the face, blanch with pressure, and are
associated with pregnancy.
VASCULAR NEOPLASMS Clinical Correlate Port wine stains are large, flat, vascular malformations that are closely related to hemangiomas and are often seen on the head in the trigeminal nerve distribution.
Benign Tumors Hemangiomas are extremely common, benign vascular tumors. They are the most common tumor in infants appearing on the skin, mucous membranes, or internal organs. The major types are capillary and cavernous hemangiomas. Hemangiomas may spontaneously regress.
© Richard P. Usatine, MD Used with permission.
Figure 12-2. Hemangioma
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Hemangioblastomas are associated with von Hippel-Lindau disease, which may cause multiple hemangioblastomas involving the cerebellum, brain stem, spinal cord, and retina, as well as renal cell carcinoma. Glomus tumors (glomangioma) are benign, small, painful tumors of the glomus body that usually occur under fingernails.
Malignant Tumors Kaposi sarcoma is a malignant tumor of endothelial cells associated with Kaposi-sarcoma–associated virus (HHV8). The condition causes multiple redpurple patches, plaques, or nodules that may remain confined to the skin or may disseminate. Microscopically, there is a proliferation of spindle-shaped endothelial cells with slit-like vascular spaces and extravasated erythrocytes. • The classic European form occurs in older men of Eastern European or
Mediterranean origin, who develop red-purple skin plaques on the lower extremities.
• The transplant-associated form occurs in patients on immunosuppression
for organ transplants; involves skin and viscera; may regress with reduction of immunosuppression.
• The African form occurs in African children and young men in whom
generalized lymphatic spread is common.
• The AIDS-associated form is most common in homosexual male AIDS
patients; it is an aggressive form with frequent widespread visceral dissemination. Common sites of involvement include skin, GI tract, lymph nodes, and lungs. This form of Kaposi sarcoma is responsive to chemotherapy and interferon-alpha, and only rarely causes death.
Angiosarcoma (hemangiosarcoma) is a malignant vascular tumor with a high mortality that most commonly occurs in skin, breast, liver, and soft tissues. Liver angiosarcomas are associated with vinyl chloride, arsenic, and thorotrast.
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Learning Objectives ❏❏ Determine the pathophysiology and different presentations of ischemic heart disease ❏❏ Define congestive heart failure and recognize the differences between left vs right heart failure ❏❏ Identify the pathophysiologic characteristics and presentation of the variousvalvular heart diseases, including carcinoid heart disease ❏❏ Differentiate the pathophysiologic characteristics of the most common congenital heart diseases ❏❏ Classify the different cardiomyopathies according to clinical presentation ❏❏ Outline the clinical characteristics of cardiac tumors and pericardial diseases
ISCHEMIC HEART DISEASE Epidemiology Ischemic heart disease is usually secondary to coronary artery disease (CAD); it is the most common cause of death in the United States. It is most often seen in middle-age men and postmenopausal women.
Clinical Presentations of Heart Disease Angina pectoris is due to transient cardiac ischemia without cell death resulting in substernal chest pain. • Stable angina (most common type) is caused by coronary artery ath-
erosclerosis with luminal narrowing >75%. Chest pain is brought on by increased cardiac demand (exertional or emotional), and is relieved by rest or nitroglycerin (vasodilation). Electrocardiogram shows ST segment depression (subendocardial ischemia).
• Prinzmetal variant angina is caused by coronary artery vasospasm and
produces episodic chest pain often at rest; it is relieved by nitroglycerin (vasodilatation). Electrocardiogram shows transient ST segment elevation (transmural ischemia).
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• Unstable or crescendo angina is caused by formation of a nonocclusive
thrombus in an area of coronary atherosclerosis, and is characterized by increasing frequency, intensity, and duration of episodes; episodes typically occur at rest. This form of angina has a high risk for myocardial infarction.
Microbiology
Myocardial infarction (MI) occurs when a localized area of cardiac muscle undergoes coagulative necrosis due to ischemia. It is the most common cause of death in the United States. The mechanism leading to infarction is coronary artery atherosclerosis (90% of cases). Other causes include decreased circulatory volume, decreased oxygenation, decreased oxygen-carrying capacity, or increased cardiac workload, due to systemic hypertension, for instance. • Distribution of coronary artery thrombosis. The left anterior descending
artery (LAD) is involved in 45% of cases; the right coronary artery (RCA) is involved in 35% of cases; and the left circumflex coronary artery (LCA) is involved in 15% of cases.
/HIWFRURQDU\DUWHU\ &LUFXPIOH[DUWHU\ /HIWDQWHULRU GHVFHQGLQJDUWHU\ 5LJKWFRURQDU\ DUWHU\
'LDJRQDODUWHU\
0DUJLQDODUWHU\ 3RVWHULRU LQWHUYHQWULFXODUDUWHU\ )LJXUH$UWHULDO6XSSO\WRWKH+HDUW
Figure 13-1. Arterial Supply to the Heart
Infarctions are classified as transmural, subendocardial, or microscopic. • Transmural infarction (most common type) is considered to have occurred
when ischemic necrosis involves >50% of myocardial wall. It is associated with regional vascular occlusion by thrombus. It causes ST elevated MIs (STEMIs) due to atherosclerosis and acute thrombosis.
• Subendocardial infarction is considered to have occurred when ischemic
necrosis involves 40–50% myocardium is necrotic); mural thrombus and thromboembolism; fibrinous pericarditis; ventricular aneurysm; and cardiac rupture. Cardiac rupture most commonly
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Clinical Correlate
Microbiology
Auscultation of a friction rub is characteristic of pericarditis. Pericarditis is most common 2–3 days after infarction, but may also occur several weeks later (Dressler syndrome—a rare autoimmune reaction (type II) where the necrotic heart muscle induces the immune system to generate autoantibodies to cardiac self-antigens).
occurs 3–7 days after MI. Effects vary with the site of rupture: ventricular free wall rupture causes cardiac tamponade; interventricular septum rupture causes left to right shunt; and papillary muscle rupture causes mitral insufficiency. Sudden cardiac death is defined to be death within 1 hour of the onset of symptoms. The mechanism is typically a fatal cardiac arrhythmia (usually ventricular fibrillation). Coronary artery disease is the most common underlying cause (80%); other causes include hypertrophic cardiomyopathy, mitral valve prolapse, aortic valve stenosis, congenital heart abnormalities, and myocarditis. Chronic ischemic heart disease is the insidious onset of progressive congestive heart failure. It is characterized by left ventricular dilation due to accumulated ischemic myocardial damage (replacement fibrosis) and functional loss of hypertrophied noninfarcted cardiac myocytes.
CONGESTIVE HEART FAILURE Physiologic Basis Clinical Correlate Clinically, the degree of orthopnea is often quantified in terms of the number of pillows the patient needs in order to sleep comfortably (e.g., “three-pillow orthopnea”).
Congestive heart failure (CHF) refers to the presence of insufficient cardiac output to meet the metabolic demand of the body’s tissues and organs. It is the final common pathway for many cardiac diseases and has an increasing incidence in the United States. Complications include both forward failure (decreased organ perfusion) and backward failure (passive congestion of organs). Right- and leftsided heart failure often occur together.
Left Heart Failure Left heart failure can be caused by ischemic heart disease, systemic hypertension, myocardial diseases, and aortic or mitral valve disease. The heart has increased heart weight and shows left ventricular hypertrophy and dilatation. The lungs are heavy and edematous. Left heart failure presents with dyspnea, orthopnea, paroxysmal nocturnal dyspnea, rales, and S3 gallop. Microscopically, the heart shows cardiac myocyte hypertrophy with “enlarged pleiotropic nuclei,” while the lung shows pulmonary capillary congestion and alveolar edema with intra-alveolar hemosiderin-laden macrophages (“heart failure cells”). Complications include passive pulmonary congestion and edema, activation of the renin-angiotensin-aldosterone system leading to secondary hyperaldosteronism, and cardiogenic shock.
Note Cor pulmonale is right-sided heart failure caused by pulmonary hypertension from intrinsic lung disease. Lung disease → pulmonary HTN → ↑ right ventricular pressure → right ventricular hypertrophy → right-sided heart failure
Right Heart Failure Right heart failure is most commonly caused by left-sided heart failure, with other causes including pulmonary or tricuspid valve disease and cor pulmonale. Right heart failure presents with JVD, hepatosplenomegaly, dependent edema, ascites, weight gain, and pleural and pericardial effusions. Grossly, right ventricular hypertrophy and dilatation develop. Chronic passive congestion of the liver may develop and may progress to cardiac sclerosis/cirrhosis (only with long-standing congestion).
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VALVULAR HEART DISEASE Left Heart • Bicuspid aortic valve is the most common heart valve defect. It is heritable,
and NOTCH1 mutations are associated with some cases. Although it is a congenital cardiac malformation, it sometimes does not cause morbidity until adult life. In the majority of cases, it causes valve stenosis (whereby the valve does not completely open), but it can cause valvular insufficiency (whereby the valve does not completely close). Infectious endocarditis and aortic dilatation and dissection are possible complications.
• Degenerative calcific aortic valve stenosis is a common valvular abnor-
mality characterized by age-related dystrophic calcification, degeneration, and stenosis of the aortic valve. Less commonly it occurs in the setting of bicuspid aortic valve. It can lead to concentric left ventricular hypertrophy (LVH) and congestive heart failure with increased risk of sudden death. The calcifications are on the outflow side of the cusps. Treatment is aortic valve replacement.
• Mitral valve prolapse has enlarged, floppy mitral valve leaflets that pro-
lapse into the left atrium and microscopically show myxomatous degeneration. The condition affects individuals with Marfan syndrome. Patients are asymptomatic and a mid-systolic click can be heard on auscultation. Complications include infectious endocarditis and septic emboli, rupture of chordae tendineae with resulting mitral insufficiency, and rarely sudden death.
Right Heart The topics tricuspid atresia and pulmonary atresia are discussed under congenital heart disease later in this chapter. Carcinoid heart disease is right-sided endocardial and valvular fibrosis secondary to serotonin exposure in patients with carcinoid tumors that have metastasized to the liver. It is a plaque-like thickening (endocardial fibrosis) of the endocardium and valves of the right side of the heart. Many patients experience carcinoid syndrome (also related to secretion of serotonin and other metabolically active products of the tumors), characterized by skin flushing, diarrhea, cramping, bronchospasm, wheezing, and telangiectasias. The diagnosis can be established by demonstrating elevated urinary 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of the breakdown of serotonin via monoamine oxidase.
Inflammatory Valvular Disease Infective bacterial endocarditis (or more aptly infective endocarditis) refers to bacterial infection of the cardiac valves, characterized by vegetations on the valve leaflets. Risk factors include rheumatic heart disease, mitral valve prolapse, bicuspid aortic valve, degenerative calcific aortic stenosis, congenital heart disease, artificial valves, indwelling catheters, dental procedures, immunosuppression, and intravenous drug use.
Clinical Correlate Endocarditis involving the tricuspid valve is highly suggestive of IV drug use or central line bacteremia.
• Acute endocarditis is typically due to a high virulence organism that can
colonize a normal valve, such as Staphylococcus aureus. Acute endocarditis produces large destructive vegetations (fibrin, platelets, bacteria, and neutrophils). The prognosis is poor, with mortality of 10–40%.
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• Subacute endocarditis is typically due to a low virulence organism, such
as Streptococcus group viridans, which usually colonizes a previously damaged valve. The disease course is typically indolent with 50% of cases) or idiopathic. The muscle hypertrophy is due to the increased synthesis of actin and myosin, and on microscopic examination, the cardiac muscle fibers are hypertrophied and in disarray. Hypertrophic cardiomyopathy is most prominent in the ventricular septum, where it can obstruct the ventricular outflow tract. This can potentially lead to death during severe exercise when the cardiac outflow tract collapses, preventing blood from exiting the heart.
Restrictive Cardiomyopathy Restrictive cardiomyopathy (uncommon form) is caused by diseases which produce restriction of cardiac filling during diastole; etiologies include amyloidosis, sarcoidosis, endomyocardial fibroelastosis, and Loeffler endomyocarditis. In all of these diseases, increased deposition of material leads to decreased compliance, affecting diastolic function. On gross examination, the ventricles are not enlarged and the cavities are not dilated. Microscopy will reflect the underlying cause.
Arrhythmogenic Right Ventricular Cardiomyopathy Note
Arrhythmogenic right ventricular cardiomyopathy causes thinning of the right ventricle due to autosomal dominant mutations that encode desmosomal junctional proteins. On microscopy, there is fatty infiltration of the myocardium.
Tuberous Sclerosis Complex • Autosomal dominant • Mutation in genes TSC1 and TSC2, which encode tumor suppressor proteins hamartin and tuberin, respectively • Multiple hamartomas
CARDIAC TUMORS General Concepts Primary cardiac tumors are rare. The majority are benign; the malignant tumors are sarcomas and lymphomas. Treatment is excision.
• Cortical tubers • Renal angiomyolipomas • Cardiac rhabdomyomas • Pulmonary hamartomas
Benign Common Tumors The myxoma is the most common tumor in adults, and the rhabdomyoma is the most common tumor in children.
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• Cardiac myxoma is a benign tumor usually arising within the left atrium
near the fossa ovalis in decades 3–6 of life; it can present like mitral valve disease. In 10% of cases there is an autosomal dominant condition known as Carney complex (myxomas with endocrine abnormalities and lentigines or pigmented nevi). Cardiac myxoma is characterized microscopically by stellate-shaped cells within a myxoid background. Complications include tumor emboli and “ball-valve” obstruction of the valves.
• Cardiac rhabdomyoma is a benign tumor usually arising within the myo
cardium that is associated with tuberous sclerosis.
PERICARDIAL DISEASE Pericarditis There are 2 kinds of pericarditis, acute and chronic. • Acute pericarditis is characterized by a fibrinous exudate (viral infection
or uremia) or by a fibrinopurulent exudate (bacterial infection).
• Chronic pericarditis can occur when acute pericarditis does not resolve
and adhesions form.
Pericardial Effusion Pericardial effusion may be serous (secondary to heart failure or hypoalbuminemia), serosanguineous (due to trauma, malignancy, or rupture of the heart or aorta) or chylous (due to thoracic duct obstruction or injury).
Tumors of the Pericardium Primary pericardial tumors are rare. Metastases from the breast and lung may spread to the pericardium. • Sarcoma occurs more commonly as the synovial sarcoma type. • Mesothelioma arising in pericardium is rarely associated with asbestos
exposure.
• Solitary fibrous tumors are benign but may recur. • Germ cell tumors occur in the pediatric population.
Tumors of the lung and breast may spread by direct extension to the pericardia.
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Pulmonary Pathology
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Learning Objectives ❏❏ Explain information related to congenital cystic lung lesions ❏❏ Demonstrate understanding of atelectasis ❏❏ Solve problems concerning pulmonary infections ❏❏ Demonstrate understanding of sarcoidosis ❏❏ Answer questions about obstructive versus restrictive lung disease ❏❏ Answer questions about vascular disorders of the lungs ❏❏ Demonstrate understanding of pulmonary and laryngeal neoplasia ❏❏ Explain information related to diseases of the pleural cavity
CONGENITAL LUNG MALFORMATIONS Congenital Pulmonary Airway Malformation Congenital pulmonary airway malformation (previously known as congenital cystic adenomatoid malformation) is a developmental defect in the pulmonary parenchyma that communicates with the tracheobronchial tree. It assumes a variety of gross features ranging from a single, large (3–10 cm) cyst to multiple smaller cysts to a mass without grossly evident cysts. It can be diagnosed prenatally with ultrasound. Rarely, it can be asymptomatic into adulthood. Symptomatic cases causing recurrent infection and pneumothorax are treated prenatally with surgical resection. Severe cases causing hydrops and mediastinal shift have been treated with prenatal surgery.
Bronchopulmonary Sequestration Bronchopulmonary sequestration is an intralobar (with pulmonary artery blood supply) or extralobar (with descending artery blood supply) malformation of pulmonary tissue that does not communicate with the tracheobronchial tree. Cases presenting with pleural effusion can require intrauterine treatment. Most cases regress spontaneously. Some cases remain undiagnosed until adulthood.
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ATELECTASIS Definition
Microbiology
Atelectasis refers to an area of collapsed or nonexpanded lung. It is reversible, but areas of atelectasis predispose for infection due to decreased mucociliary clearance.
Types of Atelectasis • Obstruction/resorption atelectasis is collapse of lung due to resorption
of air distal to an obstruction; examples include aspiration of a foreign body, chronic obstructive pulmonary disease (COPD), and postoperative atelectasis.
• Compression atelectasis is atelectasis due to fluid, air, blood, or tumor in
the pleural space.
• Contraction (scar) atelectasis is due to fibrosis and scarring of the lung. • Patchy atelectasis is due to a lack of surfactant, as occurs in hyaline mem-
brane disease of newborn or acute (adult) respiratory distress syndrome (ARDS).
PULMONARY INFECTIONS Pneumonia Bridge to Anatomy Pores of Kohn are collateral connections between alveoli through which infections and neoplastic cells can spread.
In bacterial pneumonia, acute inflammation and consolidation (solidification) of the lung are due to a bacterial agent. Clinical signs and symptoms include fever and chills; productive cough with yellow-green (pus) or rusty (bloody) sputum; tachypnea; pleuritic chest pain; and decreased breath sounds, rales, and dullness to percussion. Studies typically show elevated white blood cell count with a left shift (an increase in immature leukocytes). Chest x-ray for lobar pneumonia typically shows lobar or segmental consolidation (opacification), and for bronchopneumonia typically shows patchy opacification. Pleural effusion may also be picked up on chest x-ray. In general, the keys to effective therapy are identification of the organism and early treatment with antibiotics. Lobar pneumonia is characterized by consolidation of an entire lobe. The infecting organism is typically Streptococcus pneumoniae (95%) or Klebsiella. The lancet-shaped diplococcus Streptococcus pneumoniae is alpha-hemolytic, bile soluble, and optochin sensitive. The 4 classic phases of lobar pneumonia are congestion (active hyperemia and edema); red hepatization (neutrophils and hemorrhage); gray hepatization (degradation of red blood cells); and resolution (healing). In today’s antibiotic era, these changes are not generally observed in practice. Bronchopneumonia is characterized by scattered patchy consolidation centered on bronchioles; the inflammation tends to be bilateral, multilobar, and basilar, and particularly susceptible populations include the young, old, and terminally ill. Infecting organisms exhibit more variation than in lobar pneumonia,
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and include Staphylococci, Streptococci, Haemophilus influenzae, Pseudomonas aeruginosa, etc. Microscopic examination of tissue shows acute inflammation of bronchioles and surrounding alveoli. The diagnosis can often be established with sputum Gram stain and sputum culture, but will sometimes require blood cultures. Complications of pneumonia include fibrous scarring and pleural adhesions, lung abscess, empyema (pus in a body cavity), and sepsis. Treatment of pneumonia is generally initial empiric antibiotic treatment, modified by the results of cultures and organism sensitivities. Lung abscess is a localized collection of neutrophils (pus) and necrotic pulmonary parenchyma. The etiology varies with the clinical setting. Aspiration is the most common cause. It tends to involve right lower lobe and typically has mixed oral flora (often both anaerobic and aerobic) for infecting organisms.
Streptococcus pneumoniae
Lung abscess may also occur following a pneumonia, especially one due to S. aureus or Klebsiella. Lung abscesses may also occur following airway obstruction (postobstructive) or deposition of septic emboli in the lung. Complications of lung abscess include empyema, pulmonary hemorrhage, and secondary amyloidosis. Atypical pneumonia is the term used for interstitial pneumonitis without consolidation. It is more common in children and young adults. Infecting organisms that can cause atypical pneumonia include Mycoplasma pneumoniae, influenza virus, parainfluenza virus, respiratory syncytial virus (RSV) (which is especially important in young children), adenovirus, cytomegalovirus (CMV) (which is especially important in the immunocompromised), varicella virus, and many others. Diagnosis. Chest x-ray typically shows diffuse interstitial infiltrates. An elevated cold agglutinin titer specifically suggests Mycoplasma as a cause, which is important to identify since antibiotic therapy for Mycoplasma exists. Lung biopsy, if performed, typically shows lymphoplasmacytic inflammation within the alveolar septa. Complications include superimposed bacterial infections and Reye syndrome (potentially triggered by viral illness [influenza/varicella] treated with aspirin).
Tuberculosis (TB) The number of cases of TB is declining in the United States, but the proportion of cases in people born outside the country is rising. In this clinical setting, a positive PPD skin test may demonstrate that the person has been exposed to the mycobacterial antigens. Individuals who have received the BCG vaccine in some foreign countries may have a positive PPD test without being infected. In such cases chest x-ray and sputum smears and cultures are done.
Note BCG (Bacillus Calmette-Guérin) is a tuberculosis vaccine prepared from a strain of attenuated live bovine tuberculosis bacillus, Mycobacterium bovis.
Infection is usually acquired by inhalation of aerosolized bacilli. The clinical presentation of Mycobacterium tuberculosis includes fevers and night sweats, weight loss, cough, and hemoptysis.
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Primary pulmonary TB develops on initial exposure to the disease. The Ghon focus of primary TB is characterized by subpleural caseous granuloma formation, either above or below the interlobar fissure. The term Ghon complex refers to the combination of the Ghon focus and secondarily-involved hilar lymph nodes with granulomas. Most primary pulmonary tuberculosis lesions (95%) will undergo fibrosis and calcification. Progressive pulmonary TB can take several forms, including cavitary tuberculosis, miliary pulmonary tuberculosis, and tuberculous bronchopneumonia. Secondary pulmonary TB (also known as postprimary or reactivation TB) occurs either with reactivation of an old, previously quiescent infection or with reinfection secondary to a second exposure to the mycobacteria. In secondary pulmonary TB, the infection often produces a friable nodule at the lung apex (Simon focus) secondary to the high oxygen concentration present at that site, since the upper parts of the lung typically ventilate more efficiently than the lower parts. Biopsy of affected tissues will typically show AFB-positive caseating granulomas. Additionally, dissemination to other organ systems can occur in advanced TB via a hematogenous route that often results in a miliary pattern within each affected organ. Sites that may become involved include meninges; cervical lymph nodes (scrofula) and larynx; liver/spleen, kidneys, adrenals, and ileum; lumbar vertebrae bone marrow (Pott disease); and fallopian tubes and epididymis. Nontuberculous mycobacteria. M. avium complex (MAC) typically occurs in AIDS patients with CD4 counts 0.6, pleural fluid LDH level > two-thirds the upper limit of normal value for serum LDH. Conditions causing an exudative pleural effusion include infections (TB), malignancy, and pulmonary embolism.
• Transudative pleural effusions are sometimes assessed clinically, without
laboratory pleural fluid analysis. These effusions occur in clinical settings including left ventricular failure and cirrhosis.
Hemothorax is the presence of blood in the pleural cavity. Trauma is a common cause. There may be hypotension and shift of the trachea to the unaffected side. Chylothorax is lymphatic fluid in the pleural cavity. Malignancy is a common cause.
Air in the Pleural Space Pneumothorax is the term used for air in the pleural cavity. It can be due to traumatic penetrating chest wall injuries or spontaneous rupture of apical blebs in typically tall young adults (spontaneous pneumothorax). The term tension pneumothorax is used if a life-threatening shift of thoracic organs across midline occurs.
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© James G. Smirniotopoulos, MD; Uniformed Services University. Used with permission.
Figure 14-9. Densely Black Appearance on Chest X-Ray of a Pneumothorax
Mesothelioma (See section on asbestosis earlier in this chapter.)
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Renal Pathology
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Learning Objectives ❏❏ Demonstrate understanding of congenital anomalies of the kidney ❏❏ Use knowledge of cystic disease to solve problems ❏❏ Answer questions about nephritic/nephrotic syndrome, secondary/ chronic glomerulonephritis, tubulointerstitial nephritis, and acute tubular injury ❏❏ Describe epidemiology and course of urolithiasis ❏❏ Solve problems concerning chronic renal failure ❏❏ Solve problems concerning tumors of the kidney ❏❏ Explain information related to ureteral disorders ❏❏ Explain information related to urinary bladder pathology
CONGENITAL ANOMALIES OF THE KIDNEY Renal Agenesis • Bilateral agenesis is incompatible with life. Ultrasound shows oligohy-
dramnios. Affected fetuses typically also have Potter facies (flattened nose, posteriorly rotated ears, and recessed chin); talipes equinovarus (talus [ankle]+ pes [foot] and equino [heel] + varus [turned upward] = clubfoot); and pulmonary hypoplasia.
• In unilateral agenesis, the remaining kidney undergoes compensa-
tory hypertrophy. Patients often have adequate renal function and are asymptomatic.
Hypoplasia is failure of a kidney (usually unilateral) to develop to normal weight; the hypoplastic kidney has a decreased number of calyces and lobes. Horseshoe kidney is a common congenital anomaly that is found in 1 in 600 abdominal x-rays. The kidneys show fusion, usually at the lower pole; affected individuals have normal renal function but may be predisposed to renal calculi.
Note Oligohydramnios (Potter) Sequence Renal agenesis ↓ Oligohydramnios ↓ Fetal compression ↓ Flattened facies and positional abnormalities of hands and feet
Abnormal locations. The most common abnormal location is a pelvic kidney. The ectopic kidney usually has normal function. Tortuosity of ureters may predispose to pyelonephritis.
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CYSTIC DISEASE Genetic Cystic Disease
Microbiology
Autosomal recessive polycystic kidney disease (also called infantile polycystic kidney disease or renal dysgenesis Potter type I) is a rare autosomal recessive disease that presents in infancy with progressive and often fatal renal failure. A mutation in the PKHD1 gene is implicated. The kidneys are bilaterally enlarged and have a spongelike cut surface. The liver may have multiple hepatic cysts and cirrhosis may develop in childhood. Pulmonary hypoplasia is present to varying degrees. Autosomal dominant polycystic kidney disease (also called adult polycystic kidney disease or renal dysgenesis Potter type III) is an autosomal dominant disease that affects 1 in 1,000. There is most frequently a mutation of the PKD1 gene on chromosome 16 which produces a transmembrane protein called polycystin 1. Other mutations involve PKD2 and polycystin 2.
Clinical Correlate The cysts in autosomal dominant (adult) PKD involve 3.5 g/day)
Hypertension
Hypoalbuminemia ( Caucasians; typical age >50. Risk factors include: • Heavy smoking and alcohol use
Note
• Achalasia
Tylosis is an autosomal dominant syndrome. The phenotypic hallmarks are oral leukoplakia and hyperkeratosis of the palms and soles. SCC of the esophagus is seen in up to 95% of affected individuals.
• Plummer-Vinson syndrome • Tylosis • Lye ingestion
The presentation of squamous cell carcinoma of the esophagus varies; it is often asymptomatic until late in the course. When symptoms do develop they may include progressive dysphagia, weight loss and anorexia, bleeding, hoarseness, and cough. Diagnosis is by endoscopy with biopsy. Treatment is surgery though the prognosis is poor. Adenocarcinoma of the esophagus affects Caucasians more than African Americans. It arises in the distal esophagus. The progression from Barrett metaplasia to dysplasia and eventually to invasive carcinoma occurs due to the stepwise accumulation of genetic and epigenetic changes. The prognosis is poor. In the United States, adenocarcinoma and squamous cell carcinoma of the esophagus occur with equal frequency.
STOMACH Congenital Disorders Clinical Correlate Pyloric stenosis is congenital hypertrophy of the pylorus, which presents with projectile vomiting and a palpable abdominal “olive.”
Pyloric stenosis is a congenital stenosis of the pylorus due to marked muscular hypertrophy of the pyloric sphincter, resulting in gastric outlet obstruction. It affects male infants more than females. It is associated with Turner and Edwards syndromes. Presentation is the onset of regurgitation and vomiting in week 2 of life; waves of peristalsis are visible on the abdomen and there is a palpable oval abdominal mass. Treatment is surgical. Congenital diaphragmatic hernia occurs when a congenital defect is present in the diaphragm, resulting in herniation of the abdominal organs into the thoracic cavity. The stomach is the most commonly herniated organ due to left-sided
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congenital diaphragmatic hernia. Congenital diaphragmatic hernia is often associated with intestinal malrotation. It may be complicated by significant lung hypoplasia.
Hypertrophic Gastropathy Ménétrier disease is a rare disease of middle-aged men. It is caused by profound hyperplasia of surface mucous cells, accompanied by glandular atrophy. It is characterized by enlarged rugal folds in the body and fundus; clinically, patients experience decreased acid production, protein-losing enteropathy, and increased risk of gastric cancer. Zollinger-Ellison syndrome. See discussion of gastrinoma in the Pancreas chapter.
Acute Inflammation and Stress Ulcers Acute hemorrhagic gastritis causes acute inflammation, erosion, and hemorrhage of the gastric mucosa, secondary to a breakdown of the mucosal barrier and acid-induced injury. The etiology is diverse, with initiating agents including chronic aspirin or NSAID use, alcohol use, smoking, recent surgery, burns, ischemia, stress, uremia, and chemotherapy. Patients present with epigastric abdominal pain, or with gastric hemorrhage, hematemesis, and melena. Gastric stress ulcers are multiple, small, round, superficial ulcers of the stomach and duodenum. Predisposing factors include: • NSAID use • Severe stress • Sepsis • Shock • Severe burn or trauma • Elevated intracranial pressure (Cushing ulcers)
ICU patients have a high incidence of gastric stress ulcer. These ulcers may be complicated by bleeding.
Chronic Gastritis Chronic gastritis is chronic inflammation of the gastric mucosa, eventually leading to atrophy (chronic atrophic gastritis). Fundic type chronic gastritis is an autoimmune atrophic gastritis that involves the body and the fundus. It is caused by autoantibodies directed against parietal cells and/or intrinsic factor. The result is loss of parietal cells, decreased acid secretion, increased serum gastrin (G-cell hyperplasia), and pernicious anemia (megaloblastic anemia due to lack of intrinsic factor and B12 malabsorption). Women are affected more than men. Grossly, one sees a loss of rugal folds in the body and fundus. Microscopically, mucosal atrophy is seen with loss of glands and parietal cells, chronic lymphoplasmacytic inflammation, and intestinal metaplasia. Patients are at increased risk for gastric carcinoma.
Bradley Gibson, MD. Used with permission.
Helicobacter pylori, Warthin-Starry stain.
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Pathology Pathology
Clinical Correlate
Behavioral Science/Social Sciences
The ability of H. pylori to produce urease is clinically used for detection by the [13C]-urea breath test and Microbiology clofazimine (CLO) tests. Other methods of detection include biopsy (histologic identification is the gold standard) and serology.
Antral type chronic gastritis (also called Helicobacter pylori gastritis) is the most common form of chronic gastritis in the United States. The H. pylori organisms are curved, gram-negative rods which produce urease. The risk of infection increases with age. Infection is also associated with duodenal/gastric peptic ulcer, and gastric carcinoma with intestinal type histology. Microscopically, H. pylori organisms are visible in the mucous layer of the surface epithelium. Other microscopic features include foci of acute inflammation, chronic inflammation with lymphoid follicles, and intestinal metaplasia.
Chronic Peptic Ulcer Peptic ulcers are ulcers of the distal stomach and proximal duodenum caused by gastric secretions (hydrochloric acid and pepsin) and impaired mucosal defenses. Predisposing factors include the following: • Chronic NSAID and aspirin use • Steroid use • Smoking • H. pylori infection
Patients present with burning epigastric pain. Diagnosis is by endoscopy with or without biopsy. Treatment is acid suppression (H2 blocker, proton pump inhibitor, etc.) and eradication of H. pylori. Complications of peptic ulcer include hemorrhage, iron deficiency anemia, penetration into adjacent organs, perforation (x-ray shows free air under the diaphragm), and pyloric obstruction. Duodenal peptic ulcers are more common than gastric peptic ulcers. Associations include the following: • H. pylori (~100%)
'XRGHQDO XOFHU
• Increased gastric acid secretion *DVWULF XOFHU
• Increased rate of gastric emptying • Blood group O • Multiple endocrine neoplasia (MEN) type I • Zollinger-Ellison syndrome • Cirrhosis • Chronic obstructive pulmonary disease
Most duodenal peptic ulcers are located in the anterior wall of the proximal duodenum. Gastric peptic ulcers are associated with H. pylori (75%). Most are located in the lesser curvature of the antrum. Grossly, they are small (3 cm) ulcers with heaped-up margins and a necrotic ulcer base. They may also occur as a flat or polypoid mass. Several histological types occur. • The intestinal type shows gland-forming adenocarcinoma microscopically. • The diffuse type shows diffuse infiltration of stomach by poorly differenti-
ated tumor cells, numerous signet-ring cells (whose nuclei are displaced to the periphery by intracellular mucin), and linitis plastica (thickened “leather bottle”–like stomach) gross appearance.
Gastric carcinoma may specifically metastasize to the left supraclavicular lymph node (Virchow sentinel node) and to the ovary (Krukenberg tumor). Diagnosis is by endoscopy with biopsy; treatment is gastrectomy. The prognosis is poor, with overall 5-year survival ~30%. Gastric lymphoma can arise from mucosa-associated lymphoid tissue (MALT). Extranodal marginal zone B-cell lymphomas are frequently associated with Helicobacter pylori gastritis. Diffuse, large B-cell lymphoma can also occur in the stomach.
SMALL AND LARGE INTESTINES Mechanical Obstruction Volvulus is a twisting of a segment of bowel on its vascular mesentery, causing intestinal obstruction and infarction. It is often associated with congenital abnormalities such as intestinal malrotation. Common locations include the sigmoid colon and small bowel; complications include infarction and peritonitis. Intussusception is the telescoping of a proximal segment of the bowel into the distal segment. It is most common in infants and children. Children present with vomiting, abdominal pain, passage of blood per rectum, and lethargy; a sausage-shaped mass is often palpable in the right hypochondrium.
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Acquired megacolon may be caused by Chagas disease or ulcerative colitis (toxic megacolon).
Microbiology
In adults, intussusception may be caused by a mass or tumor. The intussuscepted segment can become infarcted. Incarcerated hernia is a segment of bowel that is imprisoned within a hernia; the condition can become complicated by intestinal obstruction and infarction.
Motility Disorders Hirschsprung disease (or congenital aganglionic megacolon) is caused by congenital absence of ganglion cells in the rectum and sigmoid colon, resulting in intestinal obstruction. The condition affects males more than females, and can be associated with Down syndrome. Hirschsprung may present with delayed passage of meconium, or with constipation, abdominal distention, and vomiting.
Bridge to Anatomy Auerbach plexus = myenteric ganglia Meissner plexus = submucosal ganglia
Grossly, the affected segment is narrowed, and there is dilation proximal to the narrow segment (megacolon). Microscopically, there is an absence of ganglion cells in Auerbach and Meissner plexuses, and the diagnosis is established when rectal biopsy demonstrates the absence of ganglion cells. Treatment is resection of the affected segment. Irritable bowel syndrome is a diagnosis of exclusion based on symptoms of diarrhea and/or constipation.
Malabsorption Syndromes Celiac sprue (or gluten-sensitive enteropathy and nontropical sprue) is caused by hypersensitivity to gluten (and gliadin), resulting in loss of small bowel villi and malabsorption. HLA-DQ2 and/or -DQ8 are carried by most patients. Microscopic exam demonstrates a loss of villi, with increased intraepithelial lymphocytes and increased plasma cells in the lamina propria. Clinically, it often presents in childhood with malabsorption. Symptoms include abdominal distention, bloating, and flatulence, along with diarrhea, steatorrhea, and weight loss. Dermatitis herpetiformis may occur age >20. In adults, celiac presents between decades 4-7. Treatment is dietary restriction of gluten. There is an increased risk of gastrointestinal cancer.
wikimedia.org.
© wikimedia.org. Used with permission.
Figure 17-3. Celiac disease
Figure 16-1. Celiac Disease
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Environmental enteropathy (previously known as tropical sprue) is a malabsorption disease of unknown etiology (infection and/or nutritional deficiency). It affects residents of low-income countries. Biopsy shows blunting of villi and a lymphocytic infiltrate. Whipple disease is a rare infectious disease involving many organs, including small intestines, joints, lung, heart, liver, spleen, and central nervous system. It typically affects Caucasian males age 30-50. The infecting organism is Tropheryma whipplei. Microscopically, the small bowel lamina propria is filled with macrophages stuffed with the PAS-positive, grampositive, rod-shaped bacilli. Patients present with malabsorption, weight loss, and diarrhea. Treatment is antibiotics.
Inflammatory Bowel Disease (IBD) There are 2 categories of IBD: • Crohn’s disease (CD) (or regional enteritis) • Ulcerative colitis (UC)
Colitis of indeterminate type describes cases that cannot be clearly classified. Caucasians develop IBD more frequently than non-Caucasians. The incidence of IBD is increasing. Age distribution varies with the disease: • CD has a bimodal distribution with peaks at age 10–30 and 50–70 • UC peaks at age 20–30
IBD can present with episodes of bloody diarrhea or stools with mucus, crampy lower abdominal pain, or fever. CD may present with malabsorption or extraintestinal manifestations. It may mimic appendicitis. CD may cause perianal fistulas. Diagnosis of IBD requires endoscopic biopsy and clinicopathologic correlation.
Note Damage to the ileal mucosa can cause deficiencies of vitamin B12 and folate.
New studies indicate that risk of colorectal carcinoma (CRC) in CD and UC are equivalent for similar extent and duration of disease; the risk of CRC is not as high as previous studies suggested.
© Katsumi M. Miyai, MD, Ph.D.; Regents of the University of California. Used with permission.
Figure 16-2. Narrowed Colon Segment in Crohn’s Disease
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Table 16-1. Crohn’s Disease Versus Ulcerative Colitis Crohn’s Disease
Ulcerative Colitis
Most common site
Terminal ileum
Rectum
Distribution
Mouth to anus
Rectum → colon “backwash” ileitis
Spread
Discontinuous/“skip”
Continuous
Gross features
• Focal aphthous ulcers with intervening normal mucosa
Extensive ulceration Pseudopolyps
• Linear fissures • Cobblestone appearance • Thickened bowel wall • “Creeping fat” Micro
Noncaseating granulomas
Crypt abscesses
Inflammation
Transmural
Limited to mucosa and submucosa
Complications
• Strictures
Toxic megacolon
• “String sign” on barium studies • Obstruction • Abscesses • Fistulas • Sinus tracts Genetic association Extraintestinal manifestations
HLA-B27 Common (e.g., migratory polyarthritis, ankylosing spondylitis, primary sclerosing cholangitis, erythema nodosum, pyoderma gangrenosum, uveitis)
Common (e.g., migratory arthritis, ankylosing spondylitis, primary sclerosing cholangitis, erythema nodosum, pyoderma gangrenosum, uveitis)
Other Inflammatory Diseases Pseudomembranous colitis (antibiotic-associated colitis) is an acute colitis characterized by the formation of inflammatory pseudomembranes in the intestines. It is usually caused by Clostridium difficile infection (often brought on by a course of broad-spectrum antibiotics, especially clindamycin and ampicillin), but it can be caused by ischemic bowel disease. Gross examination shows yellow-tan mucosal membranes. Microscopic exam shows the pseudomembranes are composed of an adherent layer of acute inflammatory cells, mucus and necrotic debris overlying sites of colonic mucosal injury. Presentation is with diarrhea, fever, and abdominal cramps. Diagnosis is established with detection of C. difficile toxin in the stool. Treatment of clostridial pseudomembranous colitis is vancomycin or metronidazole.
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Appendicitis is most commonly caused by obstruction of the appendix by a fecalith. It often starts with periumbilical pain that subsequently localizes to the right lower quadrant. Nausea, vomiting, and fever may also be present. Lab studies show an elevated white blood cell count. A complication is appendiceal rupture leading to peritonitis. Grossly, a fibrinopurulent exudate may be seen on the appendiceal serosa; microscopically, neutrophils are present within the mucosa and muscular wall (muscularis propria) of the appendix.
Vascular Disorders
Bridge to Anatomy
Ischemic bowel disease is caused by decreased blood flow and ischemia of the bowel, secondary to atherosclerosis with thrombosis, thromboembolism, or reduced cardiac output from shock. It is most common in older individuals. Typical presentation is with abdominal pain and bloody diarrhea. The disease distribution tends to involve watershed areas (e.g., splenic flexure), and affected areas typically show hemorrhagic infarction.
The splenic flexure of the colon receives blood from both the superior and inferior mesenteric arteries.
Treatment is surgical resection, but the prognosis is poor, with >50% mortality. Hemorrhoids are tortuous, dilated anal submucosal veins caused by increased venous pressure. Risk factors include constipation and prolonged straining during bowel movements, pregnancy, and cirrhosis. Complications include painful thrombosis and streaks of bright red blood on hard stool. Angiodysplasia is the most common vascular malformation of the GI tract. Individuals age >55 are most commonly affected, presenting with multiple episodes of rectal bleeding. It is associated with Osler-Weber-Rendu and CREST syndromes.
Note
Melanosis Coli
• Autosomal dominant
Melanosis coli is associated with laxative use; it causes black pigmentation of the colon due to the ingestion of the laxative pigment by macrophages in the mucosa and submucosa. It can mimic colitis or malignancy.
• Telangiectasias of skin and mucous membranes
Diverticula
• May develop iron deficiency anemia
Osler-Weber-Rendu Syndrome • a.k.a. Hereditary hemorrhagic telangiectasia
• Common on lips, tongue, and fingertips
Meckel diverticulum is a congenital small bowel diverticulum caused by persistence of a remnant of the vitelline (omphalomesenteric) duct (see Anatomy Lecture Notes). With Meckel, the “rule of 2s” applies: • 2% of the normal population • 2 feet from the ileocecal valve • Length 2 cm • Age ≤2 years at time of diagnosis
Most Meckel diverticula are asymptomatic but they may contain rests of ectopic gastric mucosa and present with intestinal bleeding.
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Given that only 2 layers of the bowel wall are involved, these acquired outpouchings are technically Microbiology pseudodiverticula.
Colonic diverticulosis is an acquired outpouching of the bowel wall, characterized by herniation of the mucosa and submucosa through the muscularis propria (pseudodiverticulum). It is extremely common in the United States. • Incidence increases with age • Major risk factor is a low-fiber diet, which leads to increased intraluminal
pressure
• Most common location is sigmoid colon
Many cases are asymptomatic and picked up on screening colonoscopy. When symptomatic, it can cause constipation alternating with diarrhea, left lower quadrant abdominal cramping and discomfort, occult bleeding and an iron deficiency anemia, or lower gastrointestinal tract hemorrhage. Complications include diverticulitis, fistulas, and perforation with accompanying peritonitis.
Polyps Hamartomatous polyps include nonfamilial juvenile polyps and polyps associated with a familial (Peutz-Jeghers) syndrome. Nonsyndromic polyps do not have malignant potential. Hyperplastic polyps are the most common histologic type; they occur most often in the left colon and are usually 100 adenomatous polyps on endoscopy. Complications: by age 40, virtually 100% will develop an invasive adenocarcinoma and increased risks for developing duodenal adenocarcinoma and adenocarcinoma of the papilla of Vater. Gardner syndrome is an autosomal dominant variant of familial adenomatous polyposis characterized by numerous colonic adenomatous polyps, multiple osteomas, fibromatosis, and epidermal inclusion cysts. Turcot syndrome is a rare variant of familial adenomatous polyposis characterized by numerous colonic adenomatous polyps and central nervous system tumors (gliomas). Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is due to an autosomal dominant mutation of a DNA nucleotide mismatch repair gene that predisposes for colon cancer. It is associated with an increased risk of cancer at other sites, including the endometrium and the ovary.
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Peutz-Jeghers syndrome is an autosomal dominant condition characterized by multiple hamartomatous polyps (primarily in the small intestine); melanin pigmentation of the oral mucosa; and increased risk of cancer at numerous sites including the lung, pancreas, breast, and uterus.
Neoplasia Colonic adenocarcinoma is the third most common tumor in the United States, in terms of incidence and mortality. Risk factors include: • Dietary factors (low fiber, low fruits/vegetables and high in red meat and
animal fat)
• Colon polyps (isolated adenomatous polyps, hereditary polyposis
syndromes)
• Other colon disease (Lynch syndrome, ulcerative colitis)
Diagnosis of colonic adenocarcinoma is established via endoscopy with biopsy.
Note
Cancer genetics: Mutations of the APC gene cause activation of the Wnt pathway, leading β-catenin to translocate to the nucleus where it causes the overexpression of growth-promoting genes. DNA mismatch repair causes microsatellite instability, which is another genetic carcinogenesis pathway.
TNM Staging of Colorectal Cancer
The pattern of spread in colonic adenocarcinoma includes lymphatic spread to mesenteric lymph nodes, with distant spread to liver, lungs, and bone. Staging is with the TNM system. Treatment can include surgical resection and chemotherapy (for metastatic disease); CEA levels can be used to monitor for disease recurrence.
Stage II (T3N0M0): tumors that have penetrated through the muscularis but have not spread to the lymph nodes
Screening for colonic adenocarcinoma and other GI neoplasias is recommended for the general population beginning age 50. Current guidelines suggest:
Stage IV (TXNXM1): metastasis to distant sites
Stage I (T1-2N0M0): tumors that do not penetrate through mucosa (T1) or muscularis (T2)
Stage III (TXN1M0): regional lymph node involvement
• Colonoscopy every 10 years or annual fecal occult blood test (FOBT), or • Combination of FOBT (every 3 years) and sigmoidoscopy (every 5 years) Table 16-2. Right-Sided Cancer Versus Left-Sided Cancer Right-Sided Cancer
Left-Sided Cancer
Gross
Polypoid mass
Circumferential growth producing a “napkin-ring” configuration
Barium studies
Polypoid mass
“Apple-core” lesion
Presentation
Bleeding
Change in bowel habits
• Occult blood in stool
• Constipation or diarrhea
• Iron deficiency anemia
• Reduced caliber stools • Obstruction
Note Carcinoid tumors are neuroendocrine tumors that often produce serotonin. Locations include the appendix (most common) and the terminal ileum. Metastasis to the liver may result in carcinoid heart disease.
Histologically, carcinoid tumors appear similar to other neuroendocrine tumors, with nests of small uniform cells.
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Bridge to Biochemistry
Microbiology
Serotonin is converted to 5-HIAA by monoamine oxidase.
Carcinoid syndrome is characterized by diarrhea, cutaneous flushing, bronchospasm and wheezing, and fibrosis. The diagnosis is substantiated by demonstrating elevated urinary 5-HIAA (5-hydroxyindoleacetic acid). Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the GI tract. Most cases have a KIT mutation. The peak incidence is in decade 7. Treatment is resection and a tyrosine-kinase inhibitor.
ANUS Anal Skin Tags Anal skin tags are fibroepithelial polyps that arise secondary to inflammation or injury. They can be mistaken clinically for condylomata and hemorrhoids.
Anal Lesions of Inflammatory Bowel Disease Manifestations of perianal Crohn disease include fissures, fistulas, abscesses, and anal canal stenosis. Fistulas can be the first sign of disease. Hemorrhoids are vascular structures in the anal canal that can become enlarged and inflamed, causing pain and bright red blood per rectum. Above the dentate line (internal hemorrhoids) they are covered by columnar epithelium; below the dentate line they are covered by anoderm and skin.
HPV-Associated Disease Condyloma acuminatum is the most common tumor of the anal region. It is caused by HPV infection. Anal intraepithelial neoplasia (AIN) is a precursor to anal squamous carcinoma. The incidences of both anal intraepithelial neoplasia and anal cancer are rising in the United States. HPV infection causes the majority of anal cancers. Screening for the disease is recommended in high-risk populations, and anoscopy with biopsy evaluation is useful for early detection.
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Pancreatic Pathology
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Pancreatic Pathology
17
Learning Objectives ❏❏ Demonstrate understanding of congenital anomalies of the pancreas ❏❏ Use knowledge of inflammation of the pancreas or tumors of the pancreas to solve problems
NONNEOPLASTIC CONDITIONS Congenital Anomalies of the Pancreas • Pancreatic agenesis is incompatible with life. • Pancreatic divisum is a variant of pancreatic duct anatomy. • Annular pancreas encircles the duodenum and presents as obstruction. • Ectopic pancreatic tissue can hemorrhage, become inflamed, or give rise
to a neuroendocrine tumor. It most often arises in the stomach, duodenum, or jejunum.
Inflammation of the Pancreas Acute pancreatitis is acute inflammation caused by injury to the exocrine portion of the pancreas. The etiology is diverse: • Gallstones • Alcohol • Hypercalcemia • Drugs • Shock • Infections • Trauma • Scorpion stings
Pancreatic acinar cell injury results in activation of pancreatic enzymes and enzymatic destruction of the pancreatic parenchyma. Symptoms include stabbing epigastric abdominal pain radiating to the back. Severe acute pancreatitis can also cause shock. Lab studies show elevated serum amylase and lipase. Complications include acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), pancreatic pseudocyst; pancreatic calcifications, and hypocalcemia. Severe cases have a 30% mortality rate.
Note Pancreatic pseudocyst is a fluid-filled sac adjacent to the pancreas. The wall of granulation tissue lacks an epithelial lining.
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• Gross pathologic examination shows focal hemorrhage and liquefication in
the pancreas, accompanied by chalky, white-yellow fat necrosis of adjacent adipose tissue.
• Microscopically there is liquefactive necrosis of the pancreatic parenchyma Microbiology
with acute inflammation and enzymatic fat necrosis.
• Necrosis of blood vessels causes hemorrhage.
Chronic pancreatitis refers to irreversible changes in pancreatic function with accompanying chronic inflammation, atrophy, and fibrosis of the pancreas secondary to repeated bouts of pancreatitis. Manifestations include abdominal pain, pancreatic insufficiency and malabsorption, pancreatic calcifications, pseudocyst, and secondary diabetes mellitus (late complication). It is common in middle-aged male alcoholics. Pathology shows grossly firm, white, and fibrotic pancreas. Microscopically there is extensive fibrosis with parenchymal atrophy and chronic inflammation. Autoimmune pancreatitis can occur in association with IgG4-associated fibrosing disorders; this variant responds to steroid therapy.
PANCREATIC NEOPLASMS Neuroendocrine Tumors Pancreatic neuroendocrine tumors (islet cell tumors) are less common than exocrine tumors. Most are considered low-grade malignancies. Some patients lack laboratory evidence of hormone overproduction. These tumors are not distinguishable from each other on the basis of gross appearance or histology. • Insulinoma (β-cell tumor) (most common type of islet cell tumor) –– Produces insulin –– Can cause hypoglycemia, sweating, hunger, confusion, and insulin coma –– Surgical excision is curative • Gastrinoma (G-cell tumor) –– Produces gastrin –– Excess gastrin manifests as Zollinger-Ellison syndrome, which is
c haracterized by thick gastric folds, elevated serum gastrin, gastric hyperacidity, and intractable peptic ulcers
–– Gastrinomas may arise outside the pancreas –– May be associated with MEN I • Glucagonoma (α-cell tumor) –– Produces glucagon –– Excess glucagon causes hyperglycemia (diabetes), anemia, and skin rash • Somatostatinoma (δ-cell tumor) –– Produces somatostatin –– Excess somatostatin inhibits insulin secretion, leading to diabetes –– Can also inhibit gastrin secretion (leading to hypochlorhydria) and cho-
lecystokinin secretion (leading to gallstones and steatorrhea)
–– Prognosis is poor
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• VIPoma –– Produces vasoactive intestinal peptide (VIP) –– Excess VIP causes WDHA syndrome: watery diarrhea, hypokalemia,
and achlorhydria
Adenocarcinoma Pancreatic carcinoma is the third most common cause of cancer death in the United States. • Most common ages 60–80 • Smoking is a risk factor • Presents with only vague signs and symptoms until late in course • When more definitive signs and symptoms develop, they can include
abdominal pain, migratory thrombophlebitis, and obstructive jaundice
The tumor may occur in the head (60%), body (15%), and tail (5%). Microscopically, the adenocarcinoma arises from the duct epithelium. Tumor desmoplasia and perineural invasion are common. Tumor markers for pancreatic carcinoma include CEA and CA19-9, but they are not useful screening assays. Treatment is surgical excision (Whipple procedure). The prognosis is very poor, with 5-year survival only ~5%.
© Gregg Barré, MD. Used with permission.
Figure 17-1. Pancreatic Adenocarcinoma with Perineural Invasion
Pancreatic Cystic Neoplasms Serous neoplasms account for 25% of pancreatic cystic neoplasms; most are benign (cystadenomas) and the tumors carry a mutation of VHL. Mucinous neoplasms: Mucinous cystic neoplasms are common in women and can harbor dysplasia or carcinoma; distal pancreatectomy is curative in most cases. Intraductal papillary mucinous neoplasms are common in men and tend to arise in the head of the pancreas; GNAS mutations are common and carcinoma may arise in the neoplasm.
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Gallbladder and Biliary Tract P athology
Gallbladder and Biliary Tract P athology
18
Learning Objectives ❏❏ Use knowledge of gallstones (cholelithiasis), inflammatory conditions of the gallbladder, and miscellaneous conditions to solve problems ❏❏ Explain information related to biliary tract cancer
GALLSTONES (CHOLELITHIASIS) Gallstones are frequently asymptomatic but can cause biliary colic (right upper quadrant pain due to impacted stones). Diagnosis is by U/S; the majority of stones are not radiopaque. Complications include cholecystitis, choledocholithiasis (calculi within the biliary tract), biliary tract obstruction, pancreatitis, and cholangitis.
Cholesterol Stones These stones are composed mostly of cholesterol monohydrate. The incidence increases with age. Risk factors include female gender, obesity, pregnancy, oral contraceptives, and hormone replacement therapy. Native American Pima and Navajo Indians have an increased incidence of cholesterol gallstones.
Note Formation of cholesterol stones involves the precipitation of cholesterol from supersaturated bile.
Pigmented Bilirubinate Stones These stones are composed of calcium salts and unconjugated bilirubin. Risk factors are chronic hemolytic anemias, cirrhosis, bacterial infection, and parasites (Ascaris or Clonorchis [Opisthorchis] sinensis).
INFLAMMATORY CONDITIONS
Clinical Correlate Murphy’s sign is inspiratory arrest in response to palpation of the right subcostal area during deep inspiration. It is seen in patients with pain due to cholecystitis.
Acute Cholecystitis Acute cholecystitis is an acute inflammation of the gallbladder, usually caused by cystic duct obstruction by gallstones. It can present with biliary colic, right upper quadrant tenderness on palpation, nausea and vomiting, low-grade fever, and leukocytosis. Complications include gangrene of the gallbladder, perforation and peritonitis, fistula formation and gallstone ileus (small bowel obstruction by a large gallstone). Acute acalculous cholecystitis is associated with surgery, trauma, and sepsis.
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Chronic Cholecystitis Chronic cholecystitis is ongoing chronic inflammation of the gallbladder, usually caused by gallstones. Well-developed examples show stromal and mural lymphocytic and plasmacytic infiltrates. Macrophages and granulomas may also be present. The wall is thickened.
© Gregg Barré, MD. Used with permission.
Figure 18-1. Chronic Cholecystitis
Ascending Cholangitis Clinical Correlate Charcot’s triad is RUQ pain, jaundice, and fever, characteristic of acute cholangitis.
Ascending cholangitis is a bacterial infection of the bile ducts ascending up to the liver, usually associated with obstruction of bile flow oftentimes from bile duct stones. It presents with biliary colic, jaundice, high fever, and chills. The infecting organisms are usually gram-negative enteric bacteria.
MISCELLANEOUS CONDITIONS Cholesterolosis Cholesterolosis refers to an accumulation of cholesterol-laden macrophages within the mucosa of the gallbladder wall. Gross examination shows yellow speckling of the red-tan mucosa (“strawberry gallbladder”). Microscopic examination shows lipid-laden macrophages within the lamina propria.
Hydrops of the Gallbladder Hydrops of the gallbladder (mucocele) occurs when chronic obstruction of the cystic duct leads to the resorption of the normal gallbladder contents and enlargement of the gallbladder by the production of large amounts of clear fluid (hydrops) or mucous secretions (mucocele).
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BILIARY TRACT CANCER Gallbladder Cancer Gallbladder cancer is frequently asymptomatic until late in the course. When the tumor does present, it may be with cholecystitis, enlarged palpable gallbladder, or biliary tract obstruction (uncommon). X-ray may show a calcified “porcelain gallbladder.” Microscopically, the tissues show adenocarcinoma. The prognosis for gallbladder cancer is poor; 5-year survival rate is ~12%.
Bile Duct Cancer Bile duct cancer. Bile duct carcinoma is carcinoma of the extrahepatic bile ducts, while cholangiocarcinoma is carcinoma of the intrahepatic bile ducts. Klatskin tumor is a carcinoma of the bifurcation of the right and left hepatic bile ducts. Risk factors for bile duct cancer include Clonorchis (Opisthorchis) sinensis (liver fluke) in Asia and primary sclerosing cholangitis. Bile duct cancer typically presents with biliary tract obstruction. Microscopic examination shows adenocarcinoma arising from the bile duct epithelium. The prognosis is poor.
Clinical Correlate Courvoisier law is a palpable gallbladder more likely to be caused by obstruction due to malignancy than by stones. “Porcelain gallbladder” is a calcification of the gallbladder due to chronic inflammation; recent studies have cast doubt on its association with carcinoma.
Adenocarcinoma of the Ampulla of Vater Adenocarcinoma of the ampulla of Vater may exhibit duodenal, biliary, or pancreatic epithelium. Patients present with painless jaundice. The 5-year survival rate is 2–3 mg/dL. The classic presentation is yellow skin (jaundice) and sclera (icterus). Causes of jaundice include overproduction of bilirubin, defective hepatic bilirubin uptake, defective conjugation, and defective excretion. Table 19-1. Unconjugated Versus Conjugated Bilirubinemia Unconjugated (Indirect) Bilirubinemia
Conjugated (Direct) Bilirubinemia
Increased RBC turnover (hemolytic anemias)
Biliary tract obstruction
Physiologic (newborn babies)
Biliary tract disease (PSC and PBC)
Hereditary (Gilbert and Crigler-Najjar syndromes)
Hereditary (Dubin-Johnson and Rotor syndromes) Liver disease (cirrhosis and hepatitis)
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In infants, increased levels of unconjugated bilirubin (lipid-soluble) may cross the blood–brain barrier Microbiology and deposit in the basal ganglia, causing irreversible brain damage (kernicterus).
Increased red blood cell (RBC) turnover. RBCs are the major source of bilirubin. Jaundice related to overproduction of bilirubin can be seen in hemolytic anemia and ineffective erythropoiesis (thalassemia, megaloblastic anemia, etc.). Laboratory studies show increased unconjugated bilirubin. Chronic hemolytic anemia patients often develop pigmented bilirubinate gallstones. The most common cause of marked jaundice in the newborn is blood group incompatibility (most commonly ABO) between mother and child, causing hemolytic disease of the newborn. Physiologic jaundice of the newborn is a transient unconjugated hyperbilirubinemia due to the immaturity of the liver. Risk factors include prematurity and hemolytic disease of the newborn (erythroblastosis fetalis). Physiologic jaundice of the newborn can be complicated by kernicterus; treatment is phototherapy. Jaundice also occurs in newborns who have infections. Hereditary hyperbilirubinemias When hyperbilirubinemia is prolonged in the newborn, a mutation affecting bilirubin conjugation enters the differential diagnosis. • Gilbert syndrome is a common benign inherited disorder that causes
unconjugated hyperbilirubinemia due to bilirubin UDP-glucuronosyltransferase (UGT) deficiency. Kernicterus rarely occurs and the treatment is phenobarbital.
• Crigler-Najjar syndrome causes unconjugated hyperbilirubinemia due to
bilirubin glucuronosyltransferase (UGT) absence or deficiency. Treatment for type 1 is gene replacement therapy and liver transplantation. For a milder type 2, phenobarbital is used.
• Dubin-Johnson syndrome is a benign autosomal recessive disorder char-
acterized by decreased bilirubin excretion due to a defect in the canalicular cationic transport protein. It produces conjugated hyperbilirubinemia and a distinctive black pigmentation of the liver, but has no clinical consequences.
• Rotor syndrome is an autosomal recessive conjugated hyperbilirubinemia
that is similar to Dubin-Johnson syndrome, but without liver pigmentation. There are no clinical consequences.
Biliary tract obstruction may have multiple etiologies, including gallstones; tumors (pancreatic, gallbladder, and bile duct); stricture; and parasites (liver flukes—Clonorchis [Opisthorchis] sinensis). The presentation can include jaundice and icterus; pruritus due to increased plasma levels of bile acids; abdominal pain, fever, and chills; dark urine (bilirubinuria); and pale clay-colored stools. Lab studies show elevated conjugated bilirubin, elevated alkaline phosphatase, and elevated 5´-nucleotidase. Primary biliary cirrhosis (PBC) is a chronic liver disease that is characterized by inflammation and granulomatous destruction of intrahepatic bile ducts. Females have 10 times the incidence of primary biliary cirrhosis compared to males; the peak incidence is age 40–50. Presentation includes obstructive jaundice and pruritus; xanthomas, xanthelasmas, and elevated serum cholesterol; fatigue; and cirrhosis (late complication). Most patients have another autoimmune disease (scleroderma, rheumatoid arthritis or systemic lupus erythematosus).
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Laboratory studies show elevated conjugated bilirubin, elevated alkaline phosphatase, and elevated 5´-nucleotidase. Treatment with oral ursodeoxycholic acid slows disease progression. Antimitochondrial autoantibodies (AMA) are present in >90% of cases, which further supports an autoimmune basis. Microscopically, lymphocytic and granulomatous inflammation involves interlobular bile ducts. Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by segmental inflammation and fibrosing destruction of intrahepatic and extrahepatic bile ducts. The exact etiologic mechanism is not known but growing evidence supports an immunologic basis. The male to female ratio is 2:1; peak age is 20–40. Most cases of PSC are associated with ulcerative colitis. The presentation is similar to PBC. Complications include biliary cirrhosis and cholangiocarcinoma. Microscopically, there is periductal chronic inflammation with concentric fibrosis around bile ducts and segmental stenosis of bile ducts. Cholangiogram shows “beaded appearance” of bile ducts.
Cirrhosis Cirrhosis is end-stage liver disease characterized by disruption of the liver architecture by bands of fibrosis which divide the liver into nodules of regenerating liver parenchyma. Causes of cirrhosis include alcohol, viral hepatitis, biliary tract disease, hemochromatosis, cryptogenic/idiopathic, Wilson disease, and α-1-antitrypsin deficiency.
Clinical Correlate Prothrombin time, not partial thromboplastin time, is used to assess the coagulopathy due to liver disease.
On gross pathology, micronodular cirrhosis has nodules 3 mm; mixed micronodular and macronodular cirrhosis can also occur. At the end stage, most diseases result in a mixed pattern, and the etiology may not be distinguished based on the appearance. Cirrhosis has a multitude of consequences, including portal hypertension, ascites, splenomegaly/hypersplenism, esophageal varices, hemorrhoids, caput medusa, decreased detoxification, hepatic encephalopathy, spider angiomata, palmar erythema, gynecomastia, decreased synthetic function, hepatorenal syndrome and coagulopathy.
Viral Hepatitis Viral hepatitis can be asymptomatic or it can present with malaise and weakness, nausea and anorexia, jaundice, or dark urine. Lab studies show markedly elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Diagnosis is by serology. Acute viral hepatitis is viral hepatitis with signs and symptoms for 6 months. It can be caused by hepatitis viruses B, C, and D. • Microscopically, chronic persistent hepatitis shows inflammation con-
fined to portal tracts.
Microbiology
• Chronic active hepatitis shows inflammation spilling into the paren-
chyma, causing interface hepatitis (piecemeal necrosis of limiting plate).
Hepatitis B often has “ground glass” hepatocytes (due to cytoplasmic HBsAg). Table 19-2. The Hepatitis Viruses Common Virus Name
Hepatitis A
Common disease name
“Infectious”
Virus
Hepatitis B (HBV)
Hepatitis C (HCV)
Hepatitis D (HDV)
Hepatitis E
“Serum”
“Post-transfusion” or “non-A, non-B”
“Delta”
“Enteric”
Hepatovirus nonenveloped capsid RNA
Hepadnavirus enveloped DNA
Flavivirus enveloped RNA
Defective enveloped circular RNA
Hepevirus nonenveloped capsid RNA
Transmission
Fecal-oral
Parenteral, sexual, perinatal
Parenteral, sexual
Parenteral, sexual
Fecal-oral
Severity
Mild
Occasionally severe
Usually subclinical
Co-infection with HBV occasionally severe; superinfection with HBV often severe
Normal patients: mild; pregnant patients: severe
Chronicity or carrier state
No
Yes
Yes (high)
Yes
No
Clinical diseases
Acute hepatitis
• Acute hepatitis
• Acute hepatitis
Acute hepatitis
• Chronic hepatitis
• Chronic hepatitis
• Cirrhosis
• Cirrhosis
• Chronic hepatitis
• Hepatocellular carcinoma (HCC)
• HCC
• Cirrhosis
Symptoms and EIA for anti-HCV
(HAV)
Laboratory diagnosis
Symptoms and anti-HAV IgM
Symptoms and serum levels of HBsAg, HBeAg, and anti-HBc IgM
Prevention
Vaccine, hygiene
Vaccine
Treatment
Supportive
Antivirals, interferons, transplant
(HEV)
• HCC Anti-HDV ELISA
Tests not routinely available Hygiene
Antivirals, interferons, transplant
See hepatitis B
Supportive
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Table 19-3. Hepatitis B Terminology and Markers Abbreviation
Name and Description
HBV
Hepatitis B virus, a hepadnavirus (enveloped, partially doublestranded DNA virus); Dane particle = infectious HBV
HBsAg
Antigen found on surface of HBV; also found on spheres and filaments in patient’s blood: positive during acute disease; continued presence indicates carrier state
HBsAb
Antibody to HBsAg; provides immunity to hepatitis B
HBcAg
Antigen associated with core of HBV
HBcAb
Antibody to HBcAg; positive during window phase; IgM HBcAb is an indicator of recent disease
HBeAg
A second, different antigenic determinant on the HBV core; important indicator of transmissibility
HBeAb
Antibody to e antigen; indicates low transmissibility
Delta agent
Small RNA virus with HBsAg envelope; defective virus that replicates only in HBV-infected cells
Table 19-4. Hepatitis A Serology Acute or recent infection
anti-HAV IgM
Prior infection or immunization
anti-HAV IgG
Table 19-5. Hepatitis B Serology HBsAg HBeAg* HBV-DNA
HBcAb IgM
HBcAb IgG
HBsAb IgG
Acute infection
+
+
−
−
Window period
−
+
−
−
Prior infection
−
−
+
+
Immunization
−
−
−
+
Chronic infection
+
−
+
−
*HBeAg—correlates with viral proliferation and infectivity
Amebic Liver Abscess Amebic liver abscess is rare in the United States except in those who have traveled to/from tropical areas with poor sanitation. The causative organism is Entamoeba histolytica. The presentation, which may occur years after travel, includes RUQ pain, fever, and hepatic tenderness. Detection of a space-occupying liver lesion with positive serology is diagnostic. Treatment is antibiotics. Drainage is rarely necessary.
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Medical Genetics
Pathology Pathology
Microbiology
Behavioral Science/Social Sciences
Alcoholic Liver Disease Fatty change (steatosis) is reversible with abstinence. The gross appearance is of an enlarged, yellow, greasy liver. Microscopically, the liver initially shows centrilobular macrovesicular steatosis (reversible) that can eventually progress to fibrosis around the central vein (irreversible). Alcoholic hepatitis is an acute illness that usually follows a heavy drinking binge. Some patients have no symptoms and others develop RUQ pain, hepatomegaly, jaundice, malaise, anorexia, or even fulminant liver failure. Microscopically, the liver shows hepatocyte swelling (ballooning) and necrosis, Mallory bodies (cytokeratin intermediate filaments), neutrophils, fatty change, and eventual fibrosis around the central vein. The prognosis can be poor, since each episode has a 20% risk of death, and repeated episodes increase the risk of developing cirrhosis. Alcoholic cirrhosis develops in 15% of alcoholics, and is typically a micronodular or Laennec cirrhosis.
© cdc.gov. Used with permission.
© cdc.gov.
Figure 20-1.Alcoholic Alcoholic Cirrhosis, Figure 19-1. Cirrhosis,Liver Liver
Metabolic Liver Disease Wilson disease (hepatolenticular degeneration) is a genetic disorder of copper metabolism resulting in the accumulation of toxic levels of copper in various organs. It affects the liver (fatty change, chronic hepatitis, and micronodular cirrhosis), cornea (Kayser-Fleischer rings [copper deposition in Descemet’s membrane]), and brain (neurological and psychiatric manifestations, movement disorder). Diagnosis is established by demonstrating decreased serum ceruloplasmin levels, increased tissue copper levels (liver biopsy), and increased urinary copper excretion. Treatment includes copper chelators (D-penicillamine); liver transplantation is curative. The disease is autosomal recessive, and the WD gene (ATP7B on chromosome 13) codes for a hepatocyte canalicular copper-transporting ATPase. Damage to
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the gene leads to a decreased biliary excretion of copper. Wilson disease presents in children or adolescents with liver disease. Hemochromatosis is a disease of increased levels of iron, leading to tissue injury. Hereditary (primary) hemochromatosis is a recessive disorder of the HFE gene on chromosome 6p. The most common mutation of the HFE gene is the C282Y mutation, which increases small intestine absorption of iron. Secondary hemochromatosis can follow transfusions for chronic anemias. Hemochromatosis affects 5 times as many males as females, and the disease is common in people of Northern European descent. Hemochromatosis can cause micronodular cirrhosis and hepatocellular carcinoma (200 times the normal risk ratio); secondary diabetes mellitus; hyperpigmented skin (“bronzing”); congestive heart failure and cardiac arrhythmias; and hypogonadism. Diagnosis is established by demonstrating markedly elevated serum iron and ferritin or increased tissue iron levels (Prussian blue stain) on liver biopsy. Treatment is phlebotomy. α-1-antitrypsin deficiency is an autosomal recessive disorder characterized by production of defective α-1-antitrypsin (α1-AT), which accumulates in hepatocytes and causes liver damage and low serum levels of α1-AT. α1-AT is produced by the SERPINA1 gene (chromosome 14); >75 gene variants are described. Normal individuals are homozygous PiMM. Heterozygotes have intermediate levels of the enzyme. Homozygous PiZZ have severe reductions (10% of normal) in enzyme levels. α-1-antitrypsin deficiency affects the liver (micronodular cirrhosis and an increased risk of hepatocellular carcinoma) and lungs (panacinar emphysema). Microscopically, PAS positive, eosinophilic cytoplasmic globules are found in hepatocytes. Treatment includes smoking abstinence/cessation to prevent emphysema; liver transplantation is curative.
Note Protease-Antiprotease Imbalance α-1-antitrypsin is an important protease inhibitor. • Responsible for inhibiting neutrophil elastase • Inhibits trypsin, chymotrypsin, and bacterial proteases
Reye syndrome is a rare, potentially fatal disease that occurs in young children with viral illness (varicella or influenza) treated with aspirin. The disease mechanism is unknown; mitochondrial injury and dysfunction play an important role. Reye causes hepatic fatty change (microvesicular steatosis) and cerebral edema/ encephalopathy. There is complete recovery in 75% of patients, but those that do not recover may experience permanent neurologic deficits. Coma and death may result. Treatment is supportive. Nonalcoholic fatty liver disease is a disease of lipids accumulating in hepatocytes that is not associated with heavy alcohol use. It occurs equally in men and women, and is strongly associated with obesity, hyperinsulinemia, insulin resistance, and type 2 diabetes mellitus. The pathogenesis involves lipid accumulation in hepatocytes that can progress to steatohepatitis (NASH—nonalcoholic steatohepatitis) and finally cirrhosis. Nonalcoholic fatty liver disease is a diagnosis of exclusion.
Hemodynamic Liver Diseases Budd-Chiari syndrome (hepatic vein thrombosis) refers to occlusion of the hepatic vein by a thrombus, often resulting in death. While a few cases are idiopathic, more often there is an underlying process predisposing for the thrombosis e.g., polycythemia vera, pregnancy, oral contraceptives, paroxysmal nocturnal
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Pathology Pathology
Microbiology
Behavioral Science/Social Sciences
hemoglobinuria, or hepatocellular carcinoma. It presents with abdominal pain, hepatomegaly, ascites, jaundice, splenomegaly, and in some cases, death. The initial diagnostic test is ultrasonography. Microscopically, the liver shows centrilobular congestion and necrosis. In the chronic form, fibrosis develops. Treatment includes supportive care and treatment of the underlying condition. Some patients require lifelong anticoagulation. Chronic passive congestion of the liver refers to a “backup of blood” into the liver, usually due to right-sided heart failure. Grossly, the liver characteristically has a nutmeg pattern of alternating dark (congested central areas) and light (portal tract areas) liver parenchyma. Microscopically, the liver shows centrilobular congestion. Complications include centrilobular necrosis, which is an ischemic necrosis of centrilobular hepatocytes. Long-standing congestion can lead to centrilobular fibrosis, which can eventually become cardiac cirrhosis (sclerosis).
LIVER TUMORS Benign Tumors Hemangioma is the most common primary tumor of the liver, mostly affecting women. It is a benign vascular tumor that typically forms a subcapsular, red, spongy mass. It is often asymptomatic and detected incidentally on CT or MRI. Resection is rarely indicated, and liver biopsy carries the risk of bleeding. Hepatocellular adenoma (HCA) affects young women and is related to oral contraceptive use. Half of cases are asymptomatic. Symptoms include abdominal pain or spontaneous intraperitoneal hemorrhage (25% of cases). Due to the risk of transformation to HCC, resection is often recommended. There are 3 subtypes of HCA: • H-HCA is a solitary or multiple tan steatotic nodule with rare transforma-
tion into HCC
–– Mutation of hepatocyte nuclear factor 1 • b-HCA can resemble HCC histologically and transforms to HCC in
some cases
–– Was named for the associated beta-catenin mutations • I-HCA shows inflammatory infiltrates, sinusoidal dilatation, and thick-
walled arteries
–– Acute inflammatory markers are elevated; malignant transformation
occurs less frequently
Focal nodular hyperplasia is a subcapsular lesion often discovered incidentally by the radiologist. Laboratory values are generally normal. It is a nodular proliferation in response to a vascular anomaly. There is a central, stellate scar. Excision is generally not required due to the characteristic appearance on imaging.
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Malignant Tumors Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver in adults. The incidence is higher in Asia and Japan than in the United States. Risk factors include cirrhosis, hepatitis B and C viruses, alcohol, aflatoxin B1. HCC has a tendency for hematogenous spread and invasion of portal and hepatic veins. The tumor marker is α-fetoprotein (AFP). The fibrolamellar variant affects younger age, has fibrous bands, and has a better prognosis. Angiosarcoma is a rare, fatal tumor associated with exposure to vinyl chloride. Hepatoblastoma is the most common hepatic malignancy in infants and children. Lobectomy is the standard of care. Histology shows immature precursor cells. Metastatic tumors are the most common tumors found within the liver. Common primary sites include the colon, breast, and lung. Metastatic tumors tend to occur as multiple well-circumscribed masses.
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Central Nervous System Pathology
Central Nervous System Pathology
20
Learning Objectives ❏❏ Solve problems concerning infections across the blood brain barrier ❏❏ Answer questions about cerebrovascular disease, CNS trauma, and brain herniation ❏❏ Use knowledge of developmental abnormalities and perinatal brain injury ❏❏ Explain information related to demyelinating disorders ❏❏ Solve problems concerning degenerative and dementing disorders ❏❏ Describe CNS tumors
INFECTIONS Meningitis Meningitis is inflammation of the 2 inner meningeal layers, the pia and the arachnoid. Acute aseptic (viral) meningitis is caused by leptomeningeal inflammation due to viruses (enterovirus most frequent); the inflammation produces a lymphocytic infiltration of leptomeninges and superficial cortex. Patients present with fever, signs of meningeal irritation, and depressed consciousness. Mortality is low. Viral meningitis carries a better prognosis than bacterial meningitis. Acute viral meningitis is the most common neurologic symptom associated with primary HIV infection; it presents around the time of seroconversion with an acute confusional state. Symptoms resolve after 1 month with supportive care. Acute purulent (bacterial) meningitis is a purulent leptomeningeal inflammation. • Streptococcus pneumoniae is the most common cause of meningitis in
infants, young children, and adults.
• Neonates are infected most frequently with group B streptococci but
Escherichia coli causes a greater number of fatalities.
• Neisseria meningitidis is seen in teens and young adults and is often
associated with a maculopapular rash.
• The incidence of Listeria monocytogenes increases after age 50. This
pathogen also tends to infect people with poor cell-mediated immunity.
The leptomeninges are opaque on gross examination. Microscopic examination shows neutrophilic infiltration of the leptomeninges, extending variably to cortex. Diffuse cerebral edema carries a risk of fatal herniations. The classic triad of bacterial meningitis is fever, nuchal rigidity, and altered mental status.
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Medical Genetics
Pathology Pathology
Behavioral Science/Social Sciences
Microbiology
Mycobacterial meningitis can be caused by Mycobacterium tuberculosis or atypical mycobacteria. It occurs in patients who have reactivation of latent infection and immunocompromised patients such as AIDS patients (Mycobacterium avium-intracellulare). Diagnosis requires microscopy/culture of large volumes of CSF. MRI is the imaging test of choice and shows basal meningeal enhancement and hydrocephalus. It usually involves the basal surface of the brain, and may cause characteristic tuberculomas within the brain and dura mater. When infection spreads into the parenchyma, the condition is known as meningoencephalitis. Fungal meningitis. Candida, Aspergillus, Cryptococcus, and Mucor species are the most frequent agents. Aspergillus and Mucor have a marked tropism for blood vessels, which leads to vasculitis, rupture of blood vessels, and hemorrhage. Cryptococcus causes diffuse meningoencephalitis, which leads to invasion of the brain through the Virchow-Robin space (a continuation of the subarachnoid space around blood vessels entering the neuropil) and soap bubble lesions.
Table 20-1. CSF Parameters in Different Forms of Meningitis Condition
Cells/μL
Glucose (μg/dL)
Proteins (mg/dL)
Pressure (mm H2O)
Normal values
50)
Normal or slightly elevated
Granulomatous (mycobacterial/ fungal)
100–1,000 most lymphocytes
Decreased (50)
Moderately elevated
Encephalitis Encephalitis is inflammation of the brain. The viral encephalitides have common features of perivascular cuffs, microglial nodules, neuron loss, and neuronophagia. Clinical manifestations are variable, and can include mental status change, fever, and headache, often progressing to coma. • Arthropod-borne forms can be due to St. Louis, Eastern and Western
equine, and Venezuelan encephalitides.
• Herpes simplex type 1 produces a characteristic hemorrhagic necrosis of
temporal lobes. Cowdry type A bodies are intranuclear inclusions seen in neurons and glial cells.
• Rabies has characteristic Negri bodies in the cytoplasm of hippocampal
and Purkinje cells.
• HIV encephalopathy shows histopathology of microglial nodules and
diagnostic multinucleated giant cells. Spinal involvement leads to vacuolar myelopathy, which is similar to vitamin B12 deficiency–associated subacute combined degeneration. HIV-associated neurocognitive disorder (HAND) presents as cognitive decline with behavioral changes and motor symptoms. Diagnosis is based on clinical features and the exclusion of other etiologies.
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• Progressive multifocal leukoencephalopathy (PML) is caused by JC poly-
omavirus. It occurs in immunocompromised patients and patients taking immunomodulatory therapies. Neurologic symptoms are varied and include impairment of cognition and motor function. There is no specific antiviral drug and mortality is high. Tissue sections show areas of demyelination and enlarged oligodendrocytes.
• Subacute sclerosing panencephalitis is a rare complication of measles
(rubeola) virus infection. Persistent immune-resistant measles virus infection causes slow-virus encephalitis. The typical scenario is a child who had measles age 280 beats/min) Pathology
Behavioral Science/Social Sciences
• Although fast, atrial conduction is still intact and coordinated. • Characteristics: “saw-tooth” appearance of waves between QRS com-
plexes; no discernible T waves; rhythm typically steady
Microbiology
Figure II-3-14. Atrial Atrial Flutter Flutter Figure II-3-14.
Atrial Fibrillation Uncoordinated atrial conduction • Lack of a coordinated conduction results in no atrial contraction • Characteristics: unsteady rhythm (usually) and no discernible P waves
Figure II-3-15. Atrial Fibrillation Figure II-3-15. Atrial Fibrillation
Wolff-Parkinson-White Syndrome Accessory pathway (Bundle of Kent) between atria and ventricles • Characteristics: short PR interval; steady rhythm and normal rate
(usually); slurred upstroke of the R wave (delta wave); widened QRS complex
• The cardiac impulse can travel in retrograde fashion to the atria over
the accessory pathway and initiate a reentrant tachycardia.
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Electrical Activity of the Heart
Figure Syndrome FigureII-3-16. II-3-16. Wolff-Parkinson-White Wolff-Parkinson-White Syndrome
Other Factors Changing the ECG ST segment changes • Elevated: transmural infarct or Prinzmetal angina (coronary
vasospasm)
• Depressed: subendocardial ischemia or exertional (stable) angina
Potassium • Hyperkalemia: increases rate of repolarization, resulting in
sharp-spiked T waves and a shortened QT interval
• Hypokalemia: decreases rate of repolarization, resulting in U waves
and a prolonged QT interval
Calcium • Hypercalcemia: decreases the QT interval • Hypocalcemia: increases the QT interval
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PART III
Muscle
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1
Learning Objectives ❏❏ Interpret scenarios on skeletal muscle structure-function relationships ❏❏ Interpret scenarios on regulation of cytosolic calcium ❏❏ Interpret scenarios on altering force in skeletal muscle ❏❏ Interpret scenarios on comparison of striated muscles (skeletal vs. cardiac) ❏❏ Interpret scenarios on smooth muscle function
SKELETAL MUSCLE STRUCTURE–FUNCTION RELATIONSHIPS Ultrastructure of a Myofibril A muscle is made up of individual cells called muscle fibers. Longitudinally within the muscle fibers, there are bundles of myofibrils. • A myofibril can be subdivided into individual sarcomeres. A sarcomere
is demarked by Z lines.
• Sarcomeres are composed of filaments creating bands. • Contraction causes no change in the length of the A band, a shortening
of the I band, and a shortening in the H zone (band).
• Titin anchors myosin and is an important component of striated
muscle’s elasticity.
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Biochemistry
Part III Physiology
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Muscle Medical Genetics
Z band Pathology
M line
Z band
Magnified muscle myofibril
Behavioral Science/Social Sciences
Myofibril Microbiology
Sarcomere
Sarcomere
Actin filament
H zone
I band
A band
Z band
Myosin filament
Titin
Figure III-1-1. Organization of Sarcomeres Figure III-1-1. Organization of Sarcomeres
Ultrastructure of the Sarcoplasmic Reticulum The external and internal membrane system of a skeletal muscle cell is d isplayed below. T-tubule Terminal cisternae Sarcolemma Myofibrils
Figure III-1-2. Skeletal Muscle Membranes Figure III-1-2. Skeletal Muscle CellCell Membranes
T-tubule membranes are extensions of the surface membrane; therefore, the interiors of the T tubules are part of the extracellular compartment. Terminal cisternae: The sarcoplasmic reticulum is part of the internal membrane system, one function of which is to store calcium. In skeletal muscle, most of the calcium is stored in the terminal cisternae close to the T-tubule system.
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Functional Proteins of the Sarcomere The figure below shows the relationships among the proteins that make up the thin and thick filaments in striated muscle (skeletal and cardiac) and the changes that occur with contraction. Changes Following Attachment of Calcium to Troponin
Resting Muscle Thin filament Actin
Troponin Tropomyosin Ca2+ binding site Myosin (cross-bridge)
Myosin-binding site
Ca2+
B
A Figure III-1-3. Regulation of Actin by Troponin Figure III-1-3. Regulation of Actin by Troponin
Proteins of the thin filaments • Actin is the structural protein of the thin filament. It possesses
attachment sites for myosin.
• Tropomyosin blocks myosin binding sites on actin. • Troponin is composed of 3 subunits: troponin-T (binds to tropomyosin),
troponin-I (binds to actin and inhibits contraction), and troponin-C (binds to calcium). –– Under resting conditions, no calcium is bound to the troponin, preventing actin and myosin from interacting.
–– When calcium binds to troponin-C, the troponin-tropomyosin complex moves, exposing actin’s binding site for myosin. (part B of the figure above)
Proteins of the thick filaments Myosin has ATPase activity. The splitting of ATP puts myosin in a “high energy” state; it also increases myosin’s affinity for actin. • Once myosin binds to actin, the chemical energy is transferred to mechanical energy, causing myosin to pull the actin filament. This generates active tension in the muscle and is commonly referred to as “the power stroke.” • If the force generated by the power stroke is sufficient to move the load
(see next chapter), then the muscle shortens (isotonic contraction).
• If the force generated is not sufficient to move the load (see next
chapter), then the muscle doesn’t shorten (isometric contraction).
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Muscle Medical Genetics
Cross-Bridge Interactions (Chemical-Mechanical Transduction) Pathology
Behavioral Science/Social Sciences
Cross-bridge cycling starts when free calcium is available and attaches to troponin, which in turn moves tropomyosin so that myosin binds to actin. Contraction (of a muscle) is the continuous cycling of cross-bridges. Cross-bridge
Microbiology
Hydrolysis of ATP puts myosin in high energy and high actin affinity state.
Z line
Resting muscle
• Tropomyosin: covers actin's binding site for myosin Cytosolic Ca2+ rises and binds to troponin-C, exposing myosin-binding site on actin.
Dissociation
• ATP dissociates actin-myosin • Myosin enters low-energy, low-affinity state
Binding of myosin to actin • Actin-myosin bind
Chemical energy converted
to mechanical aspects of contraction • Myosin "pulls" actin • Actin filament slides, producing active tension.
Figure III-1-4. Crossbridge Cycling During Figure III-1-4. Cross-bridge Cycling Contraction During Contraction
ATP is not required to form the cross-bridge linking to actin but is required to break the link with actin. Cross-bridge cycling (contraction) continues until either of the following occurs: • Withdrawal of Ca2+: cycling stops at position 1 (normal resting
muscle)
• ATP is depleted: cycling stops at position 3 (rigor mortis; this would
not occur under physiologic conditions)
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REGULATION OF CYTOSOLIC CALCIUM The sarcoplasmic reticulum (SR) has a high concentration of Ca2+. Thus, there is a strong electrochemical gradient for Ca2+ to diffuse from the SR into the cytosol. There are 2 key receptors involved in the flux of Ca2+ from the SR into the cytosol: dihydropyridine (DHP) and ryanodine (RyR). • DHP is a voltage-gated Ca2+ channel located in the sarcolemmal
membrane. Although it is a voltage-gated Ca2+ channel, Ca2+ does not flux through this receptor in skeletal muscle. Rather, DHP functions as a voltage-sensor. When skeletal muscle is at rest, DHP blocks RyR.
• RyR is a calcium channel on the SR membrane. When the muscle is in
the resting state, RyR is blocked by DHP. Thus, Ca2+ is prevented from diffusing into the cytosol.
T-tubule
Sarcolemma
Cytosol
DHP
Terminal cisternae of SR Ca2+
Ca2+
ATP
Ca2+ Ca2+
RyR (closed)
Ca2+
Ca2+ Ca2+ Ca2+
Action potential
T-tubule
SERCA
Cytosol Ca2+ Ca2+ Ca2+ DHP
Ca2+
Ca2+
Ca2+
RyR (open)
Ca2+ Ca2+ Ca2+
A. Resting skeletal muscle
Terminal cisternae of SR
Ca2+
Ca2+ Ca2+
Sarcolemma
Ca2+ ATP
SERCA
Ca2+ Ca2+
Ca2+ Ca2+ Ca2+ Ca2+
B. Action potential in sarcolemma
Figure III-1-5. Regulation of Ca2+ Release by Sarcoplasmic Reticulum Figure III-1-5. Regulation of Ca2+ Release by Sarcoplasmic Reticulum
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Muscle Medical Genetics
Sequence 1. Skeletal muscle action potential is initiated at the neuromuscular junction (see section II). Pathology
Behavioral Science/Social Sciences
2. The action potential travels down the T-tubule. 3. The voltage change causes a conformation shift in DHP (voltage sensor), removing its block of RyR (part B of the figure above).
Microbiology
4. Removal of the DHP block allows Ca2+ to diffuse into the cytosol (follows its concentration gradient). 5. The rise in cytosolic Ca2+ opens more RyR channels (calcium-induced calcium release). 6. Ca2+ binds to troponin-C, which in turn initiates cross-bridge cycle, creating active tension. 7. Ca2+ is pumped back into the SR by a calcium ATPase on the SR membrane called sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA). 8. The fall in cytosolic Ca2+ causes tropomyosin to once again cover actin’s binding site for myosin and the muscle relaxes, provided of course ATP is available to dissociate actin and myosin.
Key Points • Contraction-relaxation states are determined by cytosolic levels of
Ca2+.
• The source of the calcium that binds to the troponin-C in skeletal
muscle is solely from the cell’s sarcoplasmic reticulum. Thus, no extracellular Ca2+ is involved.
• Two ATPases are involved in contraction:
–– Myosin ATPase supplies the energy for the mechanical aspects of contraction by putting myosin in a high energy and affinity state. –– SERCA pumps Ca2+ back into the SR to terminate the contraction, i.e., causes relaxation.
ALTERING FORCE IN SKELETAL MUSCLE Mechanical Response to a Single Action Potential The figure below illustrates the mechanical contraction of skeletal muscle and the action potential on the same time scale. Note the sequence of events: action potential causes Ca2+ release. The release of Ca2+ evokes a muscle contraction (twitch).
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Excitation-Contraction Coupling
Active Force
Intracellular Free Calcium
Membrane Potential Time (msec) Figure III-1-6. Course of Events During During Contraction Figure III-1-6. Time The Time Course of Events Contraction
The muscle membrane has completely repolarized well before the start of force development.
Summation and Recruitment Under normal circumstances, enough Ca2+ is released by a single muscle action potential to completely saturate all the troponin-C binding sites. This means that all available cross-bridges are activated and thus force cannot be enhanced by increasing cytosolic Ca2+. Instead, peak force in skeletal muscle is increased in 2 ways: summation and recruitment.
Summation • Because the membrane has repolarized well before force development,
multiple action potentials can be generated prior to force development.
• Each action potential causes a pulse of Ca2+ release. • Each pulse of Ca2+ initiates cross-bridge cycling and because the
muscle has not relaxed, the mechanical force adds onto (summates) the force from the previous action potential (Figure III-1-7).
• This summation can continue until the muscle tetanizes in which case
there is sufficient free Ca2+ so that cross-bridge cycling is continuous.
Recruitment • A single alpha motor neuron innervates multiple muscle fibers.
The alpha motor neuron and all the fibers it innervates is called a motor-unit.
• Recruitment means activating more motor units, which in turn engage
more muscle fibers, causing greater force production.
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Biochemistry
Part III Physiology
Pathology
●
Muscle Medical Genetics
Behavioral Science/Social Sciences
Membrane Potential (mV)
Pharmacology
Active Force
Microbiology
+30 0 −70
Summation of twitches
Tetanus
Time (msec) Figure III-1-7. Figure III-1-7. Summation SummationofofIndividual IndividualTwitches Twitches and Fusion Fusioninto intoTetanus Tetanus and
Recall Question Which of the following is the mechanism of action of rigor mortis? A. Withdrawal of Ca2+ which stops cycling at position 1 B. Cytosolic calcium rises and binds to troponin-C, exposing myosin-binding site on actin C. Depletion of ATP which stops cycling at position 3 D. Depletion of calcium which stops cycling at position 3 E. Depletion of actin-myosin cross bridging which stops cycling at position 3 Answer: C
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Excitation-Contraction Coupling
COMPARISON OF STRIATED MUSCLES Skeletal and cardiac muscle are both striated muscle and share many similarities. Nevertheless, there are important differences.
Similarities • Both have the same functional proteins, i.e., actin, tropomyosin,
troponin, myosin, and titin.
• A rise in cytosolic Ca2+ initiates cross-bridge cycling thereby produc-
ing active tension.
• ATP plays the same role. • Both have SERCA. • Both have RyR receptors on the SR and thus show calcium-induced
calcium release.
Differences • Extracellular
Bridge to Pathology Ca2+
is involved in cardiac contractions, but not skeletal muscle. This extracellular Ca2+ causes calcium-induced calcium release in cardiac cells.
• Magnitude of SR Ca2+ release can be altered in cardiac (see section on
Dysfunction in the titin protein has been associated with dilated and restrictive cardiomyopathies (see next section).
cardiac mechanics), but not skeletal muscle.
• Cardiac cells are electrically coupled by gap junctions, which do not
exist in skeletal muscle.
• Cardiac myocytes remove cytosolic Ca2+ by 2 mechanisms: SERCA
and a Na+—Ca2+ exchanger (3 Na+ in, 1 Ca2+ out) on the sarcolemmal membrane. Skeletal muscle only utilizes SERCA.
Figure III-1-8. III-1-8. Removal Calcium in Myocardial Cells Figure RemovalofofCytosolic Cytosolic Calcium in Myocardial Cells
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Pharmacology
Biochemistry
Part III Physiology
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Muscle Medical Genetics
Pathology
• Cardiac cells have a prolonged action potential. The figure above
illustrates that the twitch tension is already falling (muscle starting to relax) while the action potential is still in the absolute refractory period. Thus, a second action potential cannot be evoked before the mechanical event is almost completed. This approximately equal mechanical and electrical event prevents summation of the force and if the muscle can’t summate, it can’t tetanize.
Behavioral Science/Social Sciences
Microbiology
Muscle twitch Action potential
Relative refractory period Absolute refractory period
0
100
200 Time (msec)
300
Figure III-1-9. Force and Refractory Periods Figure III-1-9. Force and Refractory Periods
SMOOTH MUSCLE Actin-Myosin Interaction Actin-myosin binding = Contraction
No actin-myosin binding = Relaxation Actin
Actin
Myosin binding site
P
Myosin light chain Myosin head
Myosin heavy chain
Figure III-1-10a. Relaxed Smooth Muscle
Myosin head
Myosin binding site Phosphorylation by MLCK Dephosphorylated by MLC phosphatase
Myosin heavy chain
MLC = Myosin light chain MLCK = Myosin light chain kinase
Figure III-1-10b. Contracted Smooth Muscle
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• In contrast to striated muscle, smooth muscle lacks tropomyosin,
troponin, and titin.
• Similar to striated muscle, the binding of actin and myosin produces
tension.
• In the resting state, MLC is not phosphorylated and has very low
affinity for actin. Thus they do not interact and smooth muscle is relaxed (Figure III-1-10a)
• On the other hand, phosphorylation of MLC puts myosin in a high-
affinity state for actin, resulting in the binding of actin and myosin to produce a power stroke (Figure III-1-10b).
• MLC is phosphorylated by myosin light-chain kinase (MLCK) and
dephosphorylated by MLC phosphatase.
• Similar to striated muscle, the trigger for contraction is increasing
cytosolic calcium, which activates MLCK
Regulation of Smooth Muscle • Voltage-gated calcium channels (L-type) reside in the sarcolemma of
smooth muscle. Depolarization opens these channels, resulting in calcium influx into the cytosol. This calcium triggers calcium release from the SR (calcium-induced calcium release, similar to cardiac muscle).
• Increasing IP3 also evokes calcium efflux from the SR. IP3 is increased
by an agonist binding a Gq coupled receptor (e.g., the alpha-1 receptor).
• This cytosolic calcium binds to the protein calmodulin (CAM). This
calcium-calmodulin complex activates MLCK, which in turn phosphorylates MLC.
• As indicated above, phosphorylation of MLC causes binding of actin
and myosin, in turn eliciting a contraction of smooth muscle.
• Although not illustrated in Figure III-1-11, similar to striated muscle
(see above), ATP dissociates actin and myosin. If MLC remains phosphorylated, then actin and myosin rebind to produce tension (similar to cross-bridge cycling described above for striated muscle).
• MLC phosphatase dephosphorylates myosin, reducing the affinity of
myosin for actin, causing relaxation.
• When cytosolic calcium is high, MLCK dominates. When cytosolic
calcium is low, MLC phosphatase dominates.
• Smooth muscle reduces cytosolic calcium via the same mechanisms
described above for cardiac cells.
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Muscle
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
Figure III-1-11. Smooth Muscle Cell
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Skeletal Muscle Mechanics
2
Learning Objectives ❏❏ Use knowledge of overview of muscle mechanics ❏❏ Interpret scenarios on length-tension curves ❏❏ Use knowledge of relationship between velocity and load ❏❏ Demonstrate understanding of properties of white vs. red muscle ❏❏ Solve problems concerning comparison of muscle types
MUSCLE MECHANICS Preload Preload is the load on a muscle in a relaxed state, i.e., before it contracts. Applying preload to muscle does 2 things: • Stretches the muscle: This in turn, stretches the sarcomere. The greater
the preload, the greater the stretch of the sarcomere.
• Generates passive tension in the muscle: Muscle is elastic (see titin,
previous chapter) and thus “resists” the stretch applied to it. Think of the “snap-back” that occurs when one stretches a rubber band. The force of this resistance is measured as passive tension. The greater the preload, the greater the passive tension in the muscle.
Afterload Afterload is the load the muscle works against. If one wants to lift a 10 kg weight, then this weight represents the afterload. Using the 10 kg weight example, 2 possibilities exist: • If the muscle generates more than 10 kg of force, then the weight
moves as the muscle shortens. This is an isotonic contraction.
• If the muscle is unable to generate more than 10 kg of force, then the
muscle won’t shorten. This is an isometric contraction.
• Types of tension
–– Passive: produced by the preload –– Active: produced by cross-bridge cycling –– Total: sum of active and passive tension
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Biochemistry
Part III Physiology
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Muscle Medical Genetics
LENGTH–TENSION CURVES
Pathology
Behavioral Science/Social Sciences
Length–tension curves are important for understanding both skeletal and cardiac muscle function. The graphs that follow are all generated from skeletal muscle in vitro, but the information can be applied to both skeletal muscle and heart muscle in vivo.
Passive Tension Curve
Microbiology
As seen in the figure below, the green line shows that muscle behaves like a rubber band. The elastic properties of the muscle resist this stretch and the resulting tension is recorded. There is a direct (non-linear) relationship between the degree of stretch and the passive tension created that resists this stretch.
Point A: no preload, thus no stretch and no passive tension
Point C: preload of 5 g increases muscle stretch, producing a greater resting length and thus a greater passive tension
In vitro skeletal muscle Tension (grams)
Point B: preload of 1 g stretches muscle, thus increasing its resting length, resulting in ~1 g of passive tension
C
5 4 3
Active tension curve B
2 1
Passive tension curve
A
0 1
2
A
Infinite afterload
3 4 5 6 7 Muscle Length (units) B
1g
C
5g
In vitro skeletal muscle Passive tension = 0 Active tension = 2 Total tension = 2
Passive tension = 1 Active tension = 4 Total tension = 5
Passive tension = 5 Active tension = 3 Total tension = 8
Figure III-2-1. Preload, Active and Passive Tension: Figure III-2-1. Preload, Active and Passive Tension: The Length–Tension Relationship The Length–Tension Relationship
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Active Tension In the figure above, the purple line shows the tension developed by stimulating the muscle to contract at the different preloads. In this example, the contraction is a maximal isometric contraction, i.e., the contraction produces tension, but the afterload is much greater than the tension the muscle develops and thus the muscle doesn’t shorten. Recall that active tension represents the force generated by cross-bridge cycling. It is important to note the shape (bell-shaped) of the active tension curve. • Preload of A: When there is no preload, the evoked muscle contraction
develops ~2 g of active tension.
• Preload of B: At this preload, the active tension produced by stimula-
tion of the muscle is greater, ~4 g.
• Preload of C: This preload results in less active tension than the
previous preload. Thus, active tension increases as the muscle is stretched, up to a point. If stretched beyond this point, then active tension begins to fall.
• Optimal length (Lo): Lo represents the muscle length (preload) that
produces the greatest active tension. (In the figure above, this occurs at the preload designated by B.)
Explanation of Bell-shaped Active Tension Curve The same figure above shows a simplified picture of a sarcomere. Actin is the thin brown line, while myosin is depicted in purple. The magnitude of active tension depends on the number of actin-myosin cross-bridges that can form (directly related). • Preload A: actin filaments overlap
–– Thus, the force that can be exerted by myosin tugging the actin is compromised and the active tension is less. • Preload B (Lo): all myosin heads can bind to actin, and there is separa-
tion of actin filaments
–– Thus, active tension generated is greatest here because there is optimal overlap of actin and myosin. • Preload C: the stretch is so great that actin has been pulled away from
some of the myosin filament, and thus fewer actin-myosin interactions are available, resulting in diminished active tension. –– If taken to the extreme, greater stretch could pull actin such that no actin-myosin interactions can occur, and thus no active tension results (active tension curve intersects the x-axis). This is an experimental, rather than physiologic phenomenon.
• Total tension: sum of passive and active tension (bottom of figure
above)
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Muscle Medical Genetics
RELATIONSHIP BETWEEN VELOCITY AND LOAD
Pathology
Microbiology
Behavioral Science/Social Sciences
As seen in the figure below, the maximum velocity of shortening (Vmax) occurs when there is no afterload on the muscle. Increasing afterload decreases velocity, and when afterload exceeds the maximum force generated by the muscle, shortening does not occur (isometric contraction).
*Maximum velocity (Vmax) is determined by the muscle’s ATPase activity. It is the ATPase activity that determines a fast versus a slow muscle. **Maximum force generated by a muscle occurs when summation is maximal (complete summation) and all motor units for the given muscle are fully recruited. The absolute amount of force is directly related to muscle mass and preload, with the greatest force occurring when the preload is at Lo.
* Velocity
B
A
** Afterload Figure III-2-2. Force–Velocity Curve Figure III-2-2. Force–Velocity Curve
In the figure above, muscle A is a smaller, slower muscle (red muscle), while muscle B is a larger, faster muscle (white muscle). As load increases, the distance shortened during a single contraction decreases. So, with increased afterload, both the velocity of contraction and the distance decrease.
PROPERTIES OF WHITE VS. RED MUSCLE White Muscle Generally, white muscle is the large (powerful) muscle that is utilized shortterm, e.g., ocular muscles, leg muscles of a sprinter. Major characteristics are as follows: • Large mass per motor unit • High ATPase activity (fast muscle) • High capacity for anaerobic glycolysis • Low myoglobin
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Skeletal Muscle Mechanics
Red Muscle Generally, red muscle is the smaller (less powerful) muscle utilized long-term (endurance muscle), e.g., postural muscle. Major characteristics are as follows: • Small mass per motor unit • Lower ATPase activity (slower muscle) • High capacity for aerobic metabolism (mitochondria) • High myoglobin (imparts red color)
Recall Question Which of the following is a characteristic of white muscle? A. It is reponsible for slower muscle movements. B. It has a high mitochondria content. C. It primarily utilizes aerobic metabolism. D. It has a greater mass per motor unit. E. It contains high amounts of myoglobin. Answer: D
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PART IV
Cardiovascular
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Hemodynamics and Important Principles
1
Learning Objectives ❏❏ Answer questions about systolic performance of the ventricle ❏❏ Explain information related to ventricular function curves ❏❏ Solve problems concerning chronic changes: systolic and diastolic dysfunction
THE CARDIOVASCULAR SYSTEM Cardiac Output The cardiovascular system consists of 2 pumps (left and right ventricles) and 2 circuits (pulmonary and systemic) connected in series. Pulmonary Right Heart (venous return ↑)
Circuit
Systemic
Left Heart (cardiac output ↓)
Circuit FigureFigure V-1-1. Overview of Circulatory System IV-1-1. The Circulatory System
When circuits are connected in series, flow must be equal in the 2 circuits. • Cardiac output is the output of either the left or right ventricle, and
because of the series system, they are equal.
• The chemical composition of pulmonary venous blood (high oxygen,
low carbon dioxide) is very close to the chemical composition of systemic arterial blood.
Note The function of the heart is to transport blood and deliver oxygen in order to maintain adequate tissue perfusion. It also removes waste products, e.g., CO2 created by tissue metabolism.
• Systemic mixed venous blood entering the right atrium has the same
composition (low oxygen, high carbon dioxide) as pulmonary arterial blood.
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Part IV
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Physiology
Cardiovascular Medical Genetics
Pathology
Behavioral Science/Social Sciences
Structure–Function Relationships of the Systemic Circuit The systemic circuit is a branching circuit. It begins as a large single vessel, the aorta, and branches extensively into progressively smaller vessels until the capillaries are reached. The reverse then takes place in the venous circuit.
Microbiology
Venae Veins cavae
Aorta Arteries
Venules Arterioles Capillaries FigureV-1-2. IV-1-2.Organization Organization of of the Systemic Vessels Figure Systemic Vessels
HEMODYNAMICS Pressure, Flow, Resistance The Poiseuille equation represents the relationship of flow, pressure, and resistance.
Q =
P1 − P2 R
It can be applied to a single vessel, an organ, or an entire circuit. Q: flow (mL/min) P1: upstream pressure (pressure head) for segment or circuit (mm Hg) P2: pressure at the end of the segment or circuit (mm Hg) R: resistance of vessels between P1 and P2 (mm Hg/mL/min)
Pressure gradient P1
P2 Blood flow Resistance
Figure IV-1-3. Poiseuille Equation Applied Single Vessel Figure V-1-3. Poiseuille Equation Applied to to Single Vessel
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Hemodynamics and Important Principles
The flow to an organ such as the kidney, for example, could be calculated as mean arterial pressure minus renal venous pressure divided by the resistance of all vessels in the renal circuit.
Determinants of resistance Resistance =
Units of Resistance =
P1 − P2 Q mm Hg pressure = mL /min volume/time
The resistance of a vessel is determined by 3 major variables: R ∝
vL r4
Vessel radius (r) is the most important factor determining resistance. If resistance changes, then the following occurs: • Increased resistance decreases blood flow, increases upstream pressure,
and decreases downstream pressure.
• Decreased resistance increases blood flow, decreases upstream pressure
and increases downstream pressure.
• The pressure “drop” (difference between upstream and downstream) is
directly related to the resistance. There is a big pressure drop when resistance is a high and minimal pressure drop when resistance is a low.
80
Right Heart
Venae Cavae
Veins
Venules
Capillaries
Arterioles
0
Arteries
40
Aorta
Pressure mm Hg
120
V-1-4. Systemic System Pressures Figure Figure IV-1-4. Systemic System Pressures
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Cardiovascular Medical Genetics
Whole body application of resistance The figure above shows, in a horizontal subject, the phasic and mean pressures from the aorta to the vena cava. Pathology
Behavioral Science/Social Sciences
Microbiology
• Mean arterial pressure (MAP) is measured in the aorta and is
about 93 mm Hg (time weighted average because more time is spent in diastole). This represents the pressure head (upstream pressure) for the systemic circulation.
• The pressure dissipates as the blood flows down the circulatory tree
because of resistance. The amount of pressure lost in a particular segment is proportional to the resistance of that segment.
• There is a small pressure drop in the major arteries (low-resistance
segment); the largest drop is across the arterioles (highest resistance segment), and another small pressure drop occurs in the major veins (low-resistance segment).
• Since the largest pressure drop across the systemic circulation occurs
in arterioles, they are the main site resistance. This resistance is called total peripheral resistance (TPR) or systemic vascular resistance (SVR).
• TPR/SVR is afterload to the heart (see next chapter).
If a blood sample from an adult is centrifuged in a graduated test tube, the relative volume of packed red cells is called the hematocrit. For a normal adult this volume is about 40–45% of the total, meaning the red cells occupy about 40–45% of the blood in the body. The white blood cells are less dense than the red blood cells and form a thin layer (the so-called buffy coat). That is why hematocrit is a major determinant of blood viscosity.
Blood viscosity (v) is a property of a fluid that is a measure of the fluid’s internal resistance to flow. The greater the viscosity, the greater the resistance. The prime determinant of blood viscosity is the hematocrit.
Viscosity (poise)
Note
8 7 6 5 4 3 2 1
Normal blood
0
10 20 30 40 50 60 70 Hematocrit (%)
Figure Hematocriton onBlood BloodViscosity Viscosity Figure V-1-5. IV-1-5.Effect Effect of of Hematocrit
Anemia decreases viscosity. Polycythemia increases viscosity. Vessel length (L) The greater the length, the greater the resistance. • If the length doubles, the resistance doubles. • If the length decreases by half, the resistance decreases by half. • Vessel length is constant; therefore, changes in length are not a physi-
ologic factor in regulation of resistance, pressure, or flow.
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Hemodynamics and Important Principles
Velocity
Note
Velocity is the rate at which blood travels through a blood vessel. Mean linear velocity is equal to flow divided by the cross-sectional area (CSA). Thus, velocity is directly related to flow, but if CSA changes then velocity is affected. The important functional applications of this are:
Although velocity is directly related to blood flow, it is different in that it refers to a rate, e.g., cm/sec.
• CSA is high in capillaries, but low in the aorta. • Velocity is therefore high in the aorta and low in the capillaries. • The functional consequence of this is that low velocity in the capillar-
ies optimizes exchange.
• The potential pathology of this is that because the aorta has high
velocity and a large diameter, turbulent blood flow can occur.
Laminar versus Turbulent Flow There can be 2 types of flow in a system: laminar and turbulent. Laminar flow is flow in layers. It occurs throughout the normal cardiovascular system, excluding flow in the heart. The layer with the highest velocity is in the center of the tube. Turbulent flow is nonlayered flow. It creates murmurs. These are heard as bruits in vessels with severe stenosis. Turbulent flow produces more resistance than laminar flow.
Figure V-1-6. Laminar Flow Figure IV-1-6. Laminar Flow
Figure V-1-7. Turbulent Flow Figure IV-1-7. Turbulent Flow
Relation of Reynold’s number to laminar and turbulent flow Reynold's number =
(diameter) (velocity) (density) viscosity
>2,000 = turbulent flow 55% in a normal heart)
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Part IV
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Cardiovascular
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
CHRONIC CHANGES: SYSTOLIC AND DIASTOLIC DYSFUNCTION Systolic dysfunction is an abnormal reduction in ventricular emptying due to impaired contractility or excessive afterload. Diastolic dysfunction is a decrease in ventricular compliance i.e., the ventricle is stiffer. Reduced compliance causes an elevated diastolic pressure for any given volume. EDV is often reduced, but compensatory mechanisms may result in a normal EDV (although end-diastolic pressure is elevated at this “normal” EDV).
Pressure Overload • Examples of a pressure overload on the left ventricle include hyperten-
sion and aortic stenosis.
• Initially, there is no decrease in cardiac output or an increase in
preload since the cardiac function curve shifts to the left (increased performance due to increased contractility).
• Chronically, in an attempt to normalize wall tension (actually internal
wall stress), the ventricle develops a concentric hypertrophy. There is a dramatic increase in wall thickness and a decrease in chamber diameter.
• The consequence of concentric hypertrophy (new sarcomeres laid down
in parallel, i.e., the myofibril thickens) is a decrease in ventricular compliance and diastolic dysfunction, followed eventually by a systolic dysfunction and ventricular failure.
Volume Overload • Examples of a volume overload on the left ventricle include mitral and
aortic insufficiency and patent ductus arteriosus.
• Fairly well tolerated if developed slowly. A large acute volume overload
less well tolerated and can precipitate heart failure.
• Due to the LaPlace relationship, a dilated left ventricle must develop a
greater wall tension to produce the same ventricular pressures.
r
P=T/r The greater the radius, the greater the wall tension needed to generate the same ventricular pressure.
Figure IV-1-5 Figure IV-2-5 • Chronically, in an attempt to normalize wall tension (actually external
wall stress), the ventricle develops an eccentric hypertrophy (new sarcomeres laid down end-to-end, i.e., the myofibril lengthens).
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As cardiac volumes increase, there is a modest increase in wall thickness that does not reduce chamber size. • Compliance of the ventricle is not compromised and diastolic function
is maintained.
• Eventual failure is usually a consequence of systolic dysfunction.
Cardiomyopathy Cardiac failure or more specifically, congestive failure, is a syndrome with many etiologies. Cardiomyopathy is a failure of the myocardium where the underlying cause originates within the myocyte (excluded would be valvular heart disease, afterload problems, and coronary heart disease). There are 3 basic types: • Dilated cardiomyopathy • Restrictive cardiomyopathy • Hypertrophic cardiomyopathy
Dilated cardiomyopathy Dilated cardiomyopathy is ventricular dilation with only a modest hypertrophy that is less than appropriate for the degree of dilation. It can occur for the left heart, right heart, or can include both. • Diastolic function remains intact and helps compensate for the cham-
ber dilation.
• Compensation also includes increased sympathetic stimulation to the
myocardium.
• Systolic dysfunction despite compensations via Frank-Starling and
increased contractility
• Further dilation over time and mitral and tricuspid failure enhance
systolic dysfunction with eventual complete failure.
Restrictive cardiomyopathy Restrictive cardiomyopathy is decreased ventricular compliance with diastolic dysfunction and a decrease in ventricular cavity size. • Increased filling pressures lead to left- and right-sided congestion. • Ventricular hypertrophy may or may not be present. • Systolic maintained close to normal
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Cardiovascular Medical Genetics
Hypertrophic cardiomyopathy • Septal or left ventricular hypertrophy is unrelated to a pressure overload. • Diastolic dysfunction due to increased muscle stiffness and impaired Pathology
Behavioral Science/Social Sciences
relaxation
• Is a subtype of hypertrophic cardiomyopathy, often resulting in a Microbiology
restriction of the ventricular outflow tract (idiopathic hypertrophic subaortic stenosis) and pulmonary congestion. Currently this is referred to clinically as hypertrophic obstructive cardiomyopathy (HOCM).
• Hypertrophy may be related to septal fiber disarray.
Recall Question Which of the following physiological changes is characteristic of hypertrophic cardiomyopathy, as opposed to other types of cardiomyopathies? A. Septal hypertrophy unrelated to pressure overload B. Decreased ventricular compliance C. Ventricular dilation with intact diastolic function D. Systolic dysfunction with mitral valve failure E. Increased filling pressures leading to left and right sided congestion Answer: A
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CV Regulation and Cardiac Output
3
Learning Objectives ❏❏ Answer questions on short-term regulation of systemic arterial pressure ❏❏ Demonstrate understanding wall tension and the application of the LaPlace relationship
SHORT-TERM REGULATION OF SYSTEMIC ARTERIAL PRESSURE Arterial Baroreceptors The baroreceptor reflex is the short-term regulation of blood pressure. Its main features can be seen below.
IX Carotid sinus
Aortic arch
X
Medulla
Parasympathetic Heart HR
Heart HR + cont.
Sympathetic Arterioles TPR
Venous constriction
Figure V-1-8. Baroreflexes
Figure IV-3-1. Baroreflexes
The reninangiotensin-aldosterone system is the long-term regulation of blood pressure. MAP = CO × TPR Key points regarding arterial baroreceptors: • Mechanoreceptors imbedded in the walls of the aortic arch and carotid
sinus are stimulated by a rise in intravascular pressure.
• Afferent activity is relayed to the medulla via cranial nerves IX (carotid
sinus) and X (aortic arch).
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• Baroreceptor activity exists at the person’s resting arterial blood pressure. • Afferent activity stimulates the parasympathetic nervous system and
inhibits the sympathetic nervous system.
Pathology
Behavioral Science/Social Sciences
• A fall in arterial blood pressure evokes a reflex decrease in parasympa-
thetic activity and increase in sympathetic activity. This is a negative feedback system to bring blood pressure back to its original level.
• A rise in arterial blood pressure evokes a reflex increase in parasympa-
Microbiology
thetic activity and fall in sympathetic activity. This is a negative feedback system to bring blood pressure back to its original level.
• Activation of arterial baroreceptors inhibits the secretion of ADH.
Table IV-3-1. Reflex Changes for Specific Maneuvers Condition
Afferent Activity
Parasympathetic Activity
Sympathetic Activity
BP increase
↑
↑
↓
BP decrease
↓
↓
↑
BP
HR
Carotid occlusion
↓
↓
↑
↑
↑
Carotid massage
↑
↑
↓
↓
↓
Cut afferents
↓
↓
↑
↑
↑
Lying to stand
↓
↓
↑
↑ toward normal
↑
↑
↑
↓
↓ toward normal
↓
Orthostatic hypotension Fluid loss Volume load Weightlessness
Cardiopulmonary Mechanoreceptors (Baroreceptors) Mechanoreceptors are embedded in the walls of the heart (all 4 chambers), great veins where they empty into the right atrium, and pulmonary artery. • Afferent activity is relayed to the medulla via cranial nerve X (vagus). • Because this region is highly compliant, volume changes are the
primary stimulus.
• A reduction in volume in the heart and/or the vessels leading to the heart
evokes a reflex increase in SNS activity and a decrease in PNS activity.
• A rise in volume in the heart and/or the vessels leading to the heart
evokes a reflex decrease in SNS activity and an increase in PNS activity.
• Similar to arterial baroreceptors, this represents a negative feedback
regulation of arterial blood pressure. Further, like arterial baroreceptors, activation of these receptors inhibits ADH release.
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Application of Hemodynamics to the Systemic Circulation A simplified model of the circulation can be used to examine whole-body cardiovascular regulation. Blood flows from the aorta to the large arteries that supply the various organs. Within each organ, there are muscular arterioles that serve as the primary site of resistance. The sum of these resistors (added as reciprocals because of the parallel arrangement) is TPR/SVR. This represents afterload to the heart.
Lungs Cerebral RA
LA RV
Liver
Coronary LV
Stomach, Spleen Pancreas
Endocrine glands
Intestines
Kidneys
Skin, Muscle, Bone Systemic Circuit FigureFigure V-1-9.IV-3-2. Systemic Circuit
There are 2 functional consequences related to the fact arterioles serve as the primary site of resistance: • They regulate blood flow to the capillaries (site of exchange with the
tissue).
• They regulate upstream pressure, which is mean arterial pressure
(MAP).
Tissues need nutrient delivery and thus have mechanisms to regulate the tone of arterioles (intrinsic regulation, discussed in the next chapter). However, from a whole body perspective it is imperative to maintain an adequate MAP because this is the pressure head (upstream pressure) for the entire body (extrinsic regulation).
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Bridge to Pathology Sepsis, anaphylaxis, and neurogenic shock are examples of uncontrolled Pathologyvasodilation in the periphery, Behavioral Science/Social Sciences leading to diminished MAP.
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Given the above, consider arterioles to effectively function as faucets. The tissues need to regulate the faucet to ensure adequate nutrient delivery (intrinsic regulation). On the other hand, these arterioles need a sufficient tone to maintain MAP (extrinsic regulation). If all the faucets were fully opened simultaneously then upstream pressure (MAP) plummets, in turn compromising blood flow to all the organs. Thus, a balance must exist with respect to the level of arteriolar tone (“how tight the faucet is”) so there is enough flow to meet the metabolic demands without compromising MAP. A variety of extrinsic mechanisms exist to regulate arterioles and thus maintain an adequate MAP. Factors that cause vasoconstriction, resulting in increased MAP and reduced flow to the capillary include: • Norepinephrine (NE) released from sympathetic postganglionic
neurons
Bridge to Pharmacology Drugs that mimic NE cause the same cardiovascular effects that NE produces. These include alpha-1 agonists, NE releasers, and NE reuptake inhibitors.
–– NE binds alpha-1 receptors to activate Gq which increases cytosolic calcium in smooth muscle cells, in turn causing vasoconstriction. The sympathetic nervous system is the dominant regulator of vascular tone and has a tonic effect on skeletal muscle and cutaneous vessels at rest. During times of stress, it can exert its effects on the splanchnic and renal circulations as well. • Epinephrine (EPI) released from the adrenal medulla also activates
alpha-1 receptors.
• Ang II via the AT1 receptor (Gq) • Arginine vasopressin (AVP), also known as anti-diuretic hormone
(ADH), via the V1 receptor (Gq)
Vasodilation of arterioles results in a drop in MAP with an increased flow to capillaries (provided MAP doesn’t fall too much). Vasodilatory mechanisms include:
Bridge to Pharmacology Drugs that block NE’s vascular effects (alpha blockers), prevent NE release, liberate NO, activate beta-2 receptors, block calcium entry into smooth muscle cells, and/or open smooth muscle potassium channels mimic the vasodilatory effects indicated.
• Decreased sympathetic activity: reduced NE release decreases alpha-1
vasoconstriction
• EPI stimulates vascular beta-2 receptors (Gs–cAMP) • Nitric oxide (NO): tonically released from vascular endothelium and
activates soluble guanylyl cyclase to increase smooth muscle cGMP
• A variety of compounds produced by tissue metabolism, e.g.,
adenosine, CO2, K+, and H+
VENOUS RETURN To understand vascular function and thus ultimately the regulation of cardiac output, one can “split” the circulation into 2 components: • Cardiac output (CO): flow of blood exiting the heart (down arrow on
the arterial side).
• Venous return (VR): flow of blood returning to the heart (up arrow on
the venous side). Because this is the flow of blood to the heart, it determines preload for the ventricles (assuming normal ventricular function).
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Because the circulation is a closed system, these flows are intertwined and must be the same when one examines it “over time” or at steady-state. In addition, each flow is “dependent” on the other. For example: • If CO fell to zero, then ultimately VR would become zero. • If one were to stop VR, there would ultimately be no CO.
These are extreme examples to illustrate the point that altering one ultimately alters the other and a variety of factors can transiently or permanently alter each of the variables, resulting in the other variable being impacted to the same degree. Earlier in this book we discussed ventricular function, which plays a pivotal role in CO. In this section, we discuss the regulation of VR. VR represents vascular function and thus understanding its regulation sets the stage for understanding CO regulation.
CVP: central venous pressure RH CVP/ RAP
0
Pulm circ.
IPP: intrapleural pressure LH
IPP –5
MABP: mean arterial blood pressure Psf: mean systemic filling pressure 93
Psf
LH: left heart
7
MABP
RH: right heart RAP: right atrial pressure
Capillaries FigureV-1-11. IV-3-3. Pressure Pressure Gradients System Figure Gradientsininthe theCirculatory Circulatory System
VR is the flow of blood back to the heart and it determines preload. Since it is a flow, it must follow the hemodynamic principles described above, i.e., it is directly proportional to the pressure gradient and inversely related to the resistance. • Right atrial pressure (RAP): blood is flowing to the right atrium, thus
RAP is the downstream pressure.
• Mean systemic filling pressure (Psf): represents the upstream pressure
(pressure head) for VR.
Mean systemic filling pressure (Psf): Although not a “theoretical” pressure (as per numerous experiments, Psf is typically ~7 mm Hg prior to endogenous compensations), this is not a pressure that can be conveniently measured, particularly in a patient. However, because it is the pressure when no flow exists, it is primarily determined by volume and compliance:
Note Engaging the muscle pump also increases Psf.
• Blood volume: There is a direct relation between blood volume and Psf.
The greater the blood volume, the higher the Psf and vice versa.
• Venous compliance: There is an inverse relation between venous
compliance and Psf. The more compliant the veins, the lower the Psf and vice versa.
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Because Psf is the pressure head (upstream pressure) driving VR, then VR is directly related to Psf. If all other factors are unchanged, it follows that: • An increase in blood volume increases VR. • A decrease in blood volume decreases VR. • A decrease in venous compliance (sympathetic stimulation; muscle
pump) increases VR.
Microbiology
• An increase in venous compliance (sympathetic inhibition; venodila-
tors; alpha block) decreases VR.
DETERMINANTS OF CARDIAC OUTPUT Because VR plays an important role in determining cardiac output (CO), we can now discuss the regulation of CO. The key to remember is that steadystate CO is the interplay between ventricular function (see ventricular function curves in the previous chapter) and vascular function, which is defined by VR curves. The 4 determinants are as follows: • Heart rate • Contractility • Afterload • Preload (determined by VR)
The latter 3 factors can be combined on CO/VR curves, which are illustrated and discussed later.
Heart Rate CO = HR × SV (stroke volume) Although heart rate (HR) and CO are directly related, the effect of changes in HR on CO is complicated because the other variable, SV, must be considered. High heart rates decrease filling time for the ventricles, and thus can decrease SV. In short, the effect of HR on CO depends upon the cause of the rise in HR.
Endogenously mediated tachycardia, e.g., exercise In exercise, the rise in HR increases CO. Although filling time is reduced, a variety of changes occur that prevent SV from falling. These are: • Sympathetic stimulation to the heart increases contractility. This helps
maintain stroke volume. In addition, this decreases the systolic interval (see previous chapter) thus preserving some of the diastolic filling time.
• Sympathetic stimulation increases conduction velocity in the heart,
thereby increasing the rate of transmission of the electrical impulse.
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• Sympathetic stimulation venoconstricts, which helps preserve VR (see
above) and ventricular filling.
• The skeletal muscle pump increases VR, helping to maintain ventricu-
lar filling.
Pathologically mediated tachycardia, e.g., tachyarrhythmias • The sudden increase in HR curtails ventricular filling resulting in a fall
in CO.
• Although the fall in CO decreases MAP and activates the sympathetic
nervous system, this occurs “after the fact” and is thus unable to compensate.
• There is no muscle pump to increase VR.
CO
HR
Figure V-1-12 Figure IV-3-4
Contractility There is a direct relation between contractility and ventricular output. Thus, there is typically a direct relation between contractility and CO.
Afterload Afterload is the load the heart works against and the best marker of afterload is TPR. There is an inverse relation between afterload and ventricular output, thus there is generally an inverse relation between afterload and CO.
Preload As discussed earlier, there is a direct relation between preload and ventricular output (Frank-Starling). Presuming there is no change in contractility or afterload, increasing preload increases CO and vice versa.
Cardiac Output/Venous Return Curves Cardiac output/venous return (CO/VR) curves depict the interplay between ventricular and vascular function indicated in the venous return section above. Steady-state CO is determined by this interplay.
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Ventricular function • X-axis is RAP, a marker of preload. • Y-axis is CO. Pathology
Behavioral Science/Social Sciences
• Thus, this curve is the same as depicted in both figures below, and it
defines ventricular function.
• This curve shows that RAP has a positive impact on CO (Frank-
Starling mechanism) (see figure IV-2-4)
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Vascular function • X-axis is RAP, the downstream pressure for VR. • Y-axis is VR. • The curve shows that as RAP increases, VR decreases. This is because
RAP is the downstream pressure for VR. As RAP increases, the pressure gradient for VR falls, which in turn decreases VR. Thus, RAP has a negative impact on VR.
• X-intercept for the VR curve is Psf (point B on the graph). This is the
pressure in the circulation when there is no flow (see section on venous return). Psf is the pressure head (upstream pressure) for VR. Thus, when RAP = Psf, flow (VR) is zero.
Steady-state CO The intersection of the ventricular and vascular function curves determines steady-state CO (point A in the figure below). In other words, point A represents the interplay between ventricular and vascular function. • Discounting HR, the only way steady-state CO can change is if ven-
tricular function, or vascular function, or both change.
Solid line: ventricular function Dashed line: vascular function A = steady-state cardiac output
CO/VR
All individuals operate at the intersection of the ventricular function and venous return curves. B = mean systemic filling pressure (Psf) This is directly related to vascular volume and inversely related to venous compliance.
A
B Right Atrial Pressure (RAP)
Figure V-1-13 Figure IV-3-5
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Resistance The primary site of resistance for the circulation is the arterioles. • If arterioles vasodilate (decreased resistance), VR increases (line A of
the figure below). Recall that VR is a flow, and thus decreasing resistance increases flow. Note that this vasodilation provides more VR (move up the Frank-Starling curve).
Although not depicted in the graph, vasodilation decreases afterload
and thus shifts the ventricular function curve up and to the left. In short, arteriolar vasodilation enhances both ventricular and vascular function.
• If arterioles vasoconstrict (increased resistance), VR falls (line B of the
figure below). Note that this vasoconstriction reduces VR, and steadystate CO falls as one moves down the Frank-Starling curve.
Psf As indicated above (venous return section), Psf is directly related to blood volume and inversely related to venous compliance. • Increasing vascular volume (infusion; activation of RAAS) or decreas-
ing venous compliance (sympathetic stimulation; muscle pump; exercise; lying down) increases Psf, causing a right shift in the VR curve (line C of figure below). Thus, either of these changes enhances filling of the ventricles (move up the Frank-Starling curve) and CO.
• Decreasing vascular volume (hemorrhage; burn trauma; vomiting;
diarrhea) or increasing venous compliance (inhibit sympathetics; alpha block; venodilators; standing upright) decreases Psf, causing a left shift in the VR curve (line D of figure below). Thus, either of these changes reduces filling of the ventricles (move down the Frank-Starling curve) and CO.
A
CO/VR B
D RAP
C
CO/VR
A: arteriolar dilation RAP
Figure V-1-14 Figure IV-3-6
Although not depicted in the figure, vasoconstriction increases afterload, shifting the ventricular function curve down and to the right. Thus, arteriolar vasoconstriction reduces both ventricular and vascular function.
B: arteriolar constriction C: increased vascular volume; decreased venous compliance D: decreased vascular volume; increased venous compliance
Solid circles represent starting CO.
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Note
EFFECT OF GRAVITY
The Effect of Gravity Case 1. When placing a central line in Behavioral Science/Social Sciences the internal jugular or subclavian vein of a patient in the medical intensive care unit, place the patient in the Trendelenburg position, in which the Microbiology deep veins of the upper extremity are below the level of the heart. This position makes the venous pressure less negative, thus reducing the risk of forming an “air embolus,” in which the needle forms a connection between the positive atmospheric pressure and the negative vein. Pathology
Case 2. To take an accurate blood pressure reading, place the sphygmomanometer at the level of the heart. If the cuff is above the level of the heart, the reading will be falsely low; conversely, if the cuff is below the level of the heart, the reading will be falsely high.
Venous pressure
Arterial pressure
– Gravity 2 mm Hg
– Gravity 100 mm Hg
H
+ Gravity (~80 mm Hg)
+ Gravity
82 mm Hg
180 mm Hg
Figure IV-3-7.Effect EffectofofGravity Gravity Figure V-1-15.
Below heart level, there are equal increases in systemic arterial and venous pressures (assuming no muscular action). Thus, the pressure difference between arteries and veins does not change. Because veins are very compliant vessels, the higher pressures in the dependent veins mean a significant pooling of blood, a volume that is not contributing to cardiac output. Although venous compliance doesn’t “technically” increase, gravity’s impact is functionally the same as an increase in venous compliance.
Bridge to Pathology/ Pharmacology The inability to maintain MAP when standing upright is called orthostatic intolerance. In this condition, the fall in MAP reduces cerebral blood flow, causing the patient to feel dizzy or light-headed. This can lead to a syncope event. One of the more common causes for this is reduced vascular volume. The low volume reduces VR and the added fall in VR (due to venous pooling) overwhelms the compensatory mechanisms. Other factors that can lead to orthostatic intolerance are venodilators, poor ventricular function such as heart failure or cardiac transplant, and dysautonomias.
When a person goes from supine to an upright posture, the following important changes take place: • Pressure in the dependent veins increases. • Blood volume in the dependent veins increases. • VR decreases. • If no compensations occurred, then MAP would fall because of the
diminished SV.
The initial compensation arises from cardiopulmonary mechanoreceptors (described previously in this chapter), which, because their stretch is reduced, activate the SNS and inhibit the PNS. The reflex activation of the sympathetic nervous system causes: • Arteriolar vasoconstriction (TPR increases) • Increase in HR • Venoconstriction
If MAP falls, then the arterial baroreceptors also participate in the reflex changes.
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Above heart level, systemic arterial pressure progressively decreases. Because venous pressure at heart level is close to zero, venous pressure quickly becomes subatmospheric (negative). Surface veins above the heart cannot maintain a significant pressure below atmospheric and will collapse; however, deep veins and those inside the cranium supported by the tissue can maintain a pressure that is significantly below atmospheric. A consequence of the preceding is that a severed or punctured vein above heart level has the potential for introducing air into the system.
CHARACTERISTICS OF SYSTEMIC ARTERIES The following figure shows a pressure pulse for a major systemic artery.
Pressure (mm Hg)
80
Mean arterial pressure
Pulse pressure
Systolic blood pressure
120
Diastolic blood pressure
40
0
FigureV-1-16. IV-3-8. Pulse Pulse Pressure Figure Pressureand andMean MeanPressure Pressure
Pulse pressure equals systolic minus diastolic, so here, pulse pressure is 120 – 80 = 40 mm Hg.
Factors Affecting Systolic Pressure Systolic blood pressure is the highest pressure in the systemic arteries during the cardiac cycle. The main factor determining systolic blood pressure on a beat-tobeat basis is stroke volume. • An increase in stroke volume increases systolic blood pressure, while a
decrease in stroke volume decreases systolic blood pressure.
• Systolic blood pressure is also directly related to ventricular contractility.
In addition, the rate of pressure change in the aorta is directly related to contractility. Thus, if contractility increases, then the rate of pressure and the absolute level of aortic pressure increases, and vice-versa.
• In chronic conditions, a decrease in the compliance of the systemic
arteries (age-related arteriosclerosis) also increases systolic blood pressure.
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Factors Affecting Diastolic Pressure Diastolic blood pressure is directly related to the volume of blood left in the aorta at the end of diastole. One important factor determining diastolic blood pressure is TPR. • Dilation of the arterioles decreases diastolic blood pressure,
while constriction of the arterioles increases diastolic blood pressure.
• HR is the second key factor influencing diastolic pressure and they are
Microbiology
directly related: increased HR increases diastolic blood pressure, while decreased HR decreases diastolic blood pressure.
• Diastolic blood pressure is also directly related to SV, but this is
typically not a major factor.
Note
Factors Affecting Pulse Pressure
Theoretically, the systemic pulse pressure can be conceptualized as being proportional to stroke volume, or the amount of blood ejected from the left ventricle during systole, and inversely proportional to the compliance of the aorta.
The following increase (widen) pulse pressure: • An increase in stroke volume (systolic increases more than diastolic) • A decrease in vessel compliance (systolic increases and diastolic decreases)
The aorta is the most compliant artery in the arterial system. Peripheral arteries are more muscular and less compliant. Based on the preceding information, in the figure below the pressure record on the left best represents the aorta, whereas the one on the right best represents the femoral artery.
Mean pressure
FigureV-1-17. IV-3-9. Compliance Compliance and Figure and Pulse PulsePressure Pressure
The figure demonstrates that a compliant artery has a small pulse pressure and that a stiff artery has a large pulse pressure. Also, pulse pressure increases with age because compliance is decreasing. This can produce isolated systolic hypertension, in which mean pressure is normal because the elevated systolic pressure is associated with a reduced diastolic pressure.
Factors Affecting Mean Pressure Mean pressure is pressure averaged over time. It is not the arithmetic mean and is closer to diastolic pressure than to systolic pressure. Mean pressure can be approximated by the following formulas: For a blood pressure of 120/80 mm Hg: Mean pressure = diastolic + 1/3 pulse pressure 80 + 1/3(40) = 93 mm Hg = 2/3 diastolic pressure + 1/3 systolic pressure 2/3(80) + 1/3(120) = 93 mm Hg
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Any formula that calculates mean pressure must give a value between systolic and diastolic but closer to diastolic than systolic. The factors affecting mean pressure (application of hemodynamics discussed above) include: Q: cardiac output P1: aortic pressure (mean arterial pressure) P2: pressure at the entrance of the right atrium R: resistance of all vessels in the systemic circuit (referred to as TPR) Because the major component of TPR is the arterioles, TPR can be considered an index of arteriolar resistance. Because P1 is a very large number (93 mm Hg) and P2 is a very small one (~0 mm Hg), that doesn’t change dramatically in most situations, we can simplify the equation if we approximate P2 as zero. Then: CO =
MAP or MAP = CO × TPR TPR
This equation simply states that:
MAP: mean arterial pressure CO: cardiac output TPR: total peripheral resistance
• MAP is determined by only 2 variables: cardiac output and TPR. • CO is the circulating volume. The blood stored in the systemic veins
and the pulmonary circuit would not be included in this volume.
• TPR is the resistance of all vessels in the systemic circuit. By far the
largest component is the resistance in the arterioles.
• However, if venous or right atrial pressure (RAP) is severely increased,
it must be taken into account when estimating TPR. In this case, the formula is: (MAP - RAP) = CO × TPR or rearranged to solve for resistance:TPR TPR = =
(MAP − RAP) CO
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Recall Question
Pathology
Behavioral Science/Social Sciences
Which of the following is accurate regarding mean systemic filling pressure (Psf)? A. IV fluid infusion decreases mean systemic filling pressure B. Exercising decreases mean systemic filling pressure
Microbiology
C. The volume of blood and the mean systemic filling pressure are proportional D. Venous compliance and mean systemic filling pressure are directly related E. Decreasing vascular volume causes mean systemic filling pressure to increase Answer: C
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Regulation of Blood Flow
4
Learning Objectives ❏❏ Demonstrate understanding of Fick principle of blood flow ❏❏ Interpret scenarios on blood flow regulation ❏❏ Explain information related to blood flow to the various organs ❏❏ Demonstrate understanding of fetal circulation ❏❏ Explain information related to cardiovascular stress: exercise
FICK PRINCIPLE OF BLOOD FLOW
Note
The Fick principle can be utilized to calculate the blood flow through an organ. Calculation of flow through the pulmonary circuit provides a measure of the cardiac output (CO). uptake Flow = A − V
The Fick principle was first devised as a technique for measuring CO. It is a way to calculate oxygen consumption (VO2). VO2 = CO × (CaO2 − CvO2)
Required data are: oxygen consumption of the organ
CaO2 = total arterial oxygen content
A – V oxygen content (concentration) difference across organ (not PO2) Pulmonary venous (systemic arterial) oxygen content = 20 vol% = 20 volumes O2 per 100 volumes blood = 20 mL O2 per 100 mL blood = 0.2 mL O2 per mL blood If pulmonary vessel data are not available, you may substitute arterial oxygen content for pulmonary venous blood and use venous oxygen content in place of pulmonary artery values. In a normal resting individual, that would appear as follows:
(Hgb × 1.36 × SaO2) + PaO2 × 0.0031 These values are obtained from an ABG. CvO2 = total venous oxygen content (Hgb × 1.36 × SvO2) + PvO2 × 0.0031 These values are obtained from a central venous or Swan-Ganz catheter, which samples blood from the pulmonary artery. The (CaO2 − CvO2) and CO are the 2 main factors that allow variation in the body’s total oxygen consumption.
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O2 consumption 250 mL O2/min
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Pulmonary artery
Alveolus O2
Pulmonary vein [O2] pv 0.20 mL O2/mL blood
[O2] pa 0.15 mL O2/mL blood Pulmonary capillary
Figure V-2-1. Alveolar Oxygen Uptake Figure IV-4-1. Alveolar Oxygen Uptake
Q(flow ) =
=
Cardiac index =
oxygen consumption O2 ]pv – [ O2 pa 250 mL / min = 5,000 mL / min 0.20 mL / mL – 0.15 mL / mL cardiac output body surface area
This would normalize the value for body size.
Application of the Fick Principle Rearranging the Fick Principle to O2 consumption = Q × (CaO2 − CvO2) can be applied to important concepts regarding homeostatic mechanisms and pathologic alterations. CaO2 − CvO2 represents the extraction of O2 by the tissue.
O2 consumption
O2 consumption is dependent upon flow and the extraction of O2. If tissue O2 consumption increases, then flow or extraction or both must increase. • The rise in flow in response to a rise in tissue O2 consumption is the result of increased production of vasodilator metabolites (see metabolic mechanism below). • In short, this change in flow and extraction represents homeostatic
mechanisms designed to ensure adequate O2 availability and thus sufficient ATP production.
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O2 delivery
The “first part” of the Fick Principle indicates that delivery of O2to the tissue is dependent upon Q and the total amount of O2 in the blood (CaO2). O2 delivery = Q × CaO2 • For any given tissue O2 consumption, reduced delivery of O2 results in
increased lactic acid production and possible hypoxic/ischemic damage to tissues.
• For any given tissue O2 consumption, if O2 delivery decreases, then
PvO2 and SvO2% fall.
Clinical application: A fall in PvO2 or SvO2% indicates the patient’s O2 consumption increased and/or there was a fall in O2 delivery (Q and/or CaO2). Organ X
Arterial
O2
CO2
Venous
PO2 = 100
PO2 < 100
PCO2 = 40
PCO2 > 40
Figure IV-4-2. Figure V-2-2. Application Applicationof ofthe theFick FickPrinciple Principle
BLOOD FLOW REGULATION Flow is regulated by constricting and dilating the smooth muscle surrounding the arterioles.
Intrinsic Regulation (Autoregulation) The control mechanisms regulating the arteriolar smooth muscle are entirely within the organ itself. • What is regulated is blood flow, not resistance. It is more correct to say that resistance is changed in order to regulate flow. • No nerves or circulating substances are involved in autoregulation.
Thus, the autonomic nervous system and circulating epinephrine have nothing to do with autoregulation.
There are 2 main mechanisms which explain autoregulation.
Metabolic mechanism • The tissue produces vasodilator metabolites that regulate flow, e.g.,
adenosine, CO2, H+, and K+.
• A dilation of the arterioles is produced when the concentration of these
metabolites increases in the tissue. The arterioles constrict if the tissue concentration decreases.
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Myogenic mechanism • Increased perfusing pressure causes stretch of the arteriolar wall and
the surrounding smooth muscle.
Pathology
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• Because an inherent property of the smooth muscle is to contract when
stretched, the arteriole radius decreases, and flow does not increase significantly.
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Major characteristics of an autoregulating tissue
Flow ( × Normal)
Blood flow should be independent of blood pressure. This phenomenon is demonstrated for a theoretically perfect autoregulating tissue. The range of pressure over which flow remains nearly constant is the autoregulatory range.
2×
Autoregulatory range
1×
Need for vasopressors (e.g., norepinephrine, dopamine, phenylephrine)
0.5× 0
50
100
Need for vasodilators (e.g., nicardipine, nitroprusside, hydralazine)
150
Blood Pressure (mm Hg) Figure V-2-3. FigureAutoregulation IV-4-3. Autoregulation
Blood flow in most cases is proportional to tissue metabolism. Blood flow is independent of nervous reflexes (e.g., carotid sinus) or circulating humoral factors. Autoregulating tissues include (tissues least affected by nervous reflexes): • Cerebral circulation • Coronary circulation • Skeletal muscle vasculature during exercise
Extrinsic Regulation These tissues are controlled by nervous and humoral factors originating outside the organ, e.g., resting skeletal muscle. Extrinsic mechanisms were covered earlier in the book. The figure below illustrates an arteriole in skeletal muscle and the factors regulating flow under resting conditions.
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(+) NE α (sympathetic adrenergic) (+) Angiotensin II
(–) β2
+ Constricts – Dilates
No significant effects of parasympathetics Figure V-2-4. Resting Figure IV-4-4.Skeletal Resting Muscle SkeletalBlood MuscleFlow Blood Flow
Note Use caution with drugs such as dobutamine, which can increase contractility through β1 receptors but can also cause hypotension with some β2 activation.
The key points for extrinsic regulation are: • Norepinephrine (NE) released from sympathetic nerves has a tonic influence on arteriolar tone (α receptors) in resting skeletal muscle and skin vasculature in a thermo-neutral environment. • In times of stress, sympathetic activation can evoke substantial vaso-
constriction in the aforementioned tissues, but can also greatly affect renal and splanchnic circulations.
• Epinephrine can evoke vasodilation by binding to vascular β2 receptors. • With the exception of the penis, the parasympathetic nervous system
does not affect arteriolar tone.
Control of Resting versus Exercising Muscle Resting muscle Flow is controlled mainly by increasing or decreasing sympathetic α-adrenergic activity.
Exercising muscle The elevated metabolism in exercising skeletal muscle demands an increase in blood flow (see application of the Fick principle above). In addition, the increased tissue O2 consumption results in a fall in the PvO2 of blood leaving the working muscle. The primary mechanisms for increasing flow are: • Production of vasodilator metabolites, e.g., adenosine, CO2, H+, and K+ causes marked vasodilation. In addition, these metabolites diminish NE’s ability to vasoconstrict the arterioles. Further, the increased endothelial shear-stress of the high flow liberates NO. • Muscle pump
BLOOD FLOW TO THE VARIOUS ORGANS Coronary Circulation Coronary flow patterns Characteristics of left coronary flow (flow to the left ventricular myocardium):
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Left ventricular contraction causes severe mechanical compression of subendocardial vessels. Therefore: • Very little if any blood flow occurs during systole. • Most of the blood flow is during diastole. • Some subepicardial flow occurs during systole.
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Characteristics of right coronary blood flow (flow to the right ventricular myocardium): Right ventricular contraction causes modest mechanical compression of intramyocardial vessels. Therefore: • Significant flow can occur during systole. • The greatest flow under normal conditions is still during diastole.
Oxygenation In the coronary circulation, the tissues extract almost all the oxygen they can from the blood, even under “basal” conditions. Therefore: • The venous PO2 is extremely low. It is the lowest venous PO2 in a resting individual. • Because the extraction of oxygen is almost maximal under resting
conditions, increased oxygen delivery to the tissue can be accomplished only by increasing blood flow (Fick principle).
• In the coronary circulation, flow must match metabolism. • Coronary blood flow is most closely related to cardiac tissue oxygen
consumption and demand.
Pumping action Coronary blood flow (mL/min) is determined by the pumping action, or stroke work times heart rate, of the heart. Increased pumping action means increased metabolism, which increases the production of vasodilatory metabolites. In turn, coronary flow increases. Increased pump function occurs with the following: • An increase in any of the parameters which determine CO: HR,
contractility, afterload, preload
• HR, contractility, and afterload (often called pressure work) are more
metabolically costly than the work associated with preload (volume work).
• Thus, conditions in which HR, contractility, and/or afterload increase,
e.g., hypertension, aortic stenosis, and exercise require a greater increase in flow compared to conditions that only increase volume work (supine, aortic regurgitation, volume loading).
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Cerebral Circulation Flow is proportional to arterial PCO2. Under normal conditions, arterial PCO2 is an important factor regulating cerebral blood flow. • Hypoventilation increases arterial PCO2, thus it increases cerebral blood flow. • Hyperventilation decreases arterial PCO2, thus it decreases cerebral
blood flow.
As long as arterial PO2 is normal or above normal, cerebral blood flow is regulated via arterial PCO2.Therefore: • If a normal person switches from breathing room air to 100% oxygen, there is no significant change in cerebral blood flow. • However, a (large) decrease in arterial PO2 increases cerebral blood
flow; an example is high-altitude cerebral edema (HACE). Under these conditions, it is the low arterial PO2 that is determining flow.
• Baroreceptor reflexes do not affect flow.
Intracranial pressure is an important pathophysiologic factor that can affect cerebral blood flow.
Cutaneous Circulation Cutaneous circulation is almost entirely controlled via the sympathetic adrenergic nerves. • Large venous plexus innervated by sympathetics • A-V shunts innervated by sympathetics • Sympathetic stimulation to the skin causes:
–– Constriction of arterioles and a decrease in blood flow, which is one reason why physicians use a central line to administer vasopressors to prevent distal necrosis –– Constriction of the venous plexus and a decrease in blood volume in the skin • Sympathetic activity to the skin varies mainly with the body’s need for
heat exchange with the environment.
Increased skin temperature directly causes vasodilation, which increases heat loss.
Temperature regulation There are temperature-sensitive neurons in the anterior hypothalamus, whose firing rate reflects the temperature of the regional blood supply. • Normal set point: oral 37°C (rectal + 0.5°C) • Circadian rhythm: low point, morning; high point, evening
Bridge to Anatomy The splanchnic circulation is composed of the gastric small intestinal, colonic, pancreatic, hepatic, and splenic circulations, arranged in parallel with one another. The three major arteries that supply the splanchnic organs are the celiac, superior, and inferior mesenteric arteries.
The body does not lose the ability to regulate body temperature during a fever. It simply regulates body temperature at a higher set point.
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Vasodilation (sweating)
Vasoconstriction (shivering)
39°C Core temp.
37°C Set point raised
Set point lowered
Figure IV-4-5. Temperature Regulation Figure V-2-5. Temperature Regulation
When a fever develops, body temperature rises toward the new higher set point. Under these conditions, heat-conserving and heat-generating mechanisms include: • Shivering • Cutaneous vasoconstriction
After a fever “breaks,” the set point has returned to normal, and body temperature is decreasing. Heat-dissipating mechanisms include: • Sweating (sympathetic cholinergics) • Cutaneous vasodilation
Renal and Splanchnic Circulation A small change in blood pressure invokes an autoregulatory response to maintain renal and splanchnic blood flows. Thus, under normal conditions, the renal and splanchnic circulations demonstrate autoregulation. • Situations in which there is a large increase in sympathetic activity (e.g., hypotension) usually cause vasoconstriction and a decrease in blood flow. • Renal circulation is greatly overperfused in terms of nutrient require-
ments, thus the venous PO2 is high.
• About 25% of the CO goes to the splanchnic circulation, thus it
represents an important reservoir of blood in times of stress.
• Splanchnic blood flow increases dramatically when digesting a meal.
Pulmonary Circuit Characteristics • Low-pressure circuit, arterial = 15 mm Hg, venous = 5 mm Hg; small
pressure drop indicates a low resistance.
• High flow, receives entire CO • Very compliant circuit; both arteries and veins are compliant vessels
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• Hypoxic vasoconstriction (low alveolar PO2 causes local arteriolar
vasoconstriction)
• Blood volume proportional to blood flow: due to the very compliant
nature of the pulmonary circuit, large changes in output of the right ventricle are associated with only small changes in pulmonary pressures
Pulmonary response to exercise • A large increase in cardiac output means increased volume pumped
into the circuit. This increases pulmonary intravascular pressures.
• Because of the compliant nature of the circuit, the pulmonary arterial
system distends.
• In addition, there is recruitment of previously unperfused capillaries.
Because of this recruitment and distension, the overall response is a large decrease in pulmonary vascular resistance (PVR).
• Consequently, when CO is high, e.g., during exercise, there is only a
slight increase in pulmonary pressures.
–– Without this recruitment and distension, increasing CO would result in a very high pulmonary artery pressure.
Pulmonary response to hemorrhage • A large decrease in CO reduces intravascular pulmonary pressures. • Because these vessels have some elasticity, pulmonary vessels recoil. In
addition, there is derecruitment of pulmonary capillaries, both of which contribute to a rise in PVR.
• Consequently, during hemorrhage, there is often only a slight decrease
in pulmonary artery pressure.
• Vessel recoil also means less blood is stored in this circuit.
FETAL CIRCULATION The general features of the fetal circulatory system are shown below. The bolded numbers refer to the percent hemoglobin (%HbO2) saturation. • Of the fetal CO, 55% goes to the placenta. • The umbilical vein and ductus venosus have highest %HbO2 saturation
(80%).
• When mixed with inferior vena caval blood (26% HbO2), the %HbO2
saturation of blood entering the right atrium is 67%.
• This blood is directed through the foramen ovale to the left atrium, left
ventricle, and ascending aorta to perfuse the head and the forelimbs.
• Superior vena caval blood (40% HbO2) is directed through the tricuspid
valve into the right ventricle and pulmonary artery and shunted by the ductus arteriosus to the descending aorta. Shunting occurs because fetal pulmonary vascular resistance is very high, so 90% of the right ventricular output flows into the ductus arteriosus and only 10% to the lungs.
• The percent HbO2 saturation of aortic blood is 60%.
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• Fifty-five percent of the fetal CO goes through the placenta. At birth,
the loss of the placental circulation increases systemic resistance. The subsequent rise in aortic blood pressure (as well as the fall in pulmonary arterial pressure caused by the expansion of the lungs) causes a reversal of flow in the ductus arteriosus, which leads to a large enough increase in left atrial pressure to close the foramen ovale.
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65%
Ductus arteriosus Superior vena cava
40%
Left atrium
50%
Pulmonary artery
Foramen ovale
Left ventricle Right atrium Right ventricle
Aorta
67%
Inferior vena cava
60%
Ductus venosus
26%
Portal vein 26%
Liver
80%
Umbilical vein (highest O2)
From placenta To placenta
Right and left umbilical arteries Figure V-2-6. Fetal Circulatory System Figure IV-4-6. Fetal Circulatory System
Recall Question Which of the following regulates cerebral blood flow in a patient suffering from high-altitude pulmonary edema? A. Arterial PO2 B. Arterial PCO2 C. Arterial HCO3 D. Arterial H+ E. Cerebral PO2 Answer: A 116
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CARDIOVASCULAR STRESS: EXERCISE The following assumes the person is in a steady state, performing moderate exercise at sea level.
Pulmonary Circuit • Blood flow (CO): large increase • Pulmonary arterial pressure: slight increase • Pulmonary vascular resistance: large decrease • Pulmonary blood volume: increase • Number of perfused capillaries: increase • Capillary surface area: increase, i.e., increased rate of gas exchange
Systemic Circuit Arterial system • PO2: no significant change, hemoglobin still fully saturated • PCO2: until one approaches maximal O2 consumption, there is no
significant change; thus the increase in ventilation is proportional to the increase in metabolism
• pH: no change or a decrease due mainly to the production of lactic acid • Mean arterial pressure: slight increase • Body temperature: slight increase • Vascular resistance (TPR): large decrease, dilation of skeletal muscle beds
Venous system • PO2: decrease • PCO2: increase
Regional Circulations Exercising skeletal muscle • Vascular resistance decreases. • Blood flow increases. • Capillary pressure increases. • Capillary filtration increases. • Lymph flow increases. • As predicted by the Fick principle, oxygen extraction increases and
venous PO2 falls.
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Cutaneous blood flow Initial decrease, then an increase to dissipate heat Pathology
Behavioral Science/Social Sciences
Coronary blood flow Increase due to increased work of the heart
Cerebral blood flow Microbiology
No significant change (arterial CO2 remains unchanged)
Renal and GI blood flow Both decrease
Physical conditioning
•
• Regular exercise increases maximal oxygen consumption (VO2max) by:
–– Increasing the ability to deliver oxygen to the active muscles. It does this by increasing the CO. –– The resting conditioned heart has a lower heart rate but greater stroke volume (SV) than does the resting unconditioned heart. –– At any level of exercise, stroke volume is elevated. –– However, the maximal heart rate remains similar to that of untrained individuals. • Regular exercise also increases the ability of muscles to utilize oxygen.
There are:
–– An increased number of arterioles, which decreases resistance during exercise. –– An increased capillary density, which increases the surface area and decreases diffusion distance. –– An increased number of oxidative enzymes in the mitochondria.
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5
Learning Objectives ❏❏ Interpret scenarios on normal cardiac cycle ❏❏ Interpret scenarios on pressure-volume loops ❏❏ Interpret scenarios on valvular dysfunction
NORMAL CARDIAC CYCLE The figure below illustrates the most important features of the cardiac cycle.
Pressure (mm Hg)
100 80
1
2
3
Aortic valve opens
Aortic pressure Aortic valve closes
60 40 20
4
Mitral valve closes c
a
0
Left atrial pressure v
Mitral valve opens Left ventricular pressure
Volume (ml)
150 Ventricular volume 100
50
S4 P
S1
Q
S4
Heart sounds
Electrocardiogram
T
R
0.1
S3
S2
S 0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Time (sec) Figure VI-1-1. Cardiac Cycle Figure IV-5-1. Cardiac Cycle
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Note the most important aspects: • → QRS → contraction of ventricle → rise in ventricular pressure above atrial pressure → closure of mitral valve • It is always a pressure difference that causes the valves to open or close. • Closure of the mitral valve terminates the ventricular filling phase and
begins iso-volumetric contraction.
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• Isovolumetric contraction: no change in ventricular volume, and both
valves (mitral, aortic) closed; ventricular pressure increases and volume is equivalent to end-diastolic volume
• Opening of the aortic valve terminates isovolumetric contraction and
begins the ejection phase. The aortic valve opens because pressure in the ventricle slightly exceeds aortic pressure.
• Ejection phase: ventricular volume decreases, but most rapidly in early
stages; ventricular and aortic pressures increase initially but decrease later in phase
• Closure of the aortic valve terminates the ejection phase and begins
isovolumetric relaxation. The aortic valve closes because pressure in the ventricle goes below aortic pressure. Closure of the aortic valve creates the dicrotic notch.
• Isovolumetric relaxation: no change in ventricular volume and both
valves (mitral, aortic) closed; ventricular pressure decreases and volume is equivalent to end-systolic volume
• Opening of the mitral valve terminates isovolumetric relaxation and
begins the filling phase. The mitral valve opens because pressure in the ventricle goes below atrial pressure.
• Filling phase: the final relaxation of the ventricle occurs after the
mitral valve opens and produces a rapid early filling of the ventricle; this rapid inflow will in some cases induce the third heart sound. –– The final increase in ventricular volume is due to atrial contraction, which is responsible for the fourth heart sound.
• In a young, healthy individual, atrial contraction doesn’t provide signifi-
cant filling of the ventricle. However, the contribution of atrial contraction becomes more important when ventricular compliance is reduced.
Heart Sounds The systolic sounds are due to the sudden closure of the heart valves. Normally the valves on the left side of the heart close first. Valves on the right side open first.
Systolic sounds S1: produced by the closure of the mitral and tricuspid valves • Valves close with only a separation of about 0.01 seconds which the human ear can appreciate only as a single sound S2: produced by the closure of the aortic (A2 component) and pulmonic valves (P2 component) • Heard as a single sound during expiration but during inspiration the increased output of the right heart causes a physiological splitting
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The figure below illustrates several situations where splitting of the second heart sound may become audible.
Expiration A widening of the split
Fixed splitting
S1
A 2 P2
Pulmonic stenosis Right bundle branch block
Inspiration
Clinical Correlate Site of auscultation points: • Aortic: Second intercostal space on the right side, about mid-clavicular line
Expiration S1
A2P2
Inspiration
Atrial septal defect L-R Shunt
• Pulmonic: Second intercostal space on the left side, about mid-clavicular line • Tricuspid: Fifth intercostal space, just at the left sternal border
Expiration Paradoxical splitting
S1
P2A2
Left bundle branch block Advanced aortic stenosis
• Mitral: Sixth intercostal space on the left side, about mid-clavicular line
Inspiration
Figure IV-5-2. Figure VI-1-2.Abnormal AbnormalSplitting Splitting of ofthe theSecond SecondHeart HeartSound Sound(S(S 2)2)
S3: when it is present, occurs just after the opening of the AV valves during the rapid filling of the ventricle • Tends to be produced by rapid expansion of a very compliant ventricle • In children and young adults, is a normal finding • In older adults, it occurs with volume overload and is often a sign of
cardiac disease
S4: coincident with atrial contraction and is produced when the atrium contracts against a stiff ventricle • Examples include concentric hypertrophy, aortic stenosis, and myocar-
dial infarction
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Venous Pulse The jugular pulse is generated by changes on the right side of the heart. The pressures will generally vary with the respiratory cycle and are typically read at the end of expiration when intrapleural pressure is at its closest point to zero. A normal jugular venous pulse tracing can be seen below.
Microbiology
a
c x
v
y Venous pulse
R
T
P Q 0
ECG
P
S
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Time (sec) Figure Figure VI-1-3. IV-5-3. Venous Venous Pulse Pulse and and the the ECG ECG
a wave • Highest deflection of the venous pulse and produced by the contrac-
tion of the right atrium
• Correlates with the PR interval • Is prominent in a stiff ventricle, pulmonic stenosis, and insufficiency • Is absent in atrial fibrillation
c wave • Mainly due to the bulging of the tricuspid valve into the atrium (rise in
right atrial pressure)
• Occurs near the beginning of ventricular contraction (is coincident
with right ventricular isovolumic contraction)
• Is often not seen during the recording of the venous pulse
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x descent • Produced by a decreasing atrial pressure during atrial relaxation • Separated into two segments when the c wave is recorded • Alterations occur with atrial fibrillation and tricuspid insufficiency
v wave • Produced by the filling of the atrium during ventricular systole when
the tricuspid valve is closed
• Corresponds to T wave of the EKG • A prominent v wave would occur in tricuspid insufficiency and right
heart failure
y descent • Produced by the rapid emptying of the right atrium immediately after
the opening of the tricuspid valve
• A more prominent wave in tricuspid insufficiency and a blunted wave
in tricuspid stenosis.
Some abnormal venous pulses are shown below. a
c x c
a
v
x
v
a a
v
y y
Normal A Fib
y Tricuspid regurgitation
c x
v
y
Tricuspid stenosis
Figure IV-5-4. Normal Versus Abnormal Jugular Pulses Figure VI-1-4. Normal Versus Abnormal Jugular Pulses
Similar recordings to the systemic venous pulse are obtained when recording pulmonary capillary wedge pressure. Left atrium mechanical events are transmitted in a retrograde manner, although they are somewhat damped and delayed.
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The figure below shows the pressure recording from the tip of a Swan-Ganz catheter inserted through a systemic vein through the right side of the heart into the pulmonary circulation and finally with the tip wedged in a small pulmonary artery. The pressure recorded at the tip of the catheter is referred to as pulmonary capillary wedge pressure and is close to left atrial pressure and is an index of preload on the left ventricle.
R. vent pressure = 25/2
Microbiology
Pulmonary arterial pressure = 25/8 Pressure
A: passage across tricuspid valve B: passage across pulmonic valve C: pulmonary capillary wedge pressure
A
C B Time Figure VI-1-5. Catheterization FigureSwan-Ganz IV-5-5. Swan-Ganz Catheterization
PRESSURE-VOLUME LOOPS The major features of a left ventricular pressure–volume loop can be seen below. Most of the energy consumption occurs during isovolumetric contraction. Most of the work is performed during the ejection phase.
Pressure (mm Hg)
180
120
60 15 0
Aortic valve closes
Ejection
Aortic valve opens
End-systolic volume Isovolumetric relaxation Mitral valve opens 50
Isovolumetric contraction Stroke volume
Mitral valve closes End-diastolic volume
Filling 100
150
Volume (ml)
Figure IV-5-6. Pressure–Volume Loop Loop Figure VI-1-6. Left Left Ventricular Ventricular Pressure–Volume
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Mechanically Altered States • Aortic insufficiency: increased preload, increased stroke volume,
increased ventricular systolic pressure (all cardiac volumes are increased [EDV, ESV, SV])
• Heart failure (decreased contractility): decreased ventricular systolic
pressure, increased preload, loop shifts to the right
• Essential hypertension (aortic stenosis): increased ventricular systolic
pressure, little change in preload in the early stages
• Increased contractility: increased ventricular systolic pressure,
decreased preload, increased ejection fraction, loop shifts to the left
• Exercise: increased ventricular systolic pressure, ejection fraction, and
preload.
Recall Question Which of the following is seen in a pressure volume loop in patients with aortic stenosis? A. Increased preload, stroke volume, and ventricular systolic pressure B. Decreased ventricular systolic pressure, increased preload, shifts to the right C. Increased ventricular systolic pressure with little change in preload in the early stages D. Increased ventricular systolic pressure, decreased preload, increased ejection fraction, loop shifts to the left E. Increased ventricular systolic pressure, ejection fraction, and preload Answer: C
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VALVULAR DYSFUNCTION Stenosis of valves usually consists of chronic problems which develop slowly over time. Valvular insufficiency problems can be acute or chronic, the consequences of which can be quite different.
Behavioral Science/Social Sciences
Note
Aortic Stenosis
With valvular problems, note the following:
Aortic stenosis is a pathologic thickening and fusion of the valve leaflets that decrease the open valve area, creating a major resistance point in series with the systemic circuit. There is a large loss in pressure moving the blood through the narrow opening. • Ventricular systolic pressure increases (increased afterload) to overcome the increased resistance of the aortic valve.
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• A stenotic valve is a resistor and creates a murmur when the valve is open. • A regurgitant valve allows backflow of blood and creates a murmur when the valve is normally closed. • Pressure and volume “behind” the defective valve increase. Behind refers to the direction of blood flow, e.g., left ventricle is behind the aortic valve; left atrium is behind the mitral valve, etc.
• Pressure overload of the left ventricle leads to a compensatory concen-
tric hypertrophy (new sarcomeres laid down in parallel so that the myofibril thickens) which leads to decreased ventricular compliance (diastolic dysfunction) and coronary perfusion problems and eventually systolic dysfunction.
• Prominent “a” wave of the left atrium as the stiffer left ventricle
becomes more dependent on atrial contraction for filling.
• Mean aortic pressure is maintained in the normal range in the early
stages of the disorder. Arterial pressure rises slowly and the pulse pressure is reduced.
• There is a pressure gradient between the left ventricle and aorta during
ejection.
• Systolic murmur that begins after S1 (midsystolic) which is crescendo-
decrescendo in intensity.
• Slow closure of the aortic valve can cause a paradoxical splitting of the
second heart sound (aortic valve closes after the pulmonic)
Control
Aortic pressure
90
Atrial pressure
LV pressure
Pressure (mm Hg)
160
Ventricular pressure
0 S1 SM
LV volume
S2 Figure VI-1-7. Aortic Stenosis Figure IV-5-7. Aortic Stenosis
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Aortic Insufficiency Regurgitation The aortic valve does not close properly at the beginning of diastole. As a result, during diastole there is retrograde flow from the aorta into the ventricle. • Acute insufficiency does not allow development of compensatory mechanisms, which can lead to pulmonary edema and circulatory collapse. • Very large left ventricles are seen in aortic insufficiency. There is a
large increase in LVEDV (increase preload) but close to normal end diastolic pressures (eccentric hypertrophy). All cardiac volumes are increased (EDV, ESV, SV).
• Ventricular failure raises pulmonary pressures and causes dyspnea. • Increased preload causes increased stroke volume, which results in
increased ventricular and aortic systolic pressures.
• Retrograde flow from the aorta to the left ventricle produces a low
aortic diastolic pressure (the volume of blood left in the aorta at the end of diastole is rapidly reduced).
• There is no true isovolumetric relaxation and a reduced period of
isovolumetric contraction.
• Aortic insufficiency is characterized by a large aortic pulse pressure
and a low aortic diastolic pressure (hence the bounding pulse).
• Dilation of the ventricle produces a compensatory eccentric hypertrophy.
Control
Aortic pressure
40
Atrial pressure
0
Ventricular pressure
S1
S2
LV pressure
Pressure (mm Hg)
160
LV volume
S1
Figure IV-5-8. Aortic Insufficiency (Regurgitation)/(Diastolic Rumble ≈ Austin Figure VI-1-8. Aortic Insufficiency (Regurgitation) / (Diastolic Rumble ≈ Austin Flint Murmur) Flint Murmur)
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Mitral Stenosis
Clinical Correlate
A narrow mitral valve impairs emptying of the left atrium (LA) into the left ventricle (LV) during diastole. This creates a pressure gradient between the atrium and ventricle during filling. • Pressure and volume can be dramatically elevated in the left atrium, dilation of the left atrium over time, which is accelerated with atrial fibrillation.
The S2 to opening snap (OS) interval is inversely related to left atrial Pathologypressure. A short S2:OS Behavioralinterval Science/Social Sciences is a reliable indicator of severe mitral stenosis.
• Thrombi appear in the enlarged left atrium
Microbiology
• Left atrial pressures are elevated throughout the cardiac cycle.
Increased left atrial pressures transmitted to the pulmonary circulation and the right heart.
• Little change or a decrease in the size of the left ventricle. Systolic
function normal.
• Diastolic murmur begins after S2 and is associated with altered atrial
emptying; a late diastolic murmur and an exaggerated “a” wave are associated with atrial contraction.
Aortic pressure Control
Atrial pressure 20
LV pressure
Pressure (mm Hg)
100
Ventricular pressure
0
S2
LV volume
S1 IV-5-9. Stenosis FigureFigure VI-1-9. MitralMitral Stenosis
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Mitral Insufficiency Regurgitation Acute mitral insufficiency can cause a sudden dramatic rise in pulmonary pressures and pulmonary edema. It can result from structural abnormalities in the valve itself, papillary muscles, chordae tendinae, or a structural change in the mitral annulus. • No true isovolumetric contraction. Regurgitation of blood from the left ventricle to the left atrium throughout ventricular systole. • Atrial volumes and pressures increased but chronic dilation of the
atrium prevents a dramatic rise in atrial pressures.
• Ventricular volumes and pressures are increased during diastole. Most
patients develop chronic compensated left ventricular dilation and hypertrophy, then at some point the left ventricle cannot keep up with the demand and decompensated heart failure develops.
• Increased preload but with reduced afterload. • Systolic murmur that begins at S1 (pansystolic).
Aortic pressure 80
Control
Atrial pressure
LV pressure
Pressure (mm Hg)
120
Ventricular pressure
0
S1
LV volume
S2
Figure IV-5-10. Mitral Insufficiency (Regurgitation) Figure VI-1-10. Mitral Insufficiency (Regurgitation)
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Recall Question
Pathology
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Which of the following heart murmurs will be heard in a patient with aortic stenosis? A. Decrescendo diastolic murmur B. Low pitched diastolic rumble with an opening snap
Microbiology
C. Holosystolic murmur D. Crescendo-decrescendo systolic murmur E. Midsystolic murmur Answer: D
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1
Learning Objectives ❏❏ Answer questions about overview of the respiratory system ❏❏ Interpret scenarios on lung volumes and capacities ❏❏ Solve problems concerning ventilation ❏❏ Use knowledge of lung mechanics ❏❏ Answer questions about cardiovascular changes with ventilation ❏❏ Solve problems concerning positive-pressure ventilation ❏❏ Answer questions about pneumothorax ❏❏ Use knowledge of lung compliance ❏❏ Interpret scenarios on airway resistance ❏❏ Explain information related to pulmonary function testing
THE RESPIRATORY SYSTEM The purpose of understanding lung mechanics is to view them in the big clinical picture of pulmonary function test (PFT) interpretation. The PFT is the key diagnostic test for the pulmonologist, just as the EKG is to the cardiologist. PFTs consist of 3 individual tests (see Respiratory section for more detail): • Measurements of static lung compartments (i.e., lung volumes) • Airflow used to evaluate dynamic compliance using a spirometer • Alveolar membrane permeability using carbon monoxide as a marker
of diffusion
LUNG VOLUMES AND CAPACITIES The figure below graphically shows the relationships among the various lung volumes and capacities. Clinical measurements of specific volumes and capacities provide insights into lung function and the origin of disease processes. The values for the volumes and capacities given below are typical for a 70 kg male.
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Tidal volume (Vt): amount of air that enters or leaves the lung in a single respiratory cycle (500 mL) Pathology
IC
IRV
Behavioral Science/Social Sciences
Functional residual capacity (FRC): amount of gas in the lungs at the end of a passive expiration; the neutral or equilibrium point for the Microbiology respiratory system (2,700 mL) ; it is a marker for lung compliance
Lung Volume
TLC*
VT*
FRC*
Expiratory reserve volume (ERV): additional volume that can be expired after a passive expiration (1,500 mL) Residual volume (RV): amount of air in the lung after a maximal expiration (1,200 mL) Vital capacity (VC): maximal volume that can be expired after a maximal inspiration (5,500 mL) Total lung capacity (TLC): amount of air in the lung after a maximal inspiration (6,700 mL)
ERV RV*
Inspiratory capacity (IC): maximal volume of gas that can be inspired from FRC (4,000 mL) Inspiratory reserve volume (IRV): additional amount of air that can be inhaled after a normal inspiration (3,500 mL)
VC*
* Indicates those measurements providing the greatest information
Time
FigureLung V-1-1. Lung Volumes and Capacities Figure VII-1-1. Volumes and Capacities
A spirometer can measure only changes in lung volume. As such, it cannot measure residual volume (RV) or any capacity containing RV. Thus, TLC and FRC cannot be measured using simple spirometry; an indirect method must be used. Common indirect methods are helium dilution, nitrogen washout, and plethysmography.
VENTILATION Total Ventilation Total ventilation is also referred to as minute volume or minute ventilation. It is the total volume of air moved in or out (usually the volume expired) of the lungs per minute. V•E: total ventilation • VE = VT × f VT: tidal volume Normal resting values would be:
f: respiratory rate
VT = 500 mL f = 15 500 mL × 15/min = 7,500 mL/min
Dead Space Regions of the respiratory system that contain air but are not exchanging O2 and CO2 with blood are considered dead space.
Anatomic dead space Airway regions that, because of inherent structure, are not capable of O2 and CO2 exchange with the blood. Anatomic dead space (anatVD) includes the conducting zone, which ends at the level of the terminal bronchioles. Significant gas exchange (O2 uptake and CO2 removal) with the blood occurs only in the alveoli. The size of the anatVD in mL is approximately equal to a person’s weight in pounds. Thus a 150-lb individual has an anatomic dead space of 150 mL.
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Composition of the anatomic dead space and the respiratory zone
Note
The respiratory zone is a very constant environment. Under resting conditions, rhythmic ventilation introduces a small volume into a much larger respiratory zone. Thus, the partial pressure of gases in the alveolar compartment changes very little during normal rhythmic ventilation.
What is the function of functional residual capacity (FRC)?
Composition at the End of Expiration (Before Inspiration) • At the end of an expiration, the anatVD is filled with air that originated in the alveoli or respiratory zone. • Thus, the composition of the air in the entire respiratory system is the
same at this static point in the respiratory cycle.
• This also means that a sample of expired gas taken near the end of
expiration (end tidal air) is representative of the respiratory zone.
Same composition as respiratory zone (contains CO2)
Dead space
Answer: Breathing is cyclic, while blood flow through the pulmonary capillary bed is continuous. During the respiratory cycle, there are short periods of apneas at the end of inspiration and expiration when there is no ventilation but there is continuous blood flow. Without the FRC acting as a buffer for continued gas exchange during apneic periods, these conditions would in effect create an intrapulmonary shunt, inducing deoxygenated blood from the pulmonary capillaries to empty into the pulmonary veins.
Respiratory zone PO2 = 100 PCO2 = 40 PN2 = 573 PH2O = 47
Figure VII-1-2. of End Expiration FigureEnd V-1-2. of Expiration
Composition at the End of Inspiration (Before Expiration) • The first 150 mL of air to reach the alveoli comes from the anatVD. • It is air that remained in the dead space at the end of the previous
expiration and has the same composition as alveolar gas.
• After the first 150 mL enters the alveoli, room air is added to the
respiratory zone.
• At the end of inspiration the anatVD is filled with room air. • The presence of the anatVD implies the following: in order to get fresh
air into the alveoli, one must always take a tidal volume larger than the volume of the anatVD.
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Humidified room air O2, N2, H2O (no CO2)
Dead space Pathology
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Respiratory zone PO2 = 100 PCO2 = 40 PN2 = 573 PH2O = 47
Microbiology
End of Inspiration Figure VII-1-3. Figure V-1-3. End of Inspiration
Alveolar dead space Alveolar dead space (alvVD) refers to alveoli containing air but without blood flow in the surrounding capillaries. An example is a pulmonary embolus.
Physiologic dead space Physiologic dead space (physioIVD) refers to the total dead space in the lung system (anatVD + alvVD). When the physiol VD is greater than the anatVD, it implies the presence of alvVD, i.e., somewhere in the lung, alveoli are being ventilated but not perfused.
Total ventilation V = VT (f) = 500 (15) = 7,500 mL/min • Minute ventilation (V ) is the total volume of air entering the lungs per minute.
Alveolar Ventilation
• Alveolar ventilation VA represents the room air delivered to the respiratory zone per breath. • The first 150 mL of each inspiration comes from the anatomic dead
space and does not contribute to alveolar ventilation.
• VA: alveolar ventilation VT: tidal volume VD: dead space f: respiratory rate
• However, every additional mL beyond 150 does contribute to alveolar
ventilation. • VA = (VT - VD) f = (500 mL - 150 mL) 15 = 5250 mL/min
The alveolar ventilation per inspiration is 350 mL. This equation implies that the volume of fresh air that enters the respiratory zone per minute depends on the pattern of breathing (how large a VT and the rate of breathing).
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Increases in the Depth of Breathing There are equal increases in total and alveolar ventilation per breath, since dead space volume is constant. If the depth of breathing increases from a depth of 500 mL to a depth of 700 mL, the increase in total and alveolar ventilation is 200 mL per breath.
Increases in the Rate of Breathing There is a greater increase in total ventilation per minute than in alveolar ventilation per minute, because the increased rate causes increased ventilation of dead space and alveoli. For every additional inspiration with a tidal volume of 500 mL, total ventilation increases 500 mL, but alveolar ventilation only increases by 350 mL (assuming dead space is 150 mL). For example, given the following, which person has the greater alveolar ventilation? Tidal Volume
Rate
Total Ventilation
Person A
600 mL
10/min
6,000 mL/min
Person B
300 mL
20/min
6,000 mL/min
Answer: Person A. Person B has rapid, shallow breathing. This person has a large component of dead-space ventilation (first 150 mL of each inspiration). Even though total ventilation may be normal, alveolar ventilation is decreased. Therefore, the individual is hypoventilating. In rapid, shallow breathing, total ventilation may be above normal, but alveolar ventilation may be below normal.
LUNG MECHANICS Muscles of Respiration Inspiration The major muscle of inspiration is the diaphragm. Contraction of the diaphragm enlarges the vertical dimensions of the chest. Also utilized are the external intercostal muscles of the chest wall. Contraction of these muscles causes the ribs to rise and thus increases the anterior-posterior dimensions of the chest.
Expiration Under resting conditions, expiration is normally a passive process, i.e., it is due to the relaxation of the muscles of inspiration and the elastic recoil of the lungs. For a forced expiration, the muscles of the abdominal wall and the internal intercostals contract. This compresses the chest wall down and forces the diaphragm up into the chest. Included would be external oblique, rectus abdominal, internal oblique, and transverse abdominal muscles.
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Forces Acting on the Lung System In respiratory physiology, units of pressure are usually given as cm H2O. Pathology
Behavioral Science/Social Sciences
1 cm H2O = 0.74 mm Hg (1 mm Hg = 1.36 cm H2O)
Lung recoil and intrapleural pressure Microbiology
Understanding lung mechanics involves understanding the main forces acting on the respiratory system. Lung recoil represents the inward force created by the elastic recoil properties of alveoli. • As the lung expands, recoil increases; as the lung gets smaller, recoil decreases. • Recoil, as a force, always acts to collapse the lung.
Chest wall recoil represents the outward force of the chest wall. • FRC represents the point where this outward recoil of the chest wall is counterbalanced by the inward recoil of the lung. Intrapleural pressure (IPP) represents the pressure inside the thin film of fluid between the visceral pleura, which is attached to the lung, and the parietal pleura, which is attached to the chest wall. • The outward recoil of the chest and inward recoil of the lung create a negative (subatmospheric) IPP. • IPP is the outside pressure for all structures inside the chest wall.
Transmural pressure gradient (PTM) represents the pressure gradient across any tube or sphere. • Calculated as inside pressure minus outside pressure • If positive (inside greater than outside), it is a net force pushing out
against the walls of the structure
• If negative (outside greater than inside), it is a net force pushing in
against the walls of the structure; depending upon the structural components, the tube/sphere can collapse if PTM is negative or zero
• At FRC, IPP is negative, and thus PTM is positive. This positive out-
ward force prevents alveolar collapse (atelectasis).
• For the entire lung, PTM is called the transpulmonary pressure (TPP).
Before Inspiration The glottis is open, and all respiratory muscles are relaxed (FRC). This is the neutral or equilibrium point of the respiratory system. Intrapleural pressure is negative at FRC because the inward elastic recoil of the lungs is opposed by the outward-directed recoil of the chest wall. Because no air is flowing through the open glottis, alveolar pressure must be zero. By convention, the atmospheric pressure is set to equal zero.
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Patm = 0 Intrapleural pressure: –5 cm H2O PTM: 5 Alveolar pressure: O Recoil
–5
PA = 0
Figure V-1-4. Lung at at FRC Figure VII-1-4. LungForce ForceRelationships Relationships FRC
During Inspiration Inspiration is induced by the contraction of the diaphragm and external intercostal muscles that expand the chest wall. The net result is to make intrapleural pressure more negative. • The more negative IPP causes PTM (TPP) to increase, which in turn
causes expansion of the lungs. The greater the contraction, the greater the change in intrapleural pressure and the larger the PTM (TPP) expanding the lung.
• The expansion of the lung increases alveolar volume. Based upon
Boyle’s law, the rise in volume causes pressure to decrease, resulting in a negative (subatmospheric) alveolar pressure.
• Because alveolar pressure is now less than atmospheric, air rushes into
the lungs.
End of Inspiration The lung expands until alveolar pressure equilibrates with atmospheric pressure. The lungs are at their new, larger volume. Under resting conditions, about 500 mL of air flows into the lung system in order to return alveolar pressure back to zero.
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Patm = 0
Microbiology
Recoil 5
PTM = 8
Alveolar pressure = –1 cm H2O
PA = –1
Recoil
–8
Alveolar pressure = 0
PA = 0
Figure V-1-5. Forces During Inspiration Figure VII-1-5. Lung Lung Forces during Inspiration
Figure V-1-6. Lung Forces at End of Inspiration Figure VII-1-6. Lung Forces at End of Inspiration
Expiration Expiration under resting conditions is produced simply by the relaxation of the muscles of inspiration. • Relaxation of the muscles of inspiration causes intrapleural pressure to return to -5 cm H2O
Patm = 0
–5 –8 PA = +1 Expiration
• This decreases IPP back to its original level of -5 cm H2O, resulting in
a decreased PTM. The drop in PTM reduces alveolar volume, which increases alveolar pressure (Boyle’s law).
• The elevated alveolar pressure causes air to flow out of the lungs.
The outflowing air returns alveolar pressure toward zero, and when it reaches zero, airflow stops. The lung system returns to FRC.
The intrapleural pressure during a normal respiratory cycle is illustrated b elow. Under resting conditions, it is always a subatmosphere pressure. The intraalveolar pressure during a normal respiratory cycle is also illustrated below. It is slightly negative during inspiration and slightly positive during expiration. • No matter how large a breath is taken, intraalveolar pressure always returns to 0 at the end of inspiration and expiration. • By convention, total atmospheric pressure = 0.
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0.5 0.4 0.3 0.2 0.1 0
Inspiration
●
Lung Mechanics
Expiration
VT Change in lung volume (liters)
–5
FRC
Intrapleural pressure (cm H2O)
–6 –7 –8 +0.5 0 –0.5 +1 0
Flow (liters/sec)
Alveolar pressure (cm H2O)
–1
Figure VII-1-7. Essentialsof ofPulmonary PulmonaryEvents Events during a Breath Figure V-1-7. Essentials during a Breath
Recall Question The following lung volumes are noted on spirometer of a 38-year-old man with asthma: FRC 3.0 L, VC 6.0 L, and ERV 1.5 L. What is this patient's IC? A. 9.0 L B. 7.5 L C. 4.5 L D. 3.0 L E. Value cannot be determined Answer: C
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CARDIOVASCULAR CHANGES WITH VENTILATION Inspiration Pathology
Microbiology
Behavioral Science/Social Sciences
With inspiration, intrapleural pressure becomes more negative (decreases). This increases the PTM across the vasculature, causing the great veins and right atrium to expand. This expansion decreases intravascular pressure, thereby increasing the pressure gradient driving VR to the right heart. • Systemic venous return and right ventricular output are increased. • An increase in the output of the right ventricle delays closing of the
pulmonic valves and typically results in a splitting of the second heart sound.
• Pulmonary vessels expand, and the volume of blood in the pulmonary
circuit increases. In addition, because pulmonary vascular resistance (PVR) is lowest at FRC, it increases.
• In turn, venous return to the left heart, and the output of the left
ventricle is decreased, causing decreased systemic arterial pressure (drop in systolic most prominent).
• This inspiration reduces vagal outflow to the heart (mechanism
debatable) resulting in a slight rise in heart rate (respiratory sinus arrhythmia). This is why patients are asked to hold their breath, if clinically possible, when an EKG is taken.
Expiration Expiration is the reverse of the processes above. Intrapleural pressure becomes more positive (increases), i.e., returns to original negative value. PTM returns to its original level, thereby decreasing the pressure gradient for VR. • Systemic venous return and output of the right ventricle are decreased. • Pulmonary vessels are compressed, and the volume of blood in the
pulmonary circuit decreases.
• The return of blood and output of the left ventricle increases, causing
systemic arterial pressure to rise (primarily systolic).
• Vagal outflow increases (mechanism debated), reducing HR (respira-
tory sinus arrhythmia).
• A Valsalva maneuver is a forced expiration against a closed glottis.
This forced expiration creates a positive IPP (see later in this chapter), which compresses the great veins in the chest. This in turn reduces VR.
POSITIVE-PRESSURE VENTILATION Assisted Control Mode Ventilation (ACMV) In ACMV, the inspiratory cycle is initiated by patient or automatically if no signal is detected within a specified time window. Expiration is not assisted. Expiration is accomplished in the normal manner (passive recoil of the lungs).
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Positive End-Expiratory Pressure (PEEP) In PEEP, positive pressure is applied at the end of the expiratory cycle to decrease alveolar collapse. It is useful in treating the hypoxemia of acute respiratory distress syndrome (ARDS) (see Hypoxemia section.) • Small alveoli have a strong tendency to collapse, creating regions of
atelectasis.
• The larger alveoli are also better ventilated, and supplementary oxygen
is more effective at maintaining a normal arterial PO2.
• One downside to positive pressure ventilation and accentuated by PEEP
is a decrease in venous return and cardiac output. PEEP
PA +5
ACMV
0
Assist
Control
Figure Positive-Pressure Ventilation FigureV-1-8a. VII-1-8a. Positive-Pressure Ventilation
Continuous Positive Airway Pressure (CPAP) In CPAP, continuous positive pressure is applied to the airways. It is useful in treating obstructive sleep apnea (OSA) since the lung and upper airways (nasopharynx) remain at a larger volume throughout the respiratory cycle. CPAP is administered by mask (patient not intubated). The patient breathes spontaneously.
Inspiration
Expiration
PA +5
0 FigureV-1-8b. CPAP VII-1-8b. CPAP Figure
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PNEUMOTHORAX
Pathology
Behavioral Science/Social Sciences
Microbiology
The following changes occur with the development of a simple pneumothorax. The pneumothorax may be traumatic (perforation of chest wall) or spontaneous (rupture of an alveolus): • Intrapleural pressure increases from a mean at -5 cm H2O to equal atmospheric pressure. • Lung recoil decreases to zero as the lung collapses. • Chest wall expands. At FRC, the chest wall is under a slight tension directed
outward. It is this tendency for the chest wall to spring out and the opposed force of recoil that creates the intrapleural pressure of -5 cm H2O.
• Transpulmonary pressure is negative.
In some cases, the opening of the lung to the pleural space may function as a valve allowing the air to enter the pleural space but not to leave. This creates a tension pneumothorax. • Strong inspiratory efforts promote the entry of air into the pleural space, but during expiration, the valve closes and positive pressures are created in the chest cavity. Ventilation decreases but the positive pressures also decrease venous return and cardiac output.
Clinical Correlate Common clinical signs of a tension pneumothorax include:
• Tension pneumothorax most commonly develops in patients on a
positive-pressure ventilator.
• Respiratory distress
LUNG COMPLIANCE
• Asymmetry of breath sounds
A static isolated lung inflation curve is illustrated below.
• Deviation of trachea to the side opposite the tension pneumothorax
5
Lung Volume (L)
• Markedly depressed cardiac output
4
TLC
Normal
3 2
= tidal volume (600 ml)
1 0
–5
–8
–10
–20
–30
–40
Intrapleural Pressure (cm H2O) Figure LungInflation InflationCurve Curve FigureVII-1-9. V-1-9. Lung
Lung compliance is the change in lung volume (tidal volume) divided by the change in surrounding pressure. This is stated in the following formula: Compliance =
∆V ∆P
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Problem Tidal volume = 0.6 liters Intrapleural pressure before inspiration = -5 cm H2O Intrapleural pressure after inspiration = -8 cm H2O Lung compliance =
0.6 liters = 0.200 liters/cm H 2 O 3 cm H 2 O
The preceding calculation simply means that for every 1 cm H2O surrounding pressure changes, 200 mL of air flows in or out of the respiratory system. It flows into the system if surrounding pressure becomes more negative (e.g., -5 to -6 cm H2O) or out of the system if surrounding pressure becomes more positive (e.g., -5 to -4 cm H2O). • Increased compliance means more air will flow for a given change in pressure. • Reduced compliance means less air will flow for a given change in p ressure. • In the preceding curve, although the slope is changing during inflation,
its value at any point is the lung’s compliance. It is the relationship between the change in lung volume (tidal volume) and the change in intrapleural or surrounding pressure.
• The steeper the line, the more compliant the lungs. Restful breathing
works on the steepest, most compliant part of the curve.
• With a deep inspiration, the lung moves toward the flatter part of the
curve, and thus it has reduced compliance. Lung compliance is less at TLC compared to FRC.
The figure below shows pathologic states in which lung compliance changes. 5
Emphysema, aging, normal saline in alveoli TLC
Lung Volume (liters)
4
Normal
3 Fibrosis
2
TLC
1 0
–10
–20
–30
–40
Intrapleural Pressure (cm H2O) FigureVII-1-10. V-1-10. Lung Figure LungCompliance Compliance
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Increased lung compliance also occurs with aging and with a saline-filled lung. • Compliance is an index of the effort required to expand the lungs (to overcome recoil). It does not relate to airway resistance. • Compliance decreases as the lungs are inflated because the curve is not
a straight line.
• For any given fall in intrapleural pressure, large alveoli expand less Microbiology
than small alveoli.
• Very compliant lungs (easy to inflate) have low recoil. Stiff lungs
(difficult to inflate) have a large recoil force.
Components of Lung Recoil Lung recoil has the following components: • The tissue itself; more specifically, the collagen and elastin fibers of the lung –– The larger the lung, the greater the stretch of the tissue and the greater the recoil force. • The surface tension forces in the fluid lining the alveoli. Surface
tension forces are created whenever there is a liquid–air interface.
–– Surface tension forces tend to reduce the area of the surface and generate a pressure. In the alveoli, they act to collapse the alveoli; therefore, these forces contribute to lung recoil. • Surface tension forces are the greatest component of lung recoil. The
relationship between the surface tension and the pressure inside a bubble is given by the Law of LaPlace.
Pressure ∝
tension radius
P
Figure SurfaceTension Tension FigureVII-1-11. V-1-11. Surface
If wall tension is the same in 2 bubbles, the smaller bubble will have the greater pressure. Although the situation is more complex in the lung, it follows that small alveoli tend to be unstable. They have a great tendency to empty into larger alveoli and collapse (creating regions of atelectasis). Collapsed alveoli are difficult to reinflate.
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Psmall > Plarge Figure Atelectasis FigureVII-1-12. V-1-12. Atelectasis
If the alveoli were lined with a simple electrolyte solution, lung recoil would be so great that lungs theoretically should not be able to inflate. This is prevented by a chemical (produced by alveolar type II cells), surfactant, in the fluid lining a normal lung. Surfactant has 2 main functions: • It lowers surface tension forces in the alveoli; in other words, it lowers lung recoil and increases compliance. • It lowers surface tension forces more in small alveoli than in large
alveoli. This promotes stability among alveoli of different sizes by decreasing the tendency of small alveoli to collapse (decreases the tendency to develop atelectasis).
Respiratory Distress Syndrome (RDS) Infant RDS (hyaline membrane disease) is a deficiency of surfactant. Adult respiratory distress syndrome (ARDS) is an acute lung injury via the following: • Bloodstream (sepsis): develops from injury to the pulmonary capillary endothelium, leading to interstitial edema and increased lymph flow –– Leads to injury and increased permeability of the alveolar epithelium and alveolar edema –– The protein seepage into the alveoli reduces the effectiveness of surfactant. –– Neutrophils have been implicated in the progressive lung injury from sepsis. • Airway (gastric aspirations): direct acute injury to the lung epithelium
increases permeability of the epithelium followed by edema
In the figure below, curve A represents respiratory distress syndrome. The curve is shifted to the right, and it is a flatter curve (lung stiffer). • A greater change in intrapleural pressure is required to inflate the lungs. • The tendency for collapse is increased, thus PEEP is sometimes
provided.
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Curve B represents atelectasis. • Once alveoli collapse, it is difficult to reinflate them. • Note the high TPP required to open atelectic alveoli (green line, B, in
figure below).
Normal Lung Volume
Microbiology
A
B TPP or PTM
Figure DeficiencyofofSurfactant Surfactant FigureVII-1-13. V-1-13. Deficiency
AIRWAY RESISTANCE Radius of an Airway In the branching airway system of the lungs, it is the first and second bronchi that represent most of the airway resistance. • Parasympathetic nerve stimulation produces bronchoconstriction. • This is mediated by M3 receptors. In addition, M3 activation increases
airway secretions.
• Circulating catecholamines produce bronchodilation. Epinephrine is
the endogenous agent and it bronchodilates via b2 receptors.
Resistance =
1 radius 4
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Mechanical Effect of Lung Volume
Airway Resistance (cm H2O/sec)
The figure below illustrates that, as lung volume increases, airway resistance decreases.
3 2 1
0
1
2
3
4
Lung Volume (liters)
5
6
Figure VII-1-14. Airway Resistance Figure V-1-14. Airway Resistance
The mechanisms for this are: • PTM: To get to high lung volumes, IPP becomes more and more negative. This increases the PTM across small airways, causing them to expand. The result is decreased resistance. • Radial traction: The walls of alveoli are physically connected to small
airways. Thus, as alveoli expand, they pull open small airways. The result is decreased resistance.
PULMONARY FUNCTION TESTING Vital Capacity Vital capacity (VC) is the maximum volume of air that an individual can move in a single breath. The most useful assessment of the VC is to expire as quickly and forcefully as possible, i.e., a “timed” or forced VC (or FVC). During the FVC maneuver, the volume of air exhaled in the first second is called the forced expiratory volume in 1 sec (FEV1).
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This figure and those that follow differ from the output of a spirometer because they show actual lung volume (including residual volume), not only changes in volume.
Lung Volume (liters)
6 5
FEV1
4
FVC
3 2 1 0 1 second
FEV1 = 80% (or 0.80) FVC
FigureFigure VII-1-15. Pulmonary Function Test of of Forced V-1-15. Pulmonary Function Test ForcedVital VitalCapacity Capacity (FVC)
There are 2 key pieces of data from a PFT involving the measurement of FVC: • FVC: this is total volume exhaled –– Because age, gender, body size, etc., can influence the absolute amount of FVC, it is expressed as a percent of predicted (100% of predicted being the “ideal”). • FEV1 (forced expiratory volume in 1 second): although this volume
can provide information on its own, it is commonly compared to the FVC such that one determines the FEV1/FVC ratio.
–– This ratio creates a flow parameter; 0.8 (80%) or greater is considered normal. • Thus, this PFT provides a volume and a flow. • Restrictive pulmonary disease is characterized by reduced volume (low
FVC, but normal flow), while obstructive disease is characterized by reduced flow (low FEV1/FVC).
Physiology of a PFT In the figure below, the picture on the left shows that at the end of an inspiratory effort to TLC, IPP is very negative. This negative IPP exists throughout the lungs during a passive expiration and thus the PTM is positive for both alveoli and airways.
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+20 15 +20
–20 0
–20
Lung Mechanics
0 cm H2O
0 cm H2O
–20
●
+40 –20
End of Inspiration
+20
+20
During a Forced Expiration
Figure V-1-16. Dynamic Airway Compression Figure VII-1-16. Dynamic Airway Compression
The picture on the right shows the situation during a maximal forced expiration. • A forced expiration compresses the chest wall down and in, creating a positive IPP. The level of positive IPP generated is dependent upon effort. • This forced expiration creates a very positive alveolar pressure, in turn
creating a large pressure gradient to force air out of the lungs.
• However, this positive IPP creates a negative PTM in the airways. It is
more negative in the large airways, e.g., trachea and main-stem bronchi. These regions have structural support and thus do not collapse even though PTM is very negative.
• Moving down the airways toward alveoli, the negative PTM ultimately
compresses airways that lack sufficient structural support. This is dynamic compression of airways.
• This compression of airways creates a tremendous resistance to airflow.
In fact, the airway may collapse, producing infinite resistance. Regardless, this compression creates a level of resistance that overwhelms any and all other resistors that exist in the circuit and is thus the dominant resistor for airflow.
• Once this occurs, elastic recoil of the lung becomes the effective
driving force for airflow and airflow becomes independent of the effort. This means airflow is a property of the patient’s respiratory system, hence the reason this test is very diagnostic.
• Because this resistance is created in small airways, the entire volume of
the lungs cannot be expired, creating residual volume (RV).
Because PFTs measure flow (FEV1/FVC) and volume, they accurately diagnose obstructive (low flow) and restrictive disease (low volume, normal flow).
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Biochemistry
Part V
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Respiration
Physiology
Medical Genetics
Obstructive versus Restrictive Patterns The following figures demonstrate a standard PFT, the measurement of FVC, FEV1, and FEV1/FVC. Pathology
Behavioral Science/Social Sciences
Bridge to Pathology There are 4 basic pathologic Microbiology alterations that can occur in obstructive disease: • Bronchoconstriction • Hypersecretion • Inflammation • Destruction of lung parenchyma (emphysema)
Obstructive pulmonary disease Obstructive disease is characterized by an increase in airway resistance that is measured as a decrease in expiratory flow. Examples are chronic bronchitis, asthma, and emphysema. Obstructive pattern • Total lung capacity (TLC) is normal or larger than normal, but during a maximal forced expiration from TLC, a smaller than normal volume is slowly expired. • Depending upon the severity of the disease, FVC may or may not be
reduced. If severe enough, then FVC is diminished.
Treatment of obstructive disease includes b2-agonists (short- and longacting), M3 blockers such as ipratropium, PDE inhibitors, mast cell stabilizers, leukotriene-receptor blockers, and steroids.
Lung Volume (liters)
Bridge to Pharmacology
7
Normal Lung Volume (liters)
Obstructive FEV1
6
FVC
5 4 3 2
7 6 5 3 2
1
1
0
0 1 second
FVC FRC TLC RV
FEV1
FEV1 FVC
4
1 second
FEV1 = 80% (or 0.80) FVC
FEV1 = 50% FVC
Figure VII-1-17. Obstructive Pattern Figure V-1-17. Obstructive Pattern
Restrictive pulmonary disease Restrictive pulmonary disease is characterized by an increase in elastic recoil— a decrease in lung compliance—which is measured as a decrease in all lung volumes. Reduced vital capacity with low lung volumes are the indicators of restrictive pulmonary diseases. Examples are ARDS and interstitial lung diseases such as sarcoidosis and idiopathic pulmonary fibrosis (IPF).
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Lung Mechanics
Restrictive pattern • TLC is smaller than normal, but during a maximal forced expiration from TLC, the smaller volume is expired quickly and more completely than in a normal pattern. • Therefore, even though FEV1 is also reduced, the FEV1/FVC is often
increased.
• However, the critical distinction is low FVC with low FRC and RV. Normal
7
7
6
6
Lung Volume (liters)
Lung Volume (liters)
Restrictive
5 4
FEV1
3
FVC
2
4
2 1
0
0 FVC FRC TLC RV FEV1
FVC
3
1 1 second
FEV1
5
1 second
FEV1 = 80% (or 0.80) FVC
FEV1 = 88% FVC
Figure V-1-18. Restrictive Pattern Figure VII-1-18. Restrictive Pattern Table V-1-1. Obstructive Versus Restrictive Pattern Obstructive Pattern (e.g., Emphysema)
Restrictive Pattern (e.g., Fibrosis)
TLC
↑
↓↓
FEV1
↓↓
↓
FVC
↓
↓↓
FEV1/FVC
↓
↑ or normal
Peak flow
↓
↓
FRC
↑
↓
RV
↑
↓
Variable
FVC is always decreased when pulmonary function is significantly compromised. A decrease in FEV1/FVC ratio is evidence of an obstructive pattern. A normal or increased FEV1/FVC ratio is evidence of a restrictive pattern, but a low TLC is diagnostic of restrictive lung disease.
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Biochemistry
Part V Physiology
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Respiration Medical Genetics
Flow–Volume Loops
Pathology
Behavioral Science/Social Sciences
The instantaneous relationship between flow (liters/sec) and lung volume is useful in determining whether obstructive or restrictive lung disease is present. In the loop shown below, expiration starts at total lung capacity and continues to residual volume. The width of the loop is the FVC.
Expiration 0 Inspiration
Flow (liters/sec)
Microbiology
TLC
RV Lung volume (liters)
Figure VII-1-19. Flow–Volume Loop Figure V-1-19. Flow–Volume Loop
Loops found in obstructive and restrictive disease are shown below. In obstructive disease, the flow–volume loop begins and ends at abnormally high lung volumes, and the expiratory flow is lower than normal. In addition, the downslope of expiration “scallops” or “bows” inward. This scalloping indicates that at any given lung volume, flow is less. Thus, airway resistance is elevated (obstructive).
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Expiratory Flow Rate (liters/sec)
Chapter 1
●
Lung Mechanics
12 9
Obstructive Normal Restrictive
6 3
6
5
4 3 2 Lung Volume (liters)
1
0
Figure VII-1-20. Forced Expiratory Flow–Volume Loop Figure V-1-20. Forced Expiratory Flow–Volume Loop
In restrictive disease, the flow–volume loop begins and ends at unusually low lung volumes. Peak flow is less, because overall volume is less. However, when expiratory flow is compared at specific lung volumes, the flow in restrictive disease is somewhat greater than normal.
Recall Question Which of the following lung diseases decreases total lung capacity on a pulmonary function test? A. Emphysema B. Chronic bronchitis C. Interstitial pulmonary fibrosis D. Aging E. Normal saline in alveoli Answer: C
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Alveolar–Blood Gas Exchange
2
Learning Objectives ❏❏ Answer questions about the normal lung ❏❏ Solve problems concerning factors affecting alveolar PCO2 ❏❏ Use knowledge of factors affecting alveolar PO2 ❏❏ Interpret scenarios on alveolar-blood gas transfer: Fick law of diffusion ❏❏ Use knowledge of diffusing capacity of the lung
THE NORMAL LUNG Partial Pressure of a Gas in Ambient Air Pgas = Fgas × Patm By convention, the partial pressure of the gas is expressed in terms of its dry gas concentration. For example, the PO2 in ambient air is:
Patm: atmospheric pressure Pgas: partial pressure of a gas Fgas: concentration of a gas
PO2 = 0.21 × 760 = 160 mm Hg
Partial Pressure of a Gas in Inspired Air Inspired air is defined as air that has been inhaled, warmed to 37°C, and completely humidified, but has not yet engaged in gas exchange. It is the fresh air in the anatVD that is about to enter the respiratory zone. The partial pressure of H2O is dependent only on temperature and at 37°C is 47 mm Hg. Humidifying the air reduces the partial pressure of the other gases present. PIgas = Fgas (Patm - PH2O) For example, the PO2 of inspired air is: PIO2 = 0.21 (760 - 47) = 150 mm Hg The figure below shows the pressures of oxygen and carbon dioxide in the alveolar, pulmonary end capillary, and systemic arterial blood.
PIgas: partial pressure of inspired gas PH2O: partial pressure of H2O vapor
Note Dalton’s law of partial pressures states that the total pressure exerted by a mixture of gases is the sum of the pressures exerted independently by each gas in the mixture. Also, the pressure exerted by each gas (its partial pressure) is directly proportional to its percentage in the total gas mixture.
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Biochemistry
Part V Physiology
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Respiration Medical Genetics
160 mm Hg
PIO2 = F(Patm – 47) I = Inspired
150 mm Hg
Alveolar • ventilation (VA)
Pathology
Behavioral Science/Social Sciences
Ambient PO2 = F(Patm)
PAO2 = 100 mm Hg PACO2 = 40 mm Hg
Microbiology
A = alveolar a = systemic arterial
End capillary PvO2 = 40 mm Hg
PO2 = 100 mm Hg
PvcO2 = 47 mm Hg
PCO2 = 40 mm Hg •
Pulmonary capillary blood flow (Qc)
Systemic Arterial PaO2 = 95 mm Hg PaCO2 = 40 mm Hg
Figure V-2-1. Pulmonary Capillary Gases Figure VII-2-1. Pulmonary Capillary Gases
• Under normal conditions, the PO2 and PCO2 in the alveolar
c ompartment and pulmonary end capillary blood are the same (perfusion-limited).
• There is a slight change (PO2↓) between the end capillary compartment
and systemic arterial blood because of a small but normal shunt through the lungs.
• Alveolar–systemic arterial PO2 differences = A - a O2 gradient. • This difference (5–10 mm Hg) often provides information about the
cause of a hypoxemia.
FACTORS AFFECTING ALVEOLAR PCO2
Only 2 factors affect alveolar PCO2: metabolic rate and alveolar ventilation. PACO22 ∝ ∝ PACO
metabolic CO CO22 production production metabolic alveolar ventilation ventilation alveolar
At rest, unless there is fever or hypothermia, CO2 production is relatively constant; so you can use changes of PACO2 to evaluate alveolar ventilation.
Alveolar Ventilation There is an inverse relationship between PACO2 and alveolar ventilation. This is the main factor affecting alveolar PCO2. Therefore, if ventilation increases, PACO2 decreases; if ventilation decreases, PACO2 increases.
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Alveolar–Blood Gas Exchange
Hyperventilation
Note
During hyperventilation, there is an inappropriately elevated level of alveolar ventilation, and PACO2 is depressed. • If VA is doubled, then PACO2 is decreased by half.
Respiratory quotient (RQ) is the ratio between CO2 production and O2 consumption at the cellular level. Respiratory exchange ratio (RER) is the ratio of CO2 output and oxygen uptake occurring in the lung.
For example, PACO2 = 40 mm Hg • 2 × VA; PACO2 = 20 mm Hg
In a steady state, RQ and RER are equal.
Hypoventilation During hypoventilation, there is an inappropriately depressed level of alveolar ventilation, and PACO2 is elevated. • If VA is halved, then PACO2 is doubled. For example, PACO2 = 40 mm Hg • 1/2 VA; PACO2 = 80 mm Hg
Metabolic Rate There is a direct relationship between alveolar PCO2 and body metabolism. For PaCO2 to remain constant, changes in body metabolism must be matched with equivalent changes in alveolar ventilation. • • If VA matches metabolism, then PACO2 remains constant. • For example, during exercise, if body metabolism doubles, then
• VA must double if PaCO2 is to remain constant.
• If body temperature decreases and there is no change in ventilation,
PaCO2 decreases, and the individual can be considered to be hyperventilating.
FACTORS AFFECTING ALVEOLAR PO2 Alveolar Air Equation The alveolar air equation includes all the factors that can affect alveolar PO2. PAO2 = (Patm − 47 )FiO2 −
PACO2 RQ
Practical application of the equation includes differential diagnosis of hypoxemia by evaluating the alveolar arterial (A–a) gradient of oxygen. There are 3 factors that can affect PAO2: Patm = atmospheric pressure, at sea level 760 mm Hg An increase in atmospheric pressure (hyperbaric chamber) increases alveolar PO2, and a decrease (high altitude) decreases alveolar PO2. FiO2 = fractional concentration of oxygen, room air 0.21
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Part V Physiology
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Respiration Medical Genetics
An increase in inspired oxygen concentration increases alveolar PO2. PaCO2 = alveolar pressure of carbon dioxide, normally 40 mm Hg
Pathology
Behavioral Science/Social Sciences
An increase in alveolar PCO2 decreases alveolar PO2, and a decrease in alveolar PCO2 increases alveolar PO2. For most purposes, you can use arterial carbon dioxide (PaCO2) in the calculation. The fourth variable is RQ.
Microbiology
RQ = respiratory exchange ratio =
CO2 produced mL/min O2 consumed mL/min
; normally 0.8
For example, a person breathing room air at sea level would have PAO2 = (760 - 47) 0.21 - 40/0.8 = 100 mm Hg.
Effect of PACO2 on PAO2
PIO2 = P inspired O2, i.e., the PO2 in the conducting airways during inspiration. Because PaCO2 affects alveolar PO2, hyperventilation and hypoventilation also affect PaO2. Hyperventilation (e.g., PaCO2 = 20 mm Hg) PaO2 = PiO2 - PaCO2 (assume R = 1) normal = 150 - 40 = 110 mm Hg hyperventilation = 150 - 20 = 130 mm Hg Hypoventilation (e.g., PaCO2 = 80 mm Hg) normal = 150 - 40 = 110 mm Hg hypoventilation = 150 - 80 = 70 mm Hg
ALVEOLAR–BLOOD GAS TRANSFER: FICK LAW OF DIFFUSION
• V gas = rate of gas diffusion
Simple diffusion is the process of gas exchange between the alveolar compartment and pulmonary capillary blood. Thus, those factors that affect the rate of diffusion also affect the rate of exchange of O2 and CO2 across alveolar membranes. (An additional point to remember is that each gas diffuses independently.) • A Vgas = × D × ( P1 − P2 ) T
Structural Features That Affect the Rate of Diffusion There are 2 structural factors and 2 gas factors affect the rate of diffusion. A = surface area for exchange, ↓ in emphysema, ↑ in exercise T = thickness of the membranes between alveolar gas and capillary blood, ↑ in fibrosis and many other restrictive diseases A structural problem in the lungs is any situation in which there is a loss of surface area and/or an increase in the thickness of the membrane system between the alveolar air and the pulmonary capillary blood. In all cases, the rate of oxygen and carbon dioxide diffusion decreases. The greater the structural problem, the greater the effect on diffusion rate.
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Alveolar–Blood Gas Exchange
Factors Specific to Each Gas Present D (diffusion constant) = main factor is solubility The only clinically significant feature of D is solubility. The more soluble the gas, the faster it diffuses across the membranes. CO2 is the most soluble gas with which we will be dealing. The great solubility of CO2 is the main reason why it diffuses faster across the alveolar membranes than O2.
Gradient across the membrane (P1 - P2): This is the gas partial pressure difference across the alveolar membrane. The greater the partial pressure difference, the greater the rate of diffusion. Under resting conditions, when blood first enters the pulmonary capillary, the gradient for O2 is: 100 - 40 = 60 mm Hg An increase in the PO2 gradient across the lung membranes helps compensate for a structural problem. If supplemental O2 is administered, alveolar PO2 increases, because of the elevated gradient. However, supplemental O2 does not improve the ability of the lungs to remove CO2 from blood. This increased gradient helps return the rate of O2 diffusion toward normal. The greater the structural problem, the greater the gradient necessary for a normal rate of O2 diffusion. The gradient for CO2 is 47 - 40 = 7 mm Hg. Even though the gradient for CO2 is less than for O2, CO2 still diffuses faster because of its greater solubility.
Recall Question Which of the following factors increases alveolar PCO2, assuming no compensation? A. Decrease in atmospheric pressure (Patm) B. Increase in fractional concentration of oxygen (FiO2) C. Decrease in compliance of alveoli D. Increase in thickness of the membranes between alveolar gas and capillary blood E. Increase in body temperature Answer: E
DIFFUSING CAPACITY OF THE LUNG There are 2 terms that describe the dynamics of the transfer of individual substances between the interstitium and the capillary: • If the substance equilibrates between the capillary and interstitium, it is said to be in a perfusion-limited situation. • If the substance does not equilibrate between the capillary and intersti-
tium, it is said to be in a diffusion-limited situation.
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Biochemistry
Part V
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Respiration
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Carbon monoxide is a unique gas in that it typically doesn’t equilibrate between the alveolar air and the capillary blood. Thus, it is a diffusion-limited gas. This is taken advantage of clinically, and the measurement of the uptake of CO in mL/ min/mm Hg is referred to as the diffusing capacity of the lung (DLCO). DLCO is an index of the lung’s structural features.
Microbiology
Carbon Monoxide: A Gas That Is Always Diffusion Limited Carbon monoxide has an extremely high affinity for hemoglobin. When it is present in the blood, it rapidly combines with hemoglobin, and the amount dissolved in the plasma is close to zero (therefore, partial pressure in the plasma is considered zero). Thus, the alveolar partial pressure gradient (P1 – P2) is simply P1 (alveolar partial pressure), since P2 is considered to be zero. At a constant and known alveolar partial pressure, the uptake of carbon monoxide depends only on the structural features of the lung. • A V gas = × D × ( P1 − P2 ) T • A VCO = × D × PA CO T
PCO = 0
PCO = 1 mm Hg •
VCO
A T
Figure CarbonMonoxide Monoxide FigureVII-2-2. V-2-2. Carbon
This measured uptake of carbon monoxide is called the diffusing capacity of the lung (DL; mL/min/mm Hg). It is an index of overall surface area and membrane thickness. • With a structural problem, it correlates with the extent of lung damage
and is particularly useful when measured serially over time.
• DL (rate of CO diffusion) decreases in emphysema and fibrosis but
increases during exercise.
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Transport of O2 and CO2 and the Regulation of Ventilation
3
Learning Objectives ❏❏ Interpret scenarios on transport of oxygen ❏❏ Answer questions about transport of carbon dioxide ❏❏ Interpret scenarios on neural regulation of alveolar ventilation ❏❏ Answer questions about respiratory stress: unusual environments
TRANSPORT OF OXYGEN Units of Oxygen Content Oxygen content = concentration of oxygen in the blood, e.g., arterial blood = 20 volumes % = 20 volumes of oxygen per 100 volumes of blood = 20 mL of oxygen per 100 mL of blood = 0.2 mL of oxygen per mL of blood
Dissolved Oxygen Oxygen dissolves in blood and this dissolved oxygen exerts a pressure. Thus, PO2 of the blood represents the pressure exerted by the dissolved gas, and this PO2 is directly related to the amount dissolved. The amount dissolved (PO2) is the primary determinant for the amount of oxygen bound to hemoglobin (Hb). There is a direct linear relationship between PO2 and dissolved oxygen. • When PO2 is 100 mm Hg, 0.3 mL O2 is dissolved in each 100 mL of blood (0.3 vol%). • Maximal hyperventilation can increase the PO2 in blood to 130 mm
Hg (0.4 vol%).
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Part V
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Respiration
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
O2 Content (dissolved) Vol %
Pharmacology
0.3 0.2 0.1 20
40
60
80
100
PO2 in Blood (mm Hg) Figure V-3-1. Dissolved Dissolved Oxygen Figure VII-3-1. OxygenininPlasma Plasma
Oxyhemoglobin Each Hb molecule can attach and carry up to four oxygen molecules. Binding sites on Hb have different affinities for oxygen. Also, the affinity of a site can and does change as oxygen is loaded or unloaded from the Hb molecule and as the chemical composition of the plasma changes. Site 4 – O2 attached when the minimal PO2 ≅ 100 mm Hg
systemic arterial blood = 97% saturated
Site 3 – O2 attached when the minimal PO2 ≅ 40 mm Hg
systemic venous blood = 75% saturated (resting state)
Site 2 – O2 attached when the minimal PO2 ≅ 26 mm Hg
P50 for arterial blood. P50 is the PO2 required for 50% saturation
Site 1 – O2 usually remains attached under physiologic conditions.
Under physiologic conditions, only sites 2, 3, and 4 need to be considered.
Most of the oxygen in systemic arterial blood is oxygen attached to Hb. The only significant form in which oxygen is delivered to systemic capillaries is oxygen bound to Hb.
Hemoglobin O2 Content
The number of mL of oxygen carried in each 100 mL of blood in combination with Hb depends on the Hb concentration [Hb]. Each gram of Hb can combine with 1.34 mL of O2. If the [Hb] is 15 g/100 mL (15 g%), then the maximal amount of O2 per 100 mL (100% saturation) in combination with Hb is: 1.34([Hb]) = 1.34(15) = 20 mL O2/100 mL blood = 20 vol% This volume represents the “carrying capacity” of the blood.
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Transport of O2 and CO2 and the Regulation of Ventilation
The Hb in systemic arterial blood is about 97% saturated with oxygen, which means slightly less than 20 vol% is carried by Hb. When blood passes through a systemic capillary, it is the dissolved oxygen that diffuses to the tissues. However, if dissolved oxygen decreases, PO2 also decreases, and there is less force to keep oxygen attached to Hb. Oxygen comes off Hb and dissolves in the plasma to maintain the flow of oxygen to the tissues. Hyperventilation or supplementing the inspired air with additional oxygen in a normal individual can significantly increase the PaO2 but has little effect on total oxygen content. For example: Dissolved O2
HbO2
Total O2 Content
If PaO2 = 100 mm Hg
0.3
≅ 19.4
≅ 19.7 vol%
If PaO2 = 130 mm Hg (hyperventilation)
0.4
≅ 19.4
≅ 19.8 vol%
Oxygen–Hb Dissociation Curves The figure below represents 3 major points on the oxygen–hemoglobin dissociation curve. The numbered sites refer to the hemoglobin site numbers discussed just previously. 100
15 10 5
0
% Hemoglobin Saturation
HbO2 Content (vol %)
20
4
80
3
60 2
40 20 0
0
PO2 in Blood (mm Hg)
Figure V-3-2. Oxygen–Hb Dissociation Curves Figure VII-3-2. Oxygen–Hb Dissociation Curves
The following factors shift the curve to the right: • Increased CO2 (Bohr effect) • Increased hydrogen ion (decrease pH) • Increased temperature • Increased 2,3-bisphosphoglycerate (2,3-BPG)
In each case, the result can be explained as a reduced affinity of the Hb molecule for oxygen. However, carrying capacity is not changed, and systemic arterial blood at a PO2 of 100 mm Hg is still close to 100% saturation.
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Part V
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Respiration
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
Note that only points on the steep part of the curve are affected.
The opposite chemical changes shift the curve to the left. 20 HbO2 Content (vol %)
Pharmacology
Temperature PCO2
15
2,3-BPG H+
10
Temperature PCO2
5 0
2,3-BPG H+
0
20
40
60
80
100
PO2 in Blood (mm Hg) Figure V-3-3. Shifts in Hb–O2 Dissociation Curve Figure VII-3-3. Shifts in Hb-O 2 Dissociation Curve Shift to the Right
Shift to the Left
Easier for tissues to extract oxygen
More difficult for tissues to extract oxygen
Steep part of curve, O2 content decreased
Steep part of curve, O2 content increased
P50 increased
P50 decreased
Stored blood loses 2,3-bisphosphoglycerate, causing a left shift in the curve, while hypoxia stimulates the production of 2,3-bisphosphoglycerate, thereby causing a right shift.
Hb Concentration Effects Anemia is characterized by a reduced concentration of Hb in the blood. Polycythemia is characterized by a higher than normal concentration of Hb in the blood. P50: In simple anemia and polycythemia, the P50 does not change without tissue hypoxia; e.g., PO2 of 26 mm Hg produces 50% saturation of arterial hemoglobin. The figure below illustrates the effects of an increase and a decrease in hemoglobin concentration. The main change is the plateau or carrying capacity of the blood. Note that the point halfway up each curve, the P50, is still close to 26 mm Hg.
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Transport of O2 and CO2 and the Regulation of Ventilation
100% sat.
Arterial content increase
20
Polycythemia Normal Hb=15 Anemia
100% sat.
Arterial content decrease
16 12
38°C pH = 7.40
8 4
90 10 0 11 0 12 0 13 0 14 0
80
70
50 60
0
10 20
0
100% sat.
P50 30 40
HbO2 Content (vol %)
24
●
PO2 (mm Hg) Figure VII-3-4. Effect of Hemoglobin Content on O2 Content Figure V-3-4. Effect of Hemoglobin Content on O2 Content
Effects of Carbon Monoxide
HbO2 Content (vol %)
Carbon monoxide (CO) has a greater affinity for Hb than does oxygen (240x greater). The figure below shows that with CO, the O2–Hb dissociation curve is shifted to the left (CO increases the affinity of Hb for O2) and HbO2 content is reduced.
CO Normal
PO2 in Blood (mm Hg) Figure VII-3-5. Monoxide Poisoning FigureCarbon V-3-5. Carbon Monoxide Poisoning
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Part V
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Respiration
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
The effects of anemia, polycythemia, and carbon monoxide poisoning are summarized below. Table V-3-1. Systemic Arterial Blood PO2
Hb Concentration
O2 per g Hb
O2 Content
Anemia
Normal
↓
Normal
↓
Polycythemia
Normal
↑
Normal
↑
CO poisoning (acute)
Normal
Normal
↓
↓
O2 per g Hb = % saturation
In anemia, hemoglobin is saturated but arterial oxygen content is depressed because of the reduced concentration of hemoglobin. In polycythemia, arterial oxygen content is above normal because of an increased hemoglobin concentration. In CO poisoning, arterial PO2 is normal, but oxygen saturation of hemoglobin is depressed.
TRANSPORT OF CARBON DIOXIDE Dissolved Carbon Dioxide Carbon dioxide is 24x more soluble in blood than oxygen is. Even though the blood has a PCO2 of only 40–47 mm Hg, about 5% of the total CO2 is carried in the dissolved form.
Carbamino Compounds Carbon dioxide reacts with terminal amine groups of proteins to form carbamino compounds. The protein involved appears to be almost exclusively hemoglobin. About 5% of the total CO2 is carried as carbamino compounds. The attachment sites that bind CO2 are different from the sites that bind O2.
Bicarbonate About 90% of the CO2 is carried as plasma bicarbonate. In order to convert CO2 into bicarbonate or the reverse, carbonic anhydrase (CA) must be present. CA
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3The steps in the conversion of CO2 into bicarbonate in a systemic capillary are seen below.
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Transport of O2 and CO2 and the Regulation of Ventilation
CO2 Plasma
CO2
CO2 + H2O H2CO3 Carbonic anhydrase Hb – CO2
Cl–
HCO3–
H+ + HCO3– Hb – H
Red blood cell
Figure V-3-6.Formation Formation of of Bicarbonate Bicarbonate Ion Figure VII-3-6. Ion
Plasma contains no carbonic anhydrase; therefore, there can be no significant conversion of CO2 to HCO3- in this compartment. Because deoxygenated Hb is a better buffer, removing oxygen from hemoglobin shifts the reaction to the right and thus facilitates the formation of bicarbonate in the red blood cells (Haldane effect). To maintain electrical neutrality as HCO3- moves into the plasma, Cl- moves into the red blood cell (chloride shift). In summary: • Bicarbonate is formed in the red blood cell but it is carried in the plasma compartment. • The PCO2 determines the volume of CO2 carried in each of the forms
listed above. The relationship between the PCO2 and the total CO2 content is direct and nearly linear.
• Thus, hyperventilation not only lowers the PCO2 (mm Hg), it also
lowers the CO2 content (vol%).
CO2 Content (vol %)
54 52 50 48 46
0
10 20 30 40 50 60 70 80 PCO2 in Blood (mm Hg)
Figure VII-3-7. CO2 Content in Blood Figure V-3-7. CO2 Content in Blood
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Part V Physiology
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Respiration Medical Genetics
NEURAL REGULATION OF ALVEOLAR VENTILATION
Pathology
Microbiology
Behavioral Science/Social Sciences
The level of alveolar ventilation is driven mainly from the input of specific chemoreceptors to the central nervous system. The stronger the stimulation of these receptors, the greater the level of alveolar ventilation. Chemoreceptors monitor the chemical composition of body fluids. In this system, there are receptors that respond to pH, PCO2, and PO2. There are 2 groups of receptors, and they are classified by their location.
Central Chemoreceptors Central receptors are located in the central nervous system—more specifically, close to the surface of the medulla. Stimulation of central chemoreceptors increases ventilation. • The receptors directly monitor and are stimulated by cerebrospinal fluid [H+] and CO2. The stimulatory effect of increased CO2 may be due to the local production of H+ from CO2. • Because the blood–brain barrier is freely permeable to CO2, the activity
of these receptors changes with increased or decreased systemic arterial PCO2.
• H+ does not easily penetrate the blood-brain barrier. Thus, an acute
rise in arterial H+, not of CO2 origin, does not stimulate central chemoreceptors.
• These receptors are very sensitive and represent the main drive for
ventilation under normal resting conditions at sea level.
• Therefore, the main drive for ventilation is CO2 (H+) on the central
chemoreceptors.
The relationship between the central chemoreceptors and systemic arterial blood can be seen below.
CO2
CO2 H+
– – – Medulla –
H+
Systemic arterial blood
CSF
Figure VII-3-8. Central Chemoreceptors
Figure V-3-8. Central Chemoreceptors
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Transport of O2 and CO2 and the Regulation of Ventilation
The system does adapt, usually within 12–24 hours. The mechanism of adaptation may be the normalization of CSF H+ by the pumping of HCO3– into or out of the CSF. There are no central PO2 receptors.
Peripheral Chemoreceptors Peripheral receptors are found within small bodies at 2 locations: • Carotid bodies: near carotid sinus, afferents to CNS in glossopharyngeal nerve IX • Aortic bodies: near aortic arch, afferents to CNS in vagus nerve X
The peripheral chemoreceptors are bathed in arterial blood, which they monitor directly. These bodies have 2 different receptors: • H+/CO2 receptors –– These receptors are less sensitive than the central chemoreceptors, but they still contribute to the normal drive for ventilation. –– Therefore, under normal resting conditions at sea level, for all practical purposes, the total drive for ventilation is CO2, mainly via the central chemoreceptors but with a small contribution via the peripheral chemoreceptors. • PO2 receptors
–– The factor monitored by these receptors is PO2, not oxygen content. –– Because they respond to PO2, they are actually monitoring dissolved oxygen and not oxygen on Hb. –– When systemic arterial PO2 is close to normal (≅100 mm Hg) or above normal, there is little if any stimulation of these receptors. • They are strongly stimulated only by a dramatic decrease in systemic
arterial PO2.
Bridge to Pathology/ Pharmacology The normal CO2 drive to breathe is suppressed in COPD patients, and by narcotics and general anesthetics.
Clinical Correlate Although oxygen content is reduced in anemia, the PaO2 is normal; thus, anemia does not directly stimulate ventilation. However, the reduced oxygen delivery can cause excess lactic acid production, which would in turn stimulate peripheral chemoreceptors.
• Sensitivity to hypoxia increases with CO2 retention.
These receptors do not adapt.
Central Respiratory Centers Medullary centers Site of the inherent rhythm for respiration.
Inspiratory center
Expiratory center
For spontaneous breathing, an intact medulla must be connected to the diaphragm (via the phrenic nerve). Thus a complete C1 or C2 lesion will prevent diaphragmatic breathing but not a complete C6 or lower lesion. The main features involved in the central control of ventilation are seen below.
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Biochemistry
Part V Physiology
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Respiration Medical Genetics
Medulla
Pathology
Rhythm
Behavioral Science/Social Sciences
C3
C5
To diaphragm
Microbiology
FigureFigure VII-3-9.V-3-9. CNS Respiratory Centers Centers CNS Respiratory
Abnormal Breathing Patterns Apneustic breathing is prolonged inspirations alternating with a short period of expiration. This pattern is attributed to the loss of the normal balance between vagal input and the pons-medullary interactions. Lesions in these patients are usually found in the caudal pons. Cheyne-Stokes breathing is periodic type of breathing which has cycles of gradually increasing depth and frequency followed by a gradual decrease in depth and frequency between periods of apnea. It may result from midbrain lesions or congestive heart failure.
RESPIRATORY STRESS: UNUSUAL ENVIRONMENTS High Altitude At high altitude, atmospheric pressure is reduced from 760 mm Hg of sea level. Because atmospheric pressure is a factor that determines room air and alveolar PO2, those 2 values are also reduced; they are permanently depressed unless enriched oxygen is inspired. Therefore, PAO2 1 cm diameter) of the anterior pituitary and second in frequency to prolactinomas. • Slow onset of symptoms; disease usually present for 5–10 years before diagnosis • Ectopic GHRH secretion (rare) • Some tumors contain lactotrophs, and elevated prolactin can cause
hypogonadism and galactorrhea.
• Increased IGF-I causes most of the deleterious effects of acromegaly
but growth hormone excess directly causes the hyperglycemia and insulin resistance.
• Characteristic proliferation of cartilage, bone and soft tissue, visceral,
and cardiomegaly
• Observable changes include enlargement of the hands and feet (acral
parts) and coarsening of the facial features, including downward and forward growth of the mandible. Also, increased hat size.
• Measurement of IGF-I is a useful screening measure and confirms
diagnosis with the lack of growth hormone suppression by oral glucose.
• Diagnosis: confirm the following before treatment is started: elevated
IGF, failed suppression of GH/IGF after giving glucose, MRI showing lesion in brain in pituitary
• Never start with a scan in endocrinology. Benign pituitary “inciden-
taloma” is common in 2–10% of the population. Always confirm the presence of an overproduction of a hormone before doing a scan. This is true for adrenal lesions as well.
• Treatment:
–– Surgical removal by trans-sphenoidal approach is first. Removal of an over-producing adenoma is the first treatment in most of endocrinology with the exception of prolactinoma. –– If surgical removal fails, use the growth hormone receptor antagonist, pegvisomant, or octreotide. Octreotide is synthetic somatostatin. Cabergoline is a dopamine agonist used when other medications have failed. –– Radiation is used last, only after surgery, pegvisomant, octreotide and cabergoline have failed.
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Growth, Growth Hormone, and Puberty
Recall Question Which of the following is correct about the control of growth hormone (GH) secretion? A. Continuous and slow B. Occurs in the early stages of sleep during stage 1 and 2 C. Depends on thyroid hormone plasma levels D. Accelerates during decade 6 of life E. Depends on plasma insulin levels Answer: C
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10
Learning Objectives ❏❏ Solve problems concerning hypothalamic-pituitary-gonadal axis in males ❏❏ Solve problems concerning age-related hormonal changes in males ❏❏ Demonstrate understanding of erection, emission, and ejaculation ❏❏ Use knowledge of gonadal dysfunction in the male
HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS IN MALES
Note
The factors involved in the overall control of adult male hormone secretion can be seen below.
LH, FSH, TSH, and human chorionic gonadotropin (hCG) are glycoproteins with identical alpha subunits. The beta subunits differ and thus confer specificity.
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Biochemistry
Part VII
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Physiology
Endocrinology Medical Genetics
GnRH Pathology
Behavioral Science/Social Sciences
Microbiology
(–)
FSH
LH
Leydig Cholesterol
Sertoli cell
Testosterone DHT
Testosterone
Testosterone and DHT in blood DHT
GnRH—synthesized in preoptic region of hypothalamus and secreted in pulses into hypophyseal portal vessels • produces pulsatile release of LH and FSH (–) • pulsatile release of GnRH prevents Inhibin B downregulation of its receptors in anterior pituitary
Nurse cell for sperm circulates attached to protein—mainly testosterone–estrogen binding globulin
Some androgen target cells 5 -Reductase
LH and FSH—produced and secreted by gonadotrophs of anterior pituitary • LH stimulates Leydig cells to produce testosterone. • FSH stimulates Sertoli cells (see below). Leydig cell testosterone—some diffuses directly to Sertoli cells, where it is required for Sertoli cell function. • produces negative feedback for LH Sertoli cell inhibin B—produces negative feedback for FSH
Dihydrotestosterone (DHT) (a more active form of testosterone)
Figure VII-10-1. Control of Testes Figure X-10-1. Control of Testes
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LH/Leydig Cells Leydig cells express receptors for luteinizing hormone (LH). LH is a peptide hormone that activates Gs--cAMP, which in turn initiates testosterone production by activating steroidogenic acute regulatory protein (StAR). • Testosterone diffuses into Sertoli cells (high concentration) and into the blood. • Circulating testosterone provides negative feedback to regulate LH
secretion at the level of the hypothalamus and anterior pituitary.
• Leydig cells aromatize some of this testosterone into estradiol.
5α-reductase Some target tissue express the enzyme 5α-reductase, which converts testosterone into the more potent dihydrotestosterone. Some important physiologic effects primarily mediated by dihydrotestosterone are as follows: • Sexual differentiation: differentiation to form male external genitalia • Growth of the prostate • Male-pattern baldness • Increased activity of sebaceous glands • Synthesis of NO synthase in penile tissue
FSH/Sertoli Cells FSH binds to Sertoli cells and activates a Gs--cAMP pathway. Sertoli cells release inhibin B, which has negative feedback on FSH secretion.
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Endocrinology Medical Genetics
Hormonal Control of Testicular Function The figure below illustrates the source and nature of the hormones controlling testicular function. Pathology
Behavioral Science/Social Sciences
Pituitary LH To pituitary feedback inhibition
Microbiology
Note Sertoli cells provide the nourishment required for normal spermatogenesis. • FSH, along with a very high level of testosterone from the neighboring Leydig cells, produces growth factors necessary for growth and maturation of the sperm. • FSH and testosterone induce the synthesis of androgen binding protein, which helps maintain high local levels of testosterone. • Leydig cells express aromatase, which aromatizes testosterone into estradiol, an important hormone for growth and maturation of the sperm. • Sertoli cells secrete inhibin B, which produces feedback regulation on FSH.
cAMP Protein kinase A
Leydig Cell Nucleus Estradiol
Cholesterol
Pregnolone
Secreted testosterone
Testosterone Aromatase
FSH Testosterone cAMP
Nucleus
Sertoli cell Inhibin B
Growth factors Androgenbinding protein
Developing germ cell
Estradiol
Lumen of seminiferous tubule
Mature sperm
Figure VII-10-2. Endocrine Function of Testes Figure X-10-2. Endocrine Function of Testes
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Definitions Androgen: any steroid that controls the development and maintenance of masculine characteristics Testosterone: a natural male androgen of testicular origin, controlled by the LH Dihydrotestosterone: a more active form of testosterone made by 5-alpha- reductase. Dihydrotestosterone makes the penis, prostate, and scrotum on an embryo. Methyl testosterone: a synthetic androgen, which is an anabolic steroid sometimes used by athletes Adrenal androgens: natural weak androgens (male and female) of adrenal origin, controlled by ACTH. These are DHEA and androstenedione. Inhibins: peptide hormones secreted into the blood. They inhibit the secretion of FSH by pituitary gonadotrophs. Aromatase: an enzyme that stimulates the aromatization of the A-ring of testosterone, converting it into estradiol. Other than spermatogenesis, the physiologic importance of this c onversion is not understood; however, approximately a third of the estradiol in the blood of men arises from the testes, and the remainder arises from peripheral conversion of testosterone to estradiol by an aromatase present in adipose tissue.
AGE-RELATED HORMONAL CHANGES IN MALES The relative plasma LH and testosterone concentrations throughout the life of the normal human male can be seen below.
4
1
5 Testosterone LH
3 2
Fetal life
Birth
Puberty
Adult
Aging adult
Figure X-10-3. Development and Aging Figure VII-10-3. Development and AgingininMale MaleReproduction Reproduction
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Microbiology
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Endocrinology Medical Genetics
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1: Fetal life The development of male and female internal and external structures depends on the fetal hormonal environment. The Wolffian and Müllerian ducts are initially present in both male and female fetuses. If there is no hormonal input (the situation in the normal female fetus), female internal and female external structures develop (Müllerian ducts develop, Wolffian ducts regress). Normal male development requires the presence of 3 hormones: testosterone, dihydrotestosterone, and the Müllerian inhibiting factor (MIF). • (hCG) + LH → Leydig cells → testosterone → Wolffian ducts 5-α-reductase
• testosterone → dihydrotestosterone → urogenital sinus & genital organs • Sertoli cells → MIF → absence of female internal structures
MIF prevents the development of the Müllerian ducts, which would otherwise differentiate into female internal structures. In the absence of MIF, the Müllerian ducts develop. Thus, in addition to normal male structures, a uterus will be present. • Wolffian ducts differentiate into the majority of male internal structures; namely, epididymis, vas deferens, and seminal vesicles. –– In the absence of testosterone, the Wolffian ducts regress. • Dihydrotestosterone induces the urogenital sinus and genital tubercle
to differentiate into the external scrotum, penis, and prostate gland. –– In the absence of dihydrotestosterone, female external structures develop.
2: Childhood Within a few months after birth, LH and testosterone drop to low levels and remain low until puberty. The cause of this prolonged quiescence of reproductive hormone secretion during childhood is not known. Interestingly, LH secretion remains low in spite of low testosterone. 3: Puberty Near the onset of puberty, the amplitude of the LH pulses becomes greater, driving the mean level of LH higher. Early in puberty, this potentiation of the LH pulses is especially pronounced during sleep. This increased LH stimulates the Leydig cells to again secrete testosterone. 4: Adult During adulthood, LH secretion drives testosterone secretion. Thus, it is not surprising that the relative levels of the two hormones parallel one another. 5: Aging adult Testosterone and inhibin secretions decrease with age. Men in their seventies generally secrete only 60–70% as much testosterone as do men in their twenties. Nevertheless, there is no abrupt decrease in testosterone secretion in men that parallels the relatively abrupt decrease in estrogen secretion that women experience at menopause. The loss of feedback will cause an increase in LH and FSH secretion.
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Effect on Muscle Mass The capacity of androgens to stimulate protein synthesis and decrease protein breakdown, especially in muscle, is responsible for the larger muscle mass in men as compared with women. Exogenous androgens (anabolic steroids) are sometimes taken by men and women in an attempt to increase muscle mass.
Spermatogenesis Is Temperature-Dependent Effect on fertility For unknown reasons, spermatogenesis ceases at temperatures typical of the abdominal cavity. Thus, when the testes fail to descend before or shortly after birth, and the condition (cryptorchidism) is not surgically corrected, infertility results. Cooling mechanisms Normally, the scrotum provides an environment that is 4°C cooler than the abdominal cavity. The cooling is accomplished by a countercurrent heat exchanger located in the spermatic cord. Also, the temperature of the scrotum and the testes is regulated by the relative degree of contraction or relaxation of the cremasteric muscles and scrotal skin rugae that surround and suspend the testes.
Effect on FSH and LH Sertoli cells, and therefore germ cell maturation, are adversely affected by the elevated temperatures of cryptorchid testes. In adults with bilaterally undescended testes, FSH secretion is elevated, probably as a result of decreased Sertoli cell production of inhibins. Testosterone secretion by the Leydig cells of cryptorchid testes also tends to be low, and as a result, LH secretion of adults with bilateral cryptorchidism is elevated.
ERECTION, EMISSION, AND EJACULATION Erection Erection is caused by dilation of the blood vessels (a parasympathetic response) in the erectile tissue of the penis (the corpora- and ischiocavernous sinuses). This dilation increases the inflow of blood so much that the penile veins get compressed between the engorged cavernous spaces and the Buck’s and dartos fasciae. Nitric oxide (NO), working through cGMP, mediates the vasodilation.
Emission Emission is the movement of semen from the epididymis, vas deferens, seminal vesicles, and prostate to the ejaculatory ducts. The movement is mediated by sympathetic (thoracolumbar) adrenergic transmitters. • Simultaneously with emission, there is also a sympathetic adrenergicmediated contraction of the internal sphincter of the bladder, which prevents retrograde ejaculation of semen into the bladder. Destruction of this sphincter by prostatectomy often results in retrograde ejaculation. • Emission normally precedes ejaculation but also continues during ejaculation.
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Ejaculation
Pathology
Microbiology
Behavioral Science/Social Sciences
Ejaculation is caused by the rhythmic contraction of the bulbospongiosus and the ischiocavernous muscles that surround the base of the penis. Contraction of these striated muscles, innervated by somatic motor nerves, causes the semen to exit rapidly in the direction of least resistance, i.e., outwardly through the urethra.
GONADAL DYSFUNCTION IN THE MALE The consequences of deficient testosterone production depend upon the age of onset: • Testosterone deficiency in the second to third month of gestation results in varying degrees of ambiguity in the male genitalia and male pseudohermaphrodism. • Testosterone deficiency in the third trimester leads to problems in
testicular descent (cryptorchidism) along with micropenis.
• Pubertal testosterone deficiency leads to poor secondary sexual
development and overall eunuchoid features.
• Postpubertal testosterone deficiency leads to decreased libido, erectile
dysfunction, decrease in facial and body hair growth, low energy, and infertility.
Causes of Hypogonadism • Noonan syndrome • Klinefelter’s syndrome • Hypothalamic-pituitary disorders (Kallman’s syndrome,
panhypopituitarism)
• Gonadal failure/sex steroid synthesis failure
Definitions • Pseudohermaphrodite: an individual with the genetic constitution and
gonads of one sex and the genitalia of the other.
• Female pseudohermaphroditism: female fetus exposed to androgens
during the 8th to 13th week of development, e.g., congenital virilizing adrenal hyperplasia.
• Male pseudohermaphroditism: lack of androgen activity in male fetus,
e.g., defective testes, androgen resistance
• When the loss of receptor function is complete, testicular feminizing
syndrome results. Here MIF is present and testosterone is secreted, usually at elevated levels. The external structures are female, but the vagina ends blindly because there are no female internal structures.
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Table VII-10-1. Hormonal Changes in Specific Altered States Sex Steroids
LH
FSH
Primary hypogonadism
↓
↑
↑
Pituitary hypogonadism
↓
↓
↓
Kallman’s (↓ GnRH)
↓
↓
↓
Postmenopausal women
↓
↑
↑
Anabolic steroid therapy (male)*
↑
↓
(↓)
Inhibin infusion (male)†
-
-
↓
GnRH infusion (constant rate)‡
↓
↓
↓
GnRH infusion (pulsatile)
↑
↑
↑
*LH suppression causes Leydig cell atrophy in an adult male and therefore reduced testicular androgen production. Because Leydig cell testosterone is required for spermatogenesis, anabolic steroids suppress spermatogenesis. Although testosterone is not the normal feedback regulating FSH, high circulating testosterone activity will suppress the release of FSH. †Because FSH is required for spermatogenesis, giving inhibin suppresses spermatogenesis. ‡A
constant rate of infusion of the gonadotropin-releasing hormone (GnRH) will cause a transient increase in LH and FSH secretion, followed by a decrease caused by the downregulation of gonadotroph receptors.
Recall Question Which of the following is correct about the physiologic function of aromatase? A. It is an enzyme that stimulates the conversion of testosterone into estradiol. B. It is a natural weak androgen. C. It controls and maintains the masculine characteristics. D. It is responsible for male erection. E. A deficiency of it causes Noonan syndrome. Answer: A
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Female Reproductive System
11
Learning Objectives ❏❏ Interpret scenarios on menstrual cycle ❏❏ Explain information related to female sex steroid metabolism and excretion ❏❏ Answer questions about menstrual irregularities ❏❏ Explain information related to pregnancy ❏❏ Solve problems concerning lactation
MENSTRUAL CYCLE The Phases The menstrual cycle (~28 days) can be divided into the following phases or events: • Follicular phase (first 2 weeks) is also called the proliferative or preovulatory phase. This phase is dominated by the peripheral effects of estrogen, which include the replacement of the endometrial cells lost during menses.
Note By convention, the first day of bleeding (menses) is called day 1 of the menstrual cycle.
• Ovulation (~day 14) is preceded by the LH surge, which induces
ovulation.
• Luteal phase (~2 weeks) is dominated by the elevated plasma levels of
progesterone, and along with lower levels of secreted estrogen, creates a secretory and quiescent endometrium that prepares the uterus for implantation.
• Menses. Withdrawal of the hormonal support of the endometrium at
this time causes necrosis and menstruation.
Follicular phase (~days 1–14) • During the follicular phase, FSH secretion is slightly elevated, causing
proliferation of granulosa cells and increased estrogen secretion within a cohort of follicles.
• One follicle has greater cellular growth and secretes more estradiol
(dominant follicle). Estradiol promotes growth and increased sensitivity to FSH; thus the follicle continues to develop. The remaining follicles, lacking sufficient FSH, synthesize only androgen and become atretic (die).
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Biochemistry
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Endocrinology
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
Microbiology
The graphs below illustrate the plasma hormonal levels throughout the menstrual cycle. The length of the menstrual cycle varies, but an average length is 28 days. Each plasma hormone concentration is plotted relative to the day on which its concentration is lowest, i.e., just prior to menses (day 28).
10X Plasma LH relative to level on day 28
Follicular phase
LH
Plasma FSH relative to level on day 28 3X
Luteal phase
FSH
1X
1X Progesterone
5X Plasma estradiol relative to level on day 28
Plasma progesterone relative to level on day 28
Estradiol
1X
1X
MENSES 1
40X
9 14 16 Day of the Menstrual Cycle
23
28
GnRH
LH
(–)
cAMP Cholesterol Protein kinase Pregnenolone Androgen Theca cell
(–)
FSH
cAMP
Inhibin B
Protein kinase
Estrogen
Aromatase Estrogen Granulosa cell
(+)
Figure VII-11-1. Follicular Phase Relationships (Approximately Days1 1–14) Figure X-11-1. Follicular Phase Relationships Approximately Days to 14
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Theca Cells: Under LH stimulation, which acts intracellularly via cAMP, cholesterol is transported into the mitochondria (StAR is activated). The pathway continues through intermediates to androgens. Little androgen is secreted into the blood; most of the androgen enters the adjacent granulosa cells. Granulosa Cells: Possess the follicle’s only FSH receptors. When coupled to FSH, these act via cAMP to increase the activity of aromatase; aromatase converts the androgens to estrogens (mainly estradiol). Estrogen: Some of the estrogen produced by the granulosa cells is released into the blood and inhibits the release of LH and FSH from the anterior pituitary. However, another fraction of the estrogen acts locally on granulosa cells, increasing their proliferation and sensitivity to FSH. • This local positive effect of estrogens causes a rising level of circulating estrogens during the follicular phase, but at the same time FSH is decreasing because of the inhibitory effect of estrogen on FSH release. • Granulosa cells also release inhibin B. • Inhibin B inhibits the secretion of FSH by the pituitary but their role in
the menstral cycle is poorly understood.
Peripheral effects of estrogen produced by the granulosa cells during the follicular phase include: • Circulating estrogens stimulate the female sex accessory organs and secondary sex characteristics. • Rising levels of estrogens cause the endometrial cells of the uterine
mucosal layers to increase their rate of mitotic division (proliferate).
• Circulating estrogens cause the cervical mucus to be thin and watery,
making the cervix easy for sperm to traverse.
Ovulation Ovulation takes place ~day 14. This is an approximation. Since ovulation is always 14 days before the end of the cycle, you can subtract 14 from the cycle length to find the day of ovulation. Cycle length - 14 = ovulation day
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10X Plasma LH relative to level Behavioral Science/Social Sciences on day 28
Follicular phase
Plasma FSH relative to level on day 28 3X
Luteal phase
FSH
1X
Microbiology
Ovulation LH
1X Progesterone
5X Plasma estradiol relative to level on day 28
Plasma progesterone relative to level on day 28
Estradiol
1X
1X
MENSES 1
40X
9 14 16 Day of the Menstrual Cycle
23
28
Ovulation occurs approximately day 14
Pituitary LH
(+)
FSH
(+)
High circulating estrogen
Androgen
Estrogen
LH surge
(+)
FSH surge
Induces ovulation
Figure VII-11-2. Pituitary-Ovarian Relationships at Ovulation Figure X-11-2. Pituitary-Ovarian Relationships at Ovulation
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Estrogen Levels Near the end of the follicular phase, there is a dramatic rise in circulating estrogen. When estrogens rise above a certain level, they no longer inhibit the release of LH and FSH. Instead, they stimulate the release of LH and FSH (negative feedback loop to positive feedback loop). This causes a surge in the release of LH and FSH. Only the LH surge is essential for the induction of ovulation and formation of the corpus luteum. Notice from the figure that the LH surge and ovulation occur after estrogen peaks. Therefore, if estrogens are still rising, ovulation has not occurred. Follicular rupture occurs 24–36 hours after the onset of the LH surge. During this time interval, LH removes the restraint upon meiosis, which has been arrested in prophase for years. The first meiotic division is completed, and the first polar body is extruded. Positive feedback loops are rare in the body. Ovulation with estrogen and parturition with oxytocin are examples of positive feedback loops.
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Luteal phase (~days 14–28)
Pathology
10X Plasma LH relative to level on day 28
Microbiology
LH
Follicular phase
Behavioral Science/Social Sciences
Plasma FSH relative to level on day 28 3X
Luteal phase
FSH
1X
1X Progesterone
5X Plasma estradiol relative to level on day 28
40X Plasma progesterone relative to level on day 28
Estradiol
1X
1X
MENSES 1
9 14 16 Day of the Menstrual Cycle
23
28
Luteinization of the preovulatory follicle
LH
(+)
FSH
Cholesterol
Inhibins
(+)
LH Cholesterol
Progesterone
(+) Aromatase
Progesterone
(+) Androgen
Androgen Theca cell
Granulosa cell Luteal cells
(+)
LH
(+)
(+)
Estrogen (+) LH surge
Considerable progesterone and some estrogen Figure VII-11-3. TheThe Luteal Phase Reactions Figure X-11-3. Luteal Phase Reactions
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Preovulatory Follicle In the latter stages of the follicular phase, intracellular changes within the granulosa and theca cells occur in preparation for their conversion into luteal cells. • Estradiol, in conjunction with FSH, causes the granulosa cells to produce LH receptors. • The metabolic pathways are then altered to favor the production of
progesterone.
• This would include a decrease in the activity of aromatase and a drop
in estrogen production.
LH Surge Induced by the elevated estrogens, it causes the granulosa cells and theca cells to be transformed into luteal cells and increases the secretion of progesterone.
Corpus Luteum The process of luteinization occurs following the exit of the oocyte from the follicle. The corpus luteum is made up of the remaining granulosa cells, thecal cells, and supportive tissue. Once formed, the luteal cells are stimulated by LH to secrete considerable progesterone and some estrogen. Progesterone inhibits LH secretion (negative feedback). The corpus luteum secretes inhibin A, which has negative feedback on FSH. The increased plasma level of progesterone has several actions: • It causes the uterine endometrium to become secretory, providing a source of nutrients for the blastocyst. • It causes the cervical mucus to become thick, sealing off the uterus
from further entry of sperm or bacteria.
• It has thermogenic properties, causing the basal body temperature to
increase by 0.5–1.0° F.
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Pharmacology
Biochemistry
Part VII Physiology
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Endocrinology Medical Genetics
Menses
Pathology
Microbiology
Behavioral Science/Social Sciences
10X Plasma LH relative to level on day 28
LH
Follicular phase
Plasma FSH relative to level on day 28 3X
Luteal phase
FSH
1X
1X Progesterone
5X
*
Plasma estradiol relative to level on day 28
Estradiol
1X
9 14 16 Day of the Menstrual Cycle
Plasma progesterone relative to level on day 28 1X
MENSES 1
40X
23
28
*The fall in sex steroids causes menses. Figure X-11-4. Onset of Menses
Figure VII-11-4. Onset of Menses
• The life of the corpus luteum is finite, hence the luteal phase is only 14 days. • Initially, the corpus luteum is very responsive to LH. Over time
however, as the corpus luteum becomes less functional, it becomes less responsive to LH.
• Progesterone exerts negative feedback on LH, which contributes to the
demise of the corpus luteum.
• With the demise of the corpus luteum, progesterone and estradiol fall
to levels that are unable to support the endometrial changes, and menses begins.
Menstruation is due to a lack of gonadal sex steroids.
FEMALE SEX STEROID METABOLISM AND EXCRETION Solubilization and Excretion The female sex steroids undergo oxidation or reduction in the liver (and other target tissues), and a glucuronide or sulfate group is attached to the steroidal metabolite. This “conjugation” increases the solubility of the steroids in water, and thus they are excreted in the urine. Estradiol can be excreted as a conjugate of estradiol, but most is first converted to estrone or estriol. Progesterone is converted in the liver to pregnanediol and is excreted as pregnanediol glucuronide.
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Chapter 11
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Female Reproductive System
Monitoring the Menstrual Cycle The amount of sex steroids excreted in the urine can be used to monitor the menstrual cycle. For example: • Low progesterone metabolites and low but slowly rising estrogen metabolites characterize the early follicular phase. • Low progesterone metabolites and rapidly rising estrogen metabolites
characterize the latter part of the follicular phase just before ovulation.
• Elevated levels of progesterone metabolites characterize the luteal phase
and pregnancy. In the early luteal phase, progesterone is rising, while in the latter half it is falling.
Estrogens and Androgen Formation • Estrogen: generic term for any estrus-producing hormone, natural or
synthetic
• 17 β-estradiol: major hormone secreted by the ovarian follicle • Estrone: some is secreted from the ovary but much is formed in
peripheral tissues such as adipose tissue from androgens. These androgens originate from both the ovary and the adrenal glands. This is the main circulating estrogen following menopause. Fat cells have aromatase. Adipose tissue creates modest levels of estrogen.
• Estriol: major estrogen synthesized from circulating androgens by the
placenta
• Potency: estradiol > estrone > estriol • Androgens: The follicles also secrete androgen; DHEA, androstenedione,
and testosterone. Additional testosterone production is from the peripheral conversion of adrenal and ovarian androgen. Some testosterone is also converted via 5 α-reductase to dihydrotestosterone in the skin.
New Cycle During the 3 days prior to and during menses, plasma levels of progesterone and estradiol are at their low point; negative feedback restraint for gonadotropin secretion is removed. FSH secretion rises slightly and initiates the next cycle of follicular growth. The length of the follicular phase of the menstrual cycle is more variable than the length of the luteal phase. Long cycles are usually due to a prolonged follicular phase and short cycles to a short follicular phase. Once ovulation has occurred, menses generally follows in about 14 days. The length of the m enstrual cycle in days minus 14 gives the most likely day of ovulation.
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Pharmacology
Biochemistry
Part VII Physiology
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Endocrinology Medical Genetics
Recall Question
Pathology
Behavioral Science/Social Sciences
Which of the following is the physiologic cause of menstruation? A. LH surge increasing the secretion of progesterone
Microbiology
B. Rising levels of estrogen causing endometrial cells of the uterine to proliferate C. Withdrawal of hormonal support of the endometrium D. LH removes the restraint on meiosis E. Increase in plasma levels of progesterone Answer: C
MENSTRUAL IRREGULARITIES Amenorrhea Amenorrhea is the lack of menstral bleeding. Though in itself it does not cause harm, it may be a sign of genetic, endocrine, or anatomic abnormalities. • In the absence of anatomic abnormalities (and pregnancy), it usually indicates a disruption of the hypothalamic–pituitary axis or an ovarian problem. • A hypothalamic–pituitary origin would include Kallman’s syndrome,
functional hypothalamic amenorrhea, amenorrhea in female athletes, eating disorders, hypothyroidism (possibly because high TRH stimulates prolactin), and pituitary tumors such as prolactinomas.
• Ovarian causes could be premature ovarian failure (premature meno-
pause), repetitive ovulation failure, or anovulation (intermittent bleeding), or a polycystic ovary.
Polycystic Ovarian Syndrome Polycystic ovarian syndrome is characterized by an elevated LH/FSH ratio. • Clinical signs include infertility, hirsutism, obesity, insulin resistance, and amenorrhea and oligomenorrhea. • The enlarged polycystic ovaries are known to be associated with
increased androgen levels (DHEA).
• It typically originates in obese girls. The high extraglandular estrogens
(mainly estrone) may selectively suppress FSH. Ovarian follicles have a suppressed aromatase activity and thus a diminished capacity to convert androgen into estrogen, but the adrenals may also contribute to the excess androgens as well.
• High androgens promote atresia in developing follicles and disrupt
feedback relationships. Look for high LH and DHEA levels.
• The overall result is anovulation-induced amenorrhea with an
estrogen-induced endometrial hyperplasia and breakthrough bleeding.
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Female Reproductive System
• Although poorly understood the hyperinsulinemia is believed to be a
key etiologic factor.
• Treat insulin insensitivity with metformin, which can also help restore
menstrual cycles.
• Treat androgenization with spironolactone.
Hirsutism Hirsutism is an excessive, generally male, pattern of hair growth. It is often associated with conditions of androgen excess, e.g., congenital adrenal hyperplasia and polycystic ovarian syndrome. • Virilization refers to accompanying additional alterations, such as deepening of the voice, clitoromegaly, increased muscle bulk, and breast atrophy. • Axillary and pubic hair are sensitive to low levels of androgen. • Hair on the upper chest, face (scalp region not involved), and back
requires more androgen and represents the pattern seen in males.
• Circulating androgens involved are testosterone, DHEA, DHEAS, and
androstenedione in response to LH and ACTH.
• Measurements of DHEAS as well as a dexamethasone suppression test
helps in separating an adrenal from an ovarian source.
• Polycystic ovarian syndrome is the most common cause of ovarian
androgen excess.
PREGNANCY Ovum Pickup and Fertilization In women, the ovum is released from the rupturing follicle into the abdominal cavity, where it is “picked up” by the fimbria of the oviduct. Failure of ovum pickup may result in ectopic pregnancy, i.e., the implantation of the blastocyst at any site other than the interior of the uterus. Fertilization occurs in the upper end of the oviduct within 8–25 hours after ovulation. After this, the ovum loses its ability to be fertilized. Sperm retain their capacity to fertilize an ovum for as long as 72 hours after ejaculation. For about 48 hours around the time of ovulation the cervical mucus is copious and slightly alkaline. This environment represent a good conduit for the sperm. Weeks of gestation (gestational age) to estimate the delivery date are commonly taken from the first day of the last menstrual period. Sperm are transported from the vagina to the upper ends of the oviduct by contraction of the female reproductive tract. The swimming motions of the sperm are important for penetration of the granulosa cell layer (cumulus oophorus) and membranes surrounding the ovum. Low sperm counts ( CHO > protein > fat (> = faster than) Pathology
Behavioral Science/Social Sciences
• The pyloris of the stomach acts as a sphincter to control the rate of
stomach emptying. A wave of contraction closes the sphincter so that only a small volume is moved forward into the duodenum. CCK, GIP, and secretin increase the degree of pyloric constriction and slow stomach emptying.
Microbiology
Small Intestinal Motility Rhythmic contractions in adjacent sections create segmentation contractions, which are mixing movements. Waves of contractions preceded by a relaxation of the muscle (peristaltic movements) are propulsive. • Ileocecal sphincter, or valve between the small and large intestine, is
normally closed
• Distension of ileum creates a muscular wave that relaxes the sphincter • Distension of colon creates a nervous reflex to constrict the sphincter
Colon Motility Segmentation contractions create bulges (haustrations) along the colon. Mass movements, which are propulsive, are more prolonged than the peristaltic movements of the small intestine.
Migrating Motor Complex Migrating motor complex (MMC) is a propulsive movement initiated during fasting. It begins in the stomach and moves undigested material from the stomach and small intestine into the colon. During fasting, MMC repeats every 90–120 minutes. When one movement reaches the distal ileum, a new one starts in the stomach. • Correlated with high circulating levels of motilin, a hormone of the
small intestine
• Removes undigested material from the stomach and small intestine,
and helps reduce bacterial migration from colon into the small intestine
Defecation Defecation is a reflex involving the central nervous system. A mass movement in the terminal colon fills the rectum, causing a reflex relaxation of the internal anal sphincter and a reflex contraction of the external anal sphincter. • Voluntary relaxation of the external sphincter accompanied with
propulsive contraction of the distal colon complete defecation.
• Lack of a functional innervation of the external sphincter causes
involuntary defecation when the rectum fills.
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Secretions
2
Learning Objectives ❏❏ Demonstrate understanding of salivary, gastric, and pancreatic secretions ❏❏ Demonstrate understanding of the composition and formation of bile
SECRETIONS Salivary Secretions Parotid gland secretions are entirely serous (lack mucin). Submandibular and sublingual gland secretions are mixed mucus and serous. They are almost entirely under the control of the parasympathetic system, which promotes secretion. The initial fluid formation in the acinus is via an indirect chloride pump (secondary active transport powered by the Na/K ATPase pump), and the electrolyte composition is isotonic and similar to interstitial fluid. Duct cells modify the initial acinar secretion.
Parasympathetic Sympathetic Cl pump Na+ Cl– K+
HCO3–
FigureSalivary VIII-2-1.Secretion Salivary Secretion Figure XI-1-4.
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Part VIII Physiology
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Gastrointestinal Physiology Medical Genetics
Composition of salivary secretions • Low in Na+, Cl– because of reabsorption Pathology
Behavioral Science/Social Sciences
• High in K+, HCO3 because of secretion (pH = 8) • Low tonicity: Salivary fluid is hypotonic because of reabsorption
of NaCl and impermeability of ducts to water.
• α-amylase (ptyalin): secreted in the active form and begins the Microbiology
digestion of carbohydrates
• Mucus, glycoprotein • Immunoglobulins and lysozymes
Gastric Secretions The epithelial cells that cover the gastric mucosa secrete a highly viscous a lkaline fluid (mucin plus bicarbonate) that protects the stomach lining from the caustic action of HCl. • Fluid needs both mucin and bicarbonate to be protective. • Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin
decrease the secretion of the mucin and bicarbonate.
• Surface of the mucosa studded with the openings of the gastric glands • Except for the upper cardiac region and lower pyloric region whose
glands secrete mainly a mucoid fluid, gastric glands secrete a fluid whose pH can be initially as low as 1.0.
Secretions of the main cells composing the oxyntic gastric glands Parietal cells • HCl • Intrinsic factor combines with vitamin B12 and is reabsorbed in the
distal ileum. This is the only substance secreted by the stomach that is required for survival. It is released by the same stimuli that release HCl.
Chief Cells Pepsinogen is converted to pepsin by H+, as illustrated in the diagram below. Pepsinogen
H+
pepsin (proteins to peptides)
• Pepsinogen is initially converted to active pepsin by acid. • Active pepsin continues the process. • Pepsin is active only in the acid pH medium of the stomach. • Pepsin begins the digestion of protein but is not essential for life.
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Chapter 2
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Secretions
Mucous Neck Cells Mucous neck cells secrete the protective mucus, HCO3 combination.
H+ Stomach
Distension (+) G GRP
+ ACh + Histamine + Gastrin
Parietal cell
+ Stimulates secretion – Inhibits secretion
+ Parasympathetic (+)
VIII-2-2. Control of Gastric Secretion FigureFigure XI-1-5. Control of Gastric AcidAcid Secretion
Control of acid secretion There are 3 natural substances that stimulate parietal cells (figure above): • Acetylcholine (ACh), acting as a transmitter; release is stimulated by
sight/smell of food and reflexly in response to stomach distension (vagovagal reflex).
• Locally released histamine; stimulated by Ach and gastrin • The hormone gastrin; stimulated by release of GRP
As stomach pH falls, somatostatin (SST) is released, which inhibits gastrin and reduces acid secretion (feedback regulation of acid secretion). Cellular mechanisms of acid secretion (figure below) • Within the cell, carbonic anhydrase facilitates the conversion of CO2 into H+ and HCO3–. • The demand for CO2 can be so great following a meal that the parietial
cells extract CO2 from the arterial blood. This makes gastric venous blood the most basic in the body.
• Hydrogen ions are secreted by a H/K-ATPase pump similar to that in
the distal nephron.
• The pumping of H+ raises intracellular HCO3– and its gradient across
the basal membrane and provides the net force for pumping Cl– into the cell.
• The chloride diffuses through channels across the apical membrane,
creating a negative potential in the stomach lumen.
• Because of the extraction of CO2 and secretion of HCO3– , the venous
blood leaving the stomach following a meal is alkaline.
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Part VIII Physiology
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Gastrointestinal Physiology Medical Genetics
• Compared with extracellular fluid, gastric secretions are high in H+,
K+, Cl–, but low in Na+.
• The greater the secretion rate, the higher the H+ and the lower the Na+. Pathology
Behavioral Science/Social Sciences
• Vomiting stomach contents produces a metabolic alkalosis and a loss of
body potassium (alkalosis contributes to loss of potassium via effects on the kidney).
Microbiology
Arterial blood
H2O + CO2
CO2
Carbonic Anhydrase HCO3–
HCO3– Venous blood alkaline tide
Stomach
H+
Cl–
H/K ATPase
H+
K+ K+ Cl–
Vital enzymes
H/K-ATPase Carbonic anhydrase
Figure XI-1-6.Regulation Regulation of Figure VIII-2-3. ofParietal ParietalCell CellSecretion Secretion
Pancreatic Secretions Exocrine tissue is organized into acini and ducts very similar to that of the salivary glands. • Cholinergic nerves to the pancreas stimulate the secretion of both the
enzyme and aqueous component.
• Food in the stomach stimulates stretch receptors and, via vagovagal
reflexes, stimulates a small secretory volume.
• Sympathetics inhibit secretion but are a minor influence. • Most of the control is via secretin and CCK.
Enzymatic components • Trypsin inhibitor, a protein present in pancreatic secretions, prevents
activation of the proteases within the pancreas.
• In addition to the following groups of enzymes, pancreatic fluid
contains ribonucleases and deoxyribonucleases.
• A diet high in one type of food (protein, CHO, fat) results in the
preferential production of enzymes for that particular food.
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Secretions
Pancreatic amylases are secreted as active enzymes: • Hydrolyze a-1,4-glucoside linkage of complex carbohydrates, forming
three smaller compounds:
–– α-Limit dextrins: still a branched polysaccharide –– Maltotriose, a trisaccharide –– Maltose, a disaccharide • Cannot hydrolyze β linkages of cellulose
Pancreatic lipases are mainly secreted as active enzymes. Glycerol ester lipase (pancreatic lipase) needs colipase to be effective. Colipase displaces bile salt from the surface of micelles. This allows pancreatic lipase to attach to the droplet and digest it, leading to formation of 2 free fatty acids and one monoglyceride (a 2-monoglyceride, i.e., an ester on carbon 2). Cholesterol esterase (sterol lipase) hydrolyzes cholesterol esters to yield cholesterol and fatty acids. Pancreatic proteases are secreted as inactive zymogens. They include trypsinogen, chymotrypsinogen, and procarboxypeptidase. Activation sequence. The activation sequences are summarized below. trypsinogen
enterokinase*
chymotrypsinogen
procarboxypeptidase
trypsin (endopeptidase)
trypsin
trypsin
chymotrypsin (endopeptidase) carboxypeptidase (exopeptidase)
*Enterokinase (also known as enteropeptidase) is an enzyme secreted by the lining of the small intestine. It is not a brush border enzyme. It functions to activate some trypsinogen, and the active trypsin generated activates the remaining proteases.
Fluid and electrolyte components • Aqueous component is secreted by epithelial cells lining the ducts. • Fluid is isotonic due to the high permeability of the ducts to water and
the concentrations of Na and K are the same as plasma.
• Duct cells secrete chloride into the lumen via the cystic fibrosis
transmembrane conductance regulator (CFTR). This chloride is then removed from the lumen in exchange for bicarbonate. Thus, bicarbonate secretion is dependent upon chloride secretion.
• CFTR is activated by cAMP (see below). • In cystic fibrosis there is a mutation in the gene that encodes this
CFTR channel, resulting in less chloride and a reduced fluid component of pancreatic secretions. The smaller volume of highly viscous fluid may also contain few enzymes.
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Pharmacology
Biochemistry
Part VIII
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Gastrointestinal Physiology
Physiology
Medical Genetics
Pathology
Behavioral Science/Social Sciences
CCK (duodenal fat, aa) + Parasympathetic Initial secretion high in HCO3
Microbiology
Secretin (duodenal acid)
Enzymes HCO3– and fluid Figure VIII-2-4. Control of the Exocrine Pancreas Figure XI-1-7. Control of the Exocrine Pancreas
Control of pancreatic secretions Most of the regulation is via 2 hormones: secretin and cholecystokinin. Secretin is released from the duodenum in response to acid entering from the stomach. • Action on the pancreas is the release of fluid high in HCO3–. Secretin
is a peptide hormone that stimulates chloride entry into the lumen from duct cells. Secretin activates Gs–cAMP, which in turn activates CFTR in ductal cells.
• This released HCO3–-rich fluid is the main mechanism that neutralizes
stomach acid entering the duodenum.
Cholecystokinin (CCK) is released from the duodenum in response to partially digested materials (e.g., fat, peptide, and amino acids). • Action on the pancreas is the release of enzymes (amylases, lipases,
proteases).
Recall Question Which of the following is a characteristic of GERD? A. Failure of lower esophageal sphincter to relax B. Odynophagia C. Failure of lower esophageal sphincter to maintain its tone D. Spasms of esophageal muscle E. Presents with chest pain Answer: C 398
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Secretions
COMPOSITION AND FORMATION OF BILE
LIVER Micelles
form
Glycine taurine Primary bile salts
Conjugation
Liver fats e.g., cholesterol phospholipid Conjugated bilirubin (aqueous soluble)
Enterohepatic circulation
1. Cholic acid 2. Chenodeoxycholic acid cholesterol
Glucuronic acid Conjugation
Secretin HCO3– and fluid
Primary bile acid production
1. Micelles
Bilirubin (lipid soluble) Blood prot. O– Bilirubin
Fatsoluble material
2. Bile pigments conjugated bilirubin
Contraction stimulated by CCK
GALL BLADDER
3. Salts and H2O
CCK relaxes
Na+ — active transport K+, Cl–, H2O — follow Na+
(95%)
Active transport of 1° or 2° bile salts
Micelles for digestion and absorption lipid Duodenum
1° bile salts
2° bile salts
Bile pigments
To feces
Distal ileum
FigureXI-1-8. VIII-2-5. Productionand andMetabolism Metabolismof ofBile Bile Figure Production
Bile salts and micelles Primary bile acids known as cholic acid and chenodeoxycholic acid are synthesized by the liver from cholesterol. • The lipid-soluble bile acids are then conjugated primarily with glycine. • The conjugated forms are water-soluble but contain a lipid-soluble
segment.
• Because they are ionized at neutral pH, conjugated bile acids exist as
salts of cations (Na+) and are, therefore, called bile salts.
• Bile salts are actively secreted by the liver.
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Gastrointestinal Physiology Medical Genetics
• Secondary bile acids are formed by deconjugation and dehydroxylation
of the primary bile salts by intestinal bacteria, forming deoxycholic acid (from cholic acid) and lithocholic acid (from chenodeoxycholic acid).
Pathology
Behavioral Science/Social Sciences
• Lithocholic acid has hepatotoxic activity and is excreted. • When bile salts become concentrated, they form micelles. These are
water-soluble spheres with a lipid-soluble interior.
Microbiology
• As such, they provide a vehicle to transport lipid-soluble materials in
the aqueous medium of the bile fluid and the small intestine.
• Micelles are vital in the digestion, transport, and absorption of lipid-
soluble substances from the duodenum to the distal ileum.
• In the distal ileum, and only in the distal ileum, can the bile salts be
actively reabsorbed and recycled (enterohepatic circulation).
• Lack of active reabsorbing mechanisms (or a distal ileal resection)
causes loss in the stool and a general deficiency in bile salts, as the liver has a limited capacity to manufacture them. In turn, this can lead to fat malabsorption.
Bridge to Pathology
Bile pigments
Increased levels of plasma bilirubin produce jaundice. If severe, bilirubin can accumulate in the brain, producing profound neurological disturbances (kernicterus).
A major bile pigment, bilirubin is a lipid-soluble metabolite of hemoglobin. Transported to the liver attached to protein, it is then conjugated and excreted as water-soluble glucuronides. These give a golden yellow color to bile. Stercobilin is produced from metabolism of bilirubin by intestinal bacteria. It gives a brown color to the stool.
Salts and water The HCO3– component is increased by the action of secretin on the liver. The active pumping of sodium in the gallbladder causes electrolyte and water reabsorption, which concentrates the bile. Bile pigments and bile salts are not reabsorbed from the gallbladder.
Phospholipids (mainly lecithin) Insoluble in water but are solubilized by bile salt micelles
Cholesterol Present in small amounts. It is insoluble in water and must be solubilized by bile salt micelles before it can be secreted in the bile.
Control of bile secretion and gallbladder contraction • Secretin causes secretion of HCO3– and fluid into bile canalicular
ducts.
• Secretion of bile salts by hepatocytes is directly proportional to hepatic
portal vein concentration of bile salts.
• CCK causes gallbladder contraction and sphincter of Oddi relaxation.
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Secretions
Enterohepatic circulation • The distal ileum has high-affinity uptake of bile acids/salt (symport
with Na+).
• These bile acids/salts enter the portal vein and travel to the liver, which
in turn secretes them into the cystic duct, from which they re-enter the duodenum.
• This recycling occurs many times during the digestion of a meal and
plays a significant role in fat digestion.
• The synthesis of bile acids by the liver is directly related to the concen-
tration of bile acids in the portal vein.
Small Intestinal Secretions The most prominent feature of the small intestine is the villi. • Surface epithelial cells display microvilli. • Water and electrolyte reabsorption greatest at the villus tip. • Water and electrolyte secretion greatest at the bottom in the crypts of
Lieberkuhn.
Na+
Na+ 3Na+ Lumen
Cl–
2K+
Cl–
ISF
Na+ K+ 2Cl–
K+
Luminal membrane
Basolateral membrane
Figure VIII-2-6. Secretion of Electrolytes by a Crypt Cell of the Small Intestine Figure XI-1-9. Secretion of Electrolytes by a Crypt Cell of the Small Intestine
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Biochemistry
Part VIII Physiology
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Gastrointestinal Physiology Medical Genetics
Bridge to Pathology Cholera toxin binds and activates Gs, resulting in very high levels of Pathologyintracellular cAMP. This Behavioral Science/Social Sciences rise in cAMP opens luminal Cl− channels, causing a massive secretory diarrhea. Microbiology
Crypt secretion • A Na+-K+-2Cl– transporter in the basolateral membrane facilitates the
ion uptake by secondary active transport.
• Na+ entry drives the entry of K+ and Cl– into the cell. • The elevated intracellular Cl and negative intracellular potential drives
the diffusion of chloride through channels on the apical membrane.
• Luminal Cl then pulls water, Na, and other ions into the lumen,
creating the isotonic secretion. This is the general scheme of the chloride pump.
• Neurotransmitter secretagogues include VIP and ACh. • The Cl– channels are opened by increases in cytosolic Ca2+ and/or
cAMP. The cAMP-dependent Ca2+ channels are CFTR channels.
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Digestion and Absorption
3
Learning Objectives ❏❏ Demonstrate understanding of digestion ❏❏ Answer questions about digestive enzymes and end products ❏❏ Demonstrate understanding of absorption
DIGESTION The figure below summarizes the regional entry of the major digestive enzymes proceeding from the mouth, stomach, and through the small intestine.
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Biochemistry
Part VIII Physiology
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Gastrointestinal Physiology Medical Genetics
CHO
Triglyceride
Pathology
Behavioral Science/Social Sciences
Protein
α-Amylase
Mouth
Microbiology
*Lipase Colipase
*α-Amylase
Pepsin
Stomach
*Trypsin, etc.
Pancreas
*Bile micelles
Gallbladder
*Sucrase *Lactase (lactoseintolerant)
2'-Monoglycerides Fatty acids
Glucose, Galactose, Fructose
*Peptidases
Small intestine (brush border)
Amino acids (40%) Di-, Tripeptides (60%) *Required for digestion
Figure VIII-3-1. Digestive Processes Figure XI-1-10. Summary of Digestive Processes
Digestive Enzymes and End Products Triglycerides Stomach: Fatty materials are pulverized to decrease particle size and increase surface area. Although not essential for fat digestion, the stomach does secrete lipase. Small intestine: Bile micelles emulsify the fat, and pancreatic lipases digest it. Micelles and pancreatic lipase are required for triglyceride digestion. The major end products are 2-monoglycerides and fatty acids.
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Digestion and Absorption
Carbohydrates Mouth: Salivary α-amylase begins the digestion, and its activity continues in the stomach until acid penetrates the bolus. However, it is not a required enzyme. Small intestine: Pancreatic α-amylase, a required enzyme for CHO digestion, continues the process. α-amylase hydrolyzes interior bonds to produce oligosaccharides (limited dextrins) and disaccharides. Brush border enzymes (sucrase-isomaltase; maltase; lactase; trehalase) convert limited dextrans and disaccharides into monosaccharides. These monosaccharides are then absorbed (late duodenum and early jejunum) via the mechanisms shown in the figure below.
Proteins Stomach: Pepsin begins the digestion of protein in the acid medium of the stomach, but this is not an essential enzyme. Small intestine: Digestion continues with the pancreatic proteases (trypsin, chymotrypsin, elastase, and carboxypeptidases A and B), which are essential enzymes. Protein digestion is completed by the small intestinal brush border enzymes, dipeptidases, and an aminopeptidase. The main end products are amino acids (40%) and dipeptides and tripeptides (60%). Pancreatic enzymes are required for triglyceride, CHO, and protein digestion. Circulating CCK is almost totally responsible for their secretion following a meal.
ABSORPTION Carbohydrate and Protein The figure below illustrates the major transport processes carrying sugars and amino acids across the luminal and basal membranes of cells lining the small intestine. Small intestine
ISF
Galactose
Na
Glucose
Glucose Galactose Fructose H+ Di-, Tripeptides Na aa Na aa
Fructose ATPase
Na H+ Peptides Amino acids
Na
K Amino acids Amino acids
Figure of of Carbohydrates andand Proteins FigureVIII-3-2. XI-1-11.Absorption Absorption Carbohydrates Proteins
Bridge to Pathology Celiac disease is an immune reaction to gluten (protein found in wheat) that damages intestinal cells; the end result is diminished absorptive capacity of the small intestine.
Bridge to Pathology Many of the amino acid transporters are selective for specific amino acids. Hartnup’s disease is a genetic deficiency in the transporter for tryptophan.
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Biochemistry
Part VIII Physiology
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Gastrointestinal Physiology Medical Genetics
Carbohydrate • Luminal membrane: Glucose and galactose are actively absorbed Pathology
Behavioral Science/Social Sciences
(secondary active transport linked to sodium) via the sodium-glucose linked transporter 1 (SGLT-1). Fructose is absorbed independently by facilitated diffusion.
• Basal membrane: The monosaccharides are extruded from the cell via
facilitated diffusion.
Microbiology
Protein • Luminal membrane: amino acids are transported by secondary active
transport linked to sodium. Small peptides uptake powered by a Na-H antiporter.
• Basal membrane: simple diffusion of amino acids, although it is now
known some protein-mediated transport also occurs.
Lipids The figure below summarizes the digestion and absorption of lipid substances. The end products of triglyceride digestion, 2-monoglycerides and fatty acids, remain as lipid-soluble substances that are then taken up by the micelles. Digestive products of fats found in the micelles and absorbed from the intestinal lumen may include: • Fatty acids (long chain) • 2-monoglyceride • Cholesterol • Lysolecithin • Vitamins A, D, E, K • Bile salts, which stabilize the micelles
Bridge to Biochemistry Chylomicrons contain apolipoprotein B-48. Once in the systemic circulation, chylomicrons are converted to VLDL (very low-density lipoprotein) and they incorporate apoproteins C-II and E from HDL (high-density liproprotein).
Micelles diffuse to the brush border of the intestine, and the water-soluble exterior allows them to carry fat soluble products into the cell. In the mucosal cell, triglyceride is resynthesized and forms lipid droplets (chylomicrons). These leave the intestine via the lymphatic circulation (lacteals). They then enter the bloodstream via the thoracic duct. The more water-soluble short-chain fatty acids can be absorbed by simple diffusion directly into the bloodstream. The bile salts are actively reabsorbed in the distal ileum.
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Chapter 3
●
Digestion and Absorption
Small intestine Tri G Bile micelles (emulsify) Pancreatic lipase
2-Monoglycerides Fatty acids (long chain)
Mucosal cell
2-Monogly, fatty acids Phospholipids Cholesterol Lysolecithin Fat-soluble vitamins Vit. A, D, E, K
Diffusion 2 Monogly, Long-chain fatty acids
Shortchain fatty acids
Bile
salts
Tri G
Lymph (lacteal) Chylomicrons Blood
Active
Transport
Blood
Distal ileum Figure Figure XI-1-12. VIII-3-3. Absorption AbsorptionofofLipids Lipids
Electrolytes The net transport of electrolytes along the length of the small and large intestine is summarized in the figure below.
Duodenum • Hypertonic fluid enters this region, and following the movement of
some water into the lumen, the fluid becomes and remains isotonic (see crypt secretion above).
• The absorption of most divalent ions and water-soluble vitamins begins
here and continues through the small intestine.
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Biochemistry
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Pathology
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Gastrointestinal Physiology Medical Genetics
Behavioral Science/Social Sciences
• Ingested iron and calcium tend to form insoluble salts. The acid
environment of the stomach redissolves these salts, which facilitates their absorption in the small intestine. Iron and calcium absorption is diminished in individuals with a deficient stomach acid secretion.
• Calcium absorption is enhanced by the presence of calbindin in
intestinal cells, and calcitriol (active vitamin D) induces the synthesis of this protein.
Microbiology
• Intestinal cells express the protein ferritin, which facilitates iron
absorption.
Jejunum • Overall, there is a net reabsorption of water and electrolytes. • The cellular processes involved are almost identical to those
described in the renal physiology section for the cells lining the nephron proximal tubule.
Ileum • Net reabsorption of water, sodium, chloride, and potassium continues,
but there begins a net secretion of bicarbonate.
• It is in the distal ileum, and only in the distal ileum, where the reab-
sorption of bile salts and intrinsic factor with vitamin B12 takes place.
Colon • The colon does not have digestive enzymes or the protein transporters
to absorb the products of carbohydrate and protein digestion.
• Also, because bile salts are reabsorbed in the distal ileum, very few
lipid-soluble substances are absorbed in the colon.
• There is a net reabsorption of water and sodium chloride, but there are
limitations.
• Most of the water and electrolytes must be reabsorbed in the small
intestine, or the colon becomes overwhelmed.
• Most of the water and electrolytes are absorbed in the ascending and
transverse colon; thereafter, the colon has mainly a storage function.
• The colon is a target for aldosterone, where it increases sodium and
water reabsorption and potassium secretion.
• Because there is a net secretion of bicarbonate and potassium, diarrhea
usually produces a metabolic acidosis and hypokalemia. It commonly presents as hyperchloremic, nonanion gap metabolic acidosis, as described in the acid-base section.
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Chapter 3
Intestinal lumen
●
Digestion and Absorption
Interstitial fluid Duodenum
H 2O
isotonic
(Na, H2O, etc.) Ca2+, Fe2+ (upper small intestine) Jejunum Na+, Cl–
K+, H2O
Similar to proximal tubular cell of kidney
HCO3– Ileum Na+, Cl–
–
HCO3
K+, H2O
Cl– Bile salts Intrinsic factor - vit. B12 Colon
Smallest absorption here
HCO3–
Na+,Cl– H2O Cl–
K+
Figure VIII-3-4. Transport Electrolytes Figure XI-1-13. Transport of of Electrolytes
Diarrhea Except for the infant where it can be hypotonic, diarrhea is a loss of isotonic fluid that is high in bicarbonate and potassium.
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Index
A A–a (alveolar–arterial) gradient, 180 A band, 55, 56 ABGs (arterial blood gases) acid-base disturbances, 235–236, 242–243 normal values, 237 Absolute refractory period, 31, 64 Absorption, 405–409 carbohydrate and protein, 405–406 diarrhea, 409 electrolytes, 407–409 forces, 12 lipids, 406–407 microcirculation, 11 Acclimatization, 172 ACE (angiotensin-converting enzyme), 279 ACE (angiotensin-converting enzyme) inhibitors, 202 Acetylcholine (ACh), 32 Acetylcholinesterase (AChE), 33 Achalasia, 391 Acid-base disturbances, 230 arterial blood gases, 235–236, 242–243 bicarbonate, 237, 240 cause, 246–248 compensation, 236, 238–239, 241–242, 245 formulation of diagnosis, 235–236, 240–243 graphical representation, 244–246 metabolic acidosis bicarbonate, 237, 240 cause, 246–247 compensation, 238, 241 defined, 236 diagnosis, 240 graphical representation, 244–245 mixed respiratory and, 241, 243 plasma anion gap, 240 with respiratory alkalosis, 241 metabolic alkalosis, 237, 240 bicarbonate, 237, 240 cause, 247 compensation, 238, 242 defined, 236 diagnosis, 240 graphical representation, 244–245 mixed respiratory and, 242 with respiratory acidosis, 242 plasma anion gap, 239–240 respiratory acidosis bicarbonate, 237, 240
cause, 246 compensation, 238, 241 defined, 236 diagnosis, 240, 243 graphical representation, 244 metabolic acidosis with, 242 mixed metabolic and, 241, 243 respiratory alkalosis bicarbonate, 237, 240 cause, 247 compensation, 238, 241 defined, 236 diagnosis, 240, 243 graphical representation, 244 metabolic acidosis with, 241 mixed metabolic and, 242 types, 236–238 Acid-base regulation, 235–248 buffering systems, 235 Acidosis, 230 diagnosis, 236 metabolic bicarbonate, 237, 240 cause, 246–247 compensation, 238, 241 defined, 236 diagnosis, 240 graphical representation, 244–245 mixed respiratory and, 241, 243 plasma anion gap, 240 with respiratory alkalosis, 241 renal tubular, 228–229 respiratory bicarbonate, 237, 240 cause, 246 compensation, 238, 241 defined, 236 diagnosis, 240, 243 graphical representation, 244 metabolic acidosis with, 242 mixed metabolic and, 241, 243 Acid secretion, control, 395–396 ACMV (assisted control mode ventilation), 142 Acromegaly, 354 ACTH. See Adrenocorticotropic hormone (ACTH) Actin skeletal muscle, 57, 58 smooth muscle, 64 Action potential cardiac, 38–42 nodal cells, 41–42
non-nodal cells, 38–40 vs. skeletal muscle, 63–64 cell types, 27 changes in conductance, 31 conduction velocity, 32 defined, 27 neuronal, 27–32 properties, 31–32 refractory periods, 31 sarcolemma, 59–60 skeletal muscle, 59–60 mechanical response to single, 60–61 summation and recruitment, 61–62 subthreshold stimulus, 29 threshold stimulus, 29, 30 voltage-gated ion channels, 28–29 Activation gate (m-gate), 28 Active tension curve, 68, 69 Active transport, 203 Acute renal failure, 231–232 Addison’s disease, 283–284 Adenomas pituitary, 260, 282 toxic thyroid, 341 ADH. See Antidiuretic hormone (ADH) Adiponectin, 315 Adrenal androgens, 361 synthesis, 272, 273, 274 Adrenal cortex, 269–295 ACTH control of secretion, 276–277 ectopic, 283, 285 hypercortisolism, 282–283, 285 hypocortisolism, 283–285 aldosterone absence of, 270 control of secretion, 278–281 deficiency, 284 excess, 285–286 physiologic actions, 277–278 renin-angiotensin-aldosterone system, 279–281 specific actions, 278 synthesis pathway, 273 cortisol absence, 270 control of secretion, 276–277 deficiency, 283, 287–295 metabolic actions, 275 metabolism, 271 permissive actions, 275 stress, 274 synthesis, 273, 274
411 411
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Pharmacology
Biochemistry
Physiology Physiology
Medical Genetics
enzyme deficiencies, 287–295 functional regions, 269–270 loss of function, 270 glucocorticoids disorders, 281–285 Pathology Behavioral Science/Social Sciences physiologic actions, 274–275 mineralocorticoids disorders, 285–287 principal cells, 227 steroid hormones Microbiology regional synthesis, 272–274 synthetic pathways, 270–272 Adrenal hyperplasia, congenital, 287–295 consequences, 294–295 11β-hydroxylase deficiency, 290–291, 294 17α-hydroxylase deficiency, 292–293, 294, 295 21β-hydroxylase deficiency, 287–289, 294 Adrenal insufficiency primary, 283–284 secondary, 284 Adrenal medulla, 269, 297–299 Adrenocorticotropic hormone (ACTH) control of secretion, 276–277 ectopic, 283, 285 hypercortisolism, 282–283, 285 hypocortisolism, 283–285 Adrenocorticotropic hormone (ACTH) stimulation test, rapid, 284 Adulthood, male reproductive system, 362 Adult respiratory distress syndrome (ARDS), 147 Afterload, 67 cardiac output, 99 pumping action, 112 systolic performance of ventricle, 86 Age-related hormonal changes, males, 361–363 Aging adult, male reproductive system, 362 Airway radius, 148 Airway resistance, 148–149 Alcohol, effect on ADH secretion, 263 Aldosterone, 10 absence, 270 control of secretion, 278–281 deficiency, 284 excess, 285–286 physiologic actions, 277–278 renin-angiotensin-aldosterone system, 279–281 specific actions, 278 synthesis pathway, 273 Alkalosis, 230 “contraction,” 222 diagnosis, 236 metabolic, 222 bicarbonate, 237, 240 cause, 247 compensation, 238, 242
defined, 236 diagnosis, 240 graphical representation, 244–245 mixed respiratory and, 242 with respiratory acidosis, 242 respiratory bicarbonate, 237, 240 cause, 247 compensation, 238, 241 defined, 236 diagnosis, 240, 243 graphical representation, 244–245 metabolic acidosis with, 241 mixed metabolic and, 242 Alpha cells, 302 Altitude hypoxemia, 181 respiratory stress, 172–173 Alveolar air equation, 159–160 Alveolar–arterial (A–a) gradient, 180 Alveolar–blood gas transfer, 160–161 Alveolar dead space, 136 ventilation-perfusion mismatch, 178 Alveolar membrane, gas partial pressure difference, 161 Alveolar oxygen uptake, 108 Alveolar PCO2, factors affecting, 158–159 Alveolar PO2, factors affecting, 159–160 Alveolar pressure, 139, 140, 141 Alveolar pressure of carbon dioxide. See PaCO2 (alveolar pressure of carbon dioxide) Alveolar ventilation, 136–137 and alveolar PCO2, 158–159 neural regulation, 170–172 Ambient air, partial pressure of gas, 157 Amenorrhea, 376 Amino acids, absorption, 406 α-Amylase, 404, 405 Anabolic hormones, 304 Anatomic dead space, 134–136 Androgens, 361 adrenal, 361 synthesis, 272, 273, 274 estrogens and formation of, 375 menstrual cycle, 370 Androstenedione, 272 Anemia, 166–167, 168, 171 Aneurysm aortic, 81–82 arterial, 81–82 dissecting, 82 Angiotensin, renin-angiotensinaldosterone system, 279–281 Angiotensin-converting enzyme (ACE), 279 Angiotensin-converting enzyme (ACE) inhibitors, 202 Angiotensin I (Ang I), 279, 280 Angiotensin II (Ang II) cardiovascular regulation, 96 glomerular filtration, 201–202 renin-angiotensin-aldosterone system, 279, 280
Angiotensin II (Ang II) receptor blockers (ARBs), 202 Angiotensinogen, 279, 280 Anion gap, plasma, 239–240 ANP (atrial natriuretic peptide), 264 Anterior pituitary disorders, 259–260 effect of hypothalamic hormones, 259 pregnancy, 381 structure and function, 257–259 Antiarrhythmic agents class I, 40 class II, 42 class III, 40 class IV, 42 Antidiuretic hormone (ADH), 261–263 action, 263 aquaporins, 227 cardiovascular regulation, 96 effects of alcohol and weightlessness, 263 fluid distribution, 10 functions, 261 hyponatremia, 266–267 natriuretic peptide and, 264 regulation of ECF volume and osmolarity, 263–264 secretion pathophysiologic changes, 264–266 regulation, 261–262 syndrome of inappropriate, 265–266 synthesis and release, 263 Antiport, 204 Aorta, 76 fetal circulation, 115, 116 Aortic aneurysm, 81–82 Aortic auscultation point, 121 Aortic bodies, 171 Aortic insufficiency regurgitation, 125, 127 Aortic stenosis, 125, 126 Aortic valve closure, 119, 120 opening, 119, 120 Apneustic breathing, 172 Appetite, hormones, 315 Aquaporins, 227 ARBs (angiotensin II receptor blockers), 202 Arcuate nucleus, 258 ARDS (adult respiratory distress syndrome), 147 Arginine vasopressin (AVP). See Antidiuretic hormone (ADH) Aromatase, 361 control of testes, 360 placenta, 379 Arrhythmias, 48–51 Arterial aneurysm, 81–82 Arterial baroreceptors, 93–94 Arterial blood gases (ABGs) acid-base disturbances, 235–236, 242–243 normal values, 237 Arterial PCO2, 237 cerebral circulation, 113
412
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Index Arterial pressure, systemic, short-term regulation, 93–96 Arterial system, exercise, 117 Arteries, 76 systemic, characteristics, 103–106 Arterioles, 76 diastolic pressure, 104 mean arterial pressure, 105 Ascending aorta, fetal circulation, 115, 116 Ascending limb, loop of Henle, 224 Assisted control mode ventilation (ACMV), 142 Atelectasis, 146–147 Atmospheric pressure (Patm) and alveolar PO2, 159 Atrial fibrillation, 50 Atrial flutter, 50 Atrial natriuretic peptide (ANP), 264 Atrial septal defect, left-to-right shunt, 185 Atrioventricular (AV) node cells action potentials, 41–42 automaticity, 37 conduction, 37 Auscultation points, 121 Autoimmune thyroid disease, 341, 342 Automaticity, 37 Autoregulation blood flow, 109–110 nephron hemodynamics, 194 Autoregulatory range, 110 AV node cells. See Atrioventricular (AV) node cells AVP (arginine vasopressin). See Antidiuretic hormone (ADH) a wave, venous pulse, 122 Axon, 33, 34 Axon hillock, 33, 34 Baroreceptor(s) arterial, 93–94 cardiopulmonary mechanoreceptors, 94
B Baroreceptor reflex, 93 Baroreflexes, 93–94 Barrett esophagus, 390 Bartter syndrome, 224 Basal membrane, 406 Base electrical rhythm, 389 Basic metabolic profile/panel (BMP), 4–5 The bends, 173 Beta-blockers, 42 Beta cells, 302, 307 Bicarbonate (HCO3-) acid-base disturbances, 237, 240 carbon dioxide transport, 168–169 normal values, 5, 237 production, 278 proximal tubule, 221 Bile composition and formation, 399–401 control of secretion, 400 Bile acids, 399–400
Bile pigments, 400 Bile salts, 399–400 Bilirubin, 400 Biogenic amines, 251, 252 Bladder, micturition, 192–193 Blood carrying capacity, 164 viscosity, 78 Blood flow cardiovascular stress (exercise), 117–118 fetal circulation, 115–116 Fick principle, 107–109 laminar vs. turbulent, 79–80 pressure, resistance, and, 76–77 pulmonary circuit, 114–115 regional differences, 176 regulation, 109–111 extrinsic, 110–111 intrinsic (auto-), 109–110 resting vs. exercising muscle, 111 to various organs, 111–115 cerebral circulation, 113 coronary circulation, 111–112 cutaneous circulation, 113–114 pulmonary circuit, 114–115 renal and splanchnic circulation, 113, 114 velocity, 79 Blood pressure, 76–77 long-term regulation, 279–281 Blood urea nitrogen (BUN), normal values, 5 Blood vessels compliance, 81 wall tension, 81–82 Blood volume, 15 mean systemic filling pressure, 97–98 BMP (basic metabolic profile/panel), 4–5 BNP (brain natriuretic peptide), 264 Body compartments, 3 graphical representation, 5–8 volume measurement, 14–15 Body water, total, 3 Bone disorders, metabolic, 328–329 Bone remodeling, 319–321 Bone resorption, 321 Botulinum toxin, 36 Bowditch effect, 86 Bowman’s capsule, 190 fluid entering, 199 protein or oncotic pressure, 197 Bowman’s space hydrostatic pressure, 197 protein or oncotic pressure, 197 Brain natriuretic peptide (BNP), 264 Breastfeeding, 382–384 Breathing abnormal patterns, 172 apneustic, 172 Cheyne-Stokes, 172 Brush border enzymes, 405 Buffering systems, 235 Buffy coat, 78
BUN (blood urea nitrogen), normal values, 5 Bundle of Kent, 50
C C18 steroids, synthesis, 272 C19 steroids, synthesis, 272 C2+ steroids, synthesis, 271 Ca 2+. See Calcium (Ca 2+) Caisson’s disease, 173 Calcitonin, 322 Calcitriol actions, 323–324 calcium homeostasis, 322–324 sources and synthesis, 322–323 Calcium (Ca 2+) absorption, 317 body distribution, 317–318 bone remodeling, 319–321 bound vs. free, 318 calcitonin, 322 cytosolic regulation, 59–60 removal in myocardial cells, 63 disorders, 324–326 distal tubule, 226 hormonal control, 317–329 metabolic bone disorders, 328–329 parathyroid hormone, 321–322 phosphate and, 318–319 plasma, 318 and PTH, 322 resting membrane potential, 25 Calcium (Ca 2+) channel blockers, 42 Calcium (Ca 2+) current, inward, 41 Calcium (Ca 2+) homeostasis, vitamin D (calcitriol), 322–324 Calcium-sensing receptor (CaSR), 224 Calmodulin (CAM), 65 Canagliflozin, 221 Capillaries, 76 Capillary membranes, 3, 15 Carbamino compounds, 168 Carbohydrate(s) (CHO) absorption, 405, 406 digestion, 404, 405 Carbohydrate (CHO) metabolism cortisol, 275 insulin deficiency, 312 insulin effects, 304 thyroid hormones, 339 Carbon dioxide (CO2), dissolved, 168 Carbon dioxide (CO2) alveolar pressure. See PaCO2 (alveolar pressure of carbon dioxide) Carbon dioxide-bicarbonate (CO2-HCO3-) buffer system, 235 Carbon dioxide (CO2) content, 169 Carbon dioxide (CO2) partial pressure. See PCO2 Carbon dioxide (CO2) transport, 168–169 Carbonic acid, 235 Carbonic anhydrase inhibitors, 221
413
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Pharmacology
Biochemistry
Physiology Physiology
Medical Genetics
Carbon monoxide (CO), 162 effects on oxygen transport, 167–168 poisoning, 167–168 Carboxypeptidase, 397 Cardiac action potentials, 38–42 Pathology Behavioral Science/Social Sciences Cardiac arrhythmias, 48–51 Cardiac cycle, normal, 119–124 heart sounds, 119, 120–121 venous pulse, 122–124 Cardiac index, 108 Microbiology Cardiac muscle skeletal vs., 63–64 systolic and diastolic dysfunction, 90–92 systolic performance of ventricle, 83–86 ventricular function curves, 87–89 Cardiac output (CO), 75, 96 determinants, 98–101 Fick principle, 107 long-term regulation, 279–281 mean arterial pressure, 105 pregnancy, 381 pulmonary response, 115 pumping action, 112 steady-state, 98, 100 and venous return, 96–97, 99–101 Cardiac output/venous return (CO/VR) curves, 99–101 Cardiac tissue, properties, 37–38 Cardiomyopathy, 91–92 Cardiopulmonary mechanoreceptors, 94 Cardiovascular (CV) changes, ventilation, 142 Cardiovascular (CV) effects, thyroid hormones, 339 Cardiovascular (CV) regulation, 93–106 characteristics of systemic arteries, 103–106 determinants of cardiac output, 98–101 effects of gravity, 102–103 short-term regulation of systemic arterial pressure, 93–96 venous return, 96–98 Cardiovascular (CV) stress, 117–118 Cardiovascular (CV) system, 75–76 cardiac output, 75 hemodynamics, 76–80 pregnancy, 381 structure-function relationships of systemic circuit, 76 vessel compliance, 81 wall tension, 81–82 Carotid bodies, 171 Carrier competition, protein-mediated transport, 204 Carrying capacity, blood, 164 CaSR (calcium-sensing receptor), 224 Catecholamines control of nodal excitability, 42 half-life, 297 metabolic actions, 298 permissive actions of cortisol, 275 CCK (cholecystokinin), 389, 396, 398 CD (collecting duct), 189, 190 regional transport, 226–228
CDI (central diabetes insipidus), 255, 264–265 Celiac disease, 405 Cell membranes, 3, 15 Central chemoreceptors, 170–171 Central respiratory centers, 171–172 Central venous pressure (CVP), 84 Cerebral circulation, 113 exercise, 118 CFTR (cystic fibrosis transmembrane conductance regulator), 397 Chemical-mechanical transduction, 58 Chemical specificity, protein-mediated transport, 204 Chemoreceptors central, 170–171 peripheral, 171 Chenodeoxycholic acid, 399 Chest wall recoil, 138 Cheyne-Stokes breathing, 172 Chief cells, secretions, 394 Childhood, male reproductive system, 362 Chloride (Cl-) normal values, 5 resting membrane potential, 24, 25 CHO. See Carbohydrate(s) (CHO) Cholecystokinin (CCK), 389, 396, 398 Cholera toxin, 402 Cholesterol bile, 400 conversion to pregnenolone, 272–273 Cholesterol esterase, 397 Cholic acid, 399 Cholinergic transmission, 32–33 Chronic renal failure, 232–233 Chvostek’s sign, 326 Chylomicrons, 406 Chymotrypsin, 397 Chymotrypsinogen, 397 Circulation cerebral, 113 coronary, 111–112 cutaneous, 113–114 fetal, 115–116 pulmonary, 114–115 renal and splanchnic, 113, 114 Circulatory system, 75 Cisternae, terminal, 56, 59 Cl- (chloride) normal values, 5 resting membrane potential, 24, 25 Clearance, 207–208 estimate of glomerular filtration rate, 213–214 free water, 216 sodium and urea, 216–217 Clearance curves, characteristic substances, 214–216 Clostridium perfringens, 173 CO. See Carbon monoxide (CO); Cardiac output (CO) CO2. See Carbon dioxide (CO2) Colipase, 404 Collecting duct (CD), 189, 190 regional transport, 226–228
Colon electrolyte transport, 408, 409 motility, 392 Coma, hyperosmolar, 313 Compensation, acid-base disturbances, 236, 238–239, 241–242, 245 Complete heart block, 49 Compliance lung, 144–148 pulse pressure, 104 systolic pressure, 103 vessel, 81 Conductance (g), 19 Conduction, cardiac tissue, 37–38 Conduction pathway, cardiac tissue, 38 Conduction velocity, action potential, 32 Congenital adrenal hyperplasia, 287–295 consequences, 294–295 11β-hydroxylase deficiency, 290–291, 294 17α-hydroxylase deficiency, 292–293, 294, 295 21β-hydroxylase deficiency, 287–289, 294 Conn’s syndrome, 285–286 Continuous positive airway pressure (CPAP), 143 Contractility cardiac output, 99 increased, 125 indices, 85–86 pumping action, 112 systolic performance of ventricle, 85–86 systolic pressure, 103 Contraction, cardiac tissue, 38 “Contraction alkalosis,” 222 Coronary circulation, 111–112 exercise, 118 flow patterns, 111–112 Corpus luteum, 373 Cortical nephrons, 189 Corticosterone, synthesis, 273, 274 Corticotropin-releasing hormone (CRH), 258, 259, 276 Cortisol absence, 270 control of secretion, 276–277 deficiency, 283, 287–295 metabolic actions, 275 metabolism, 271 permissive actions, 275 stress, 274 synthesis, 273, 274 24-hour urine free, 251, 252, 254, 271, 281 Cotransport, 204 Countercurrent, loop of Henle, 223 Countertransport, 204 CPAP (continuous positive airway pressure), 143 C-peptide, 302, 303, 307 Craniopharyngioma, 259 Creatinine (Cr) clearance curve, 214, 215 glomerular filtration rate, 213–214 normal values, 5 Cretinism, 344–345
414
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Index CRH (corticotropin-releasing hormone), 258, 259, 276 Cross-bridge interactions, 58 systolic performance of ventricle, 83 Cross-sectional area (CSA), velocity of blood flow, 79 Crypt cells, 401–402 Cryptorchidism, 363, 364 Crypts of Lieberkuhn, 401–402 CSA (cross-sectional area), velocity of blood flow, 79 Cumulus oophorus, 377 Cushing disease, 281, 285 Cushing syndrome, 255, 281, 283 Cutaneous circulation, 113–114 exercise, 118 CV. See Cardiovascular (CV) CVP (central venous pressure), 84 c wave, venous pulse, 122 Cystic fibrosis, 397 Cystic fibrosis transmembrane conductance regulator (CFTR), 397 Cytosolic calcium regulation, 59–60 removal in myocardial cells, 63
D Dalton’s law, 157 Darrow-Yannet diagram, 5 Davenport plot, 244–246 Dead space, 134–136 alveolar, 136 ventilation-perfusion mismatch, 178 anatomic, 134–136 physiologic, 136 Decompression sickness, 173 Defecation, 392 Dehydration, 266 Dehydroepiandrosterone (DHEA) pregnancy, 379 synthesis, 272 Dehydroepiandrosterone (DHEA) sulfate, 272 Deiodination, thyroid hormone secretion, 336 Delta cells, 302 Demyelinating diseases, 32 Dendrites, 33, 34 Denosumab, 328 11-Deoxycorticosterone synthesis, 273 Depolarization, 22 Descending aorta, fetal circulation, 115, 116 Descending limb, loop of Henle, 224 Desmolase, 272 Detrusor muscle, micturition, 192, 193 Dexamethasone, high-dose, 282 Dexamethasone suppression test, 1-mg overnight, 281 DHEA (dehydroepiandrosterone) pregnancy, 379 synthesis, 272 DHEA (dehydroepiandrosterone) sulfate, 272
DHP (dihydropyridine), 59 Diabetes insipidus (DI), 264–265, 266 central, 255, 264–265 nephrogenic, 223, 265 Diabetes mellitus (DM), 310–313 diabetic ketoacidosis, 313 hypoglycemia, 313 metabolic syndrome (syndrome X), 311 type 1, 311–313, 314 type 2, 311, 314 Diabetic ketoacidosis (DKA), 313 Diaphragm, 137 Diarrhea, 409 Diastolic blood pressure, factors affecting, 103, 104 Diastolic dysfunction, 90–92 Diffuse esophageal spasm, 391 Diffusing capacity of lung (DLCO), 161–162 Diffusion facilitated, 203 Fick law, 160–161 simple, 203 Diffusion constant, 161 Diffusion impairment, hypoxemia, 181–182 Diffusion-limited situation, 161, 162 Diffusion rate, factors affecting, 160–161 Digestion, 403–405 Digestive enzymes, 403–405 Dihydropyridine (DHP), 59 Dihydrotestosterone, 361 normal male development, 362 Dilated cardiomyopathy, 91 Dissecting aneurysm, 82 Dissolved carbon dioxide. See PCO2 Dissolved oxygen. See PO2 Distal renal tubular acidosis, 228–229 Distal tubule, 189, 190 regional transport, 225–226, 228 Diuretics loop, 223, 224 potassium sparing, 227 thiazide, 225 DKA (diabetic ketoacidosis), 313 DLCO (diffusing capacity of lung), 161–162 DM. See Diabetes mellitus (DM) Dopamine, 258, 259 Driving force, 19 Ductus arteriosus fetal circulation, 115, 116 patent, left-to-right shunt, 185 Ductus venosus, fetal circulation, 115, 116 Duodenum, electrolyte transport, 407–408, 409 Dwarfism, 350 Dynamic airway compression, 151 Dysphagia, 391
E ECF. See Extracellular fluid (ECF) ECG. See Electrocardiogram (EKG, ECG) Ectopic ACTH syndrome, 283, 285
Ectopic pregnancy, 377 Edema, 13–14 defined, 13 non-pitting, 13 peripheral, 13–14 pitting, 13 pulmonary, 14 EDV (end-diastolic volume), 89, 90 “Effective” osmole, 4 Ejaculation, 364 Ejection fraction (EF), 85, 89 Ejection phase, 120 Electrical activity, smooth muscle, 389 Electrical synapses, 34 Electrocardiogram (EKG, ECG), 43–51 arrhythmias/alterations, 48–51 normal pattern, 43–44 reading, 45–48 standard conventions, 44 Electrocardiology, 43–51 Electrochemical gradient, 19 Electrolytes proximal tubule, 221 transport, 407–409 Em (membrane potential), 19 Emission, 363 End-diastolic volume (EDV), 89, 90 Endocrine pancreas, 301–316 diabetes mellitus, 310–313 glucagon actions, 308 control of secretion, 309–310 synthesis, 302 insulin actions, 303–306 control of secretion, 307 synthesis, 302, 303 islets of Langerhans hormones, 301–302 other hormones involved in energy balance and appetite, 315 pancreatic endocrine-secreting tumors, 314 Endocrine system control of gastrointestinal tract, 389 disorders, 255–256 primary, 255 secondary, 255 general aspects, 251–256 hormones, 251–254 pregnancy, 381 Endometrium, hormonal maintenance, 378–379 Endopeptidase, 397 Endorphins, 276 End-plate potential (EPP), 33 End-systolic volume (ESV), 89 Energy balance, hormones, 315 Energy requirements, proximal tubule, 222 Enteric nervous system, 388–389 Enterohepatic circulation, 399, 401 Enterokinase, 397 Enteropeptidase, 397 Epinephrine (EPI), 297
415
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Pharmacology
Biochemistry
Physiology Physiology
Medical Genetics
cardiovascular regulation, 96 metabolic actions, 297–298 stress, 274 EPP (end-plate potential), 33 EPSP (excitatory postsynaptic potential), 34 Pathology Behavioral Science/Social Sciences Equilibrium potential, 19, 22–25 Erection, 363 Ergocalciferol, 322 ERV (expiratory reserve volume), 133, 134 Esophageal spasm, diffuse, 391 Microbiology Esophagus Barrett, 390 disorders, 391 Essential hypertension, 125 Estradiol control of testes, 360 menstrual cycle, 367–370, 374 metabolism and excretion, 374–376 pregnancy, 378, 380 synthesis, 272 17β-Estradiol, 375 Estriol, 375 pregnancy, 380 Estrogens and androgen formation, 375 bone remodeling, 320 defined, 375 menstrual cycle, 367–371, 374 parturition, 381 pregnancy, 378, 379, 380 synthesis, 272 Estrone, 375 pregnancy, 380 ESV (end-systolic volume), 89 Euvolemia, clinical, 267 Excitable tissue, 19–20 Excitation-contraction coupling, 55–66 altering force in skeletal muscle, 60–62 comparison of striated muscles, 63–64 regulation of cytosolic calcium, 59–60 skeletal muscle structure-function relationships, 55–58 smooth muscle, 64–66 Excitatory postsynaptic potential (EPSP), 34 Excretion filtered load and, 206–207 nephron, 191–192 potassium, 230 rate, 191 Exercise blood flow to skeletal muscles, 111 cardiac output, 98–99 pressure-volume loops, 125 pulmonary circuit, 115, 117 regional circulations, 117–118 systemic circuit, 117 ventilation-perfusion relationships, 179 Exocrine pancreas, control, 398 Exopeptidase, 397 Expiration cardiovascular changes, 142 lung mechanics, 140, 141 muscles, 137
Expiratory center, 171–172 Expiratory reserve volume (ERV), 133, 134 External sphincter, micturition, 193 Extracellular fluid (ECF), 3 Extracellular fluid (ECF) volume, 6 regulation, 263–264 Extracellular solutes, 4–5 Extrinsic regulation, blood flow, 110–111
F Facilitated diffusion, 203 Facilitated transport, 203 Familial hypocalciuric hypercalcemia (FHH), 224 Fasting, migrating motor complex, 392 Fat metabolism cortisol, 275 insulin deficiency, 312 insulin effects, 304–305 thyroid hormones, 339 Feedback relationships, thyroid hormone secretion, 340 Female reproductive system, 367–384 lactation, 382–384 menstrual cycle, 367–374 menstrual irregularities, 376–377 pregnancy, 377–382 sex steroid metabolism and excretion, 374–376 Fertilization, 377 Fetal circulation, 115–116 Fetal life, male reproductive system, 362 FEV1 (forced expiratory volume in 1 sec), 149–150 FF (filtration fraction), 199–200 factors affecting, 200 FHH (familial hypocalciuric hypercalcemia), 224 Fick law of diffusion, 160–161 Fick principle, 107–109 Filling phase cardiac cycle, 120 micturition, 192 Filtered load, 191 and excretion, 206–207 Filtering membrane, 198 Filtration microcirculation, 11–12 nephron, 191, 192 Filtration coefficient, 12 Filtration fraction (FF), 199–200 factors affecting, 200 Filtration rate, 191 FiO2 (fractional concentration of oxygen) and alveolar PO2, 159–160 First-degree heart block, 48 Flow-volume loops, 154–155 Fluid distribution, 3–11 aldosterone, 10 anti-diuretic hormone, 10 extracellular solutes, 4–5 graphical representation, 5–9 negative feedback regulation, 10
osmolar gap, 5 osmosis, 4 renin, 10 total body water, 3 Fluid loss, isotonic, 8 Follicle-stimulating hormone (FSH) control of testes, 358, 359 menstrual cycle, 367–374 Follicular phase, menstrual cycle, 367–369, 370, 372, 374 Foramen ovale, fetal circulation, 115, 116 Forced expiratory flow-volume loop, 155 Forced expiratory volume in 1 sec (FEV1), 149–150 Forced vital capacity (FVC), 149–150 Force-velocity curve, 70 Fractional concentration of oxygen (FiO2) and alveolar PO2, 159–160 Frank-Starling curves, 87–89 Frank-Starling mechanism, 84 Free circulating hormones, 252–253 Free water clearance, 216 FSH (follicle-stimulating hormone) control of testes, 358, 359 menstrual cycle, 367–374 Functional residual capacity (FRC), 133, 134 lung force relationships at, 139 Funny current (If ), nodal action potential, 41, 42 Fusion, thyroid hormone secretion, 336 FVC (forced vital capacity), 149–150
G g (conductance), 19 Gallbladder contraction, 400 Gamma-aminobutyric acid (GABA) receptors, 34 Gas gangrene, 173 Gastric acid secretion, 394 control, 395–396 Gastric inhibitory peptide (GIP), 389 Gastric motility, 391–392 Gastric secretions, 394–396 Gastrin, 389 Gastrinomas, 314 Gastroesophageal reflux disease (GERD), 391 Gastrointestinal (GI) blood flow, exercise, 118 Gastrointestinal (GI) motility, 389–392 colon, 392 defecation, 392 disorders of esophagus, 391 gastric, 391–392 migrating motor complex, 392 small intestine, 392 smooth muscle characteristics, 389–390 swallowing, 390 Gastrointestinal (GI) secretions, 393–402 bile, 399–401 gastric, 394–396 pancreatic, 396–398
416
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Index salivary, 393–394 small intestinal, 401–402 Gastrointestinal (GI) tract endocrine control, 389 nervous control, 388–389 structure, 387–388 GBS (Guillain-Barre syndrome), 32 GERD (gastroesophageal reflux disease), 391 Gestational age, 377 GFR. See Glomerular filtration rate (GFR) GH. See Growth hormone (GH) Ghrelin, 315 GI. See Gastrointestinal (GI) GIP (gastric inhibitory peptide, glucose insulinotropic peptide), 389 Gitelman syndrome, 225 Glomerular capillaries, hydrostatic pressure, 197 Glomerular filtration, 196–202 angiotensin II, 201–202 filtering membrane, 198 filtration fraction, 199–200 factors affecting, 200 fluid entering Bowman’s capsule, 199 materials filtered, 198–199 net filtration pressure, 197–198 sympathetic nervous system, 200–201 Glomerular filtration rate (GFR), 196 clearance as estimator, 213–214 pregnancy, 381 Glomerular hemodynamics, 195–196 Glomerulotubular balance, 220 Glomerulus(i), 189 GLP (glucagon-like peptide), 389 Glucagon actions, 308 control of secretion, 309–310 permissive actions of cortisol, 275 stress, 274 synthesis, 302 Glucagon-like peptide (GLP), 389 Glucagonomas, 314 Glucocorticoids bone remodeling, 320 disorders, 281–285 physiologic actions, 274–275 Glucose clearance curve, 214, 215 control of insulin secretion, 307 counterregulation, 310 normal values, 5 peripheral uptake, 303 proximal tubule, 221 tubular reabsorption, 208–209, 221 Glucose insulinotropic peptide (GIP), 389 Glycine receptors, 34 Goiter, 347 toxic multinodular, 341 Gonadal dysfunction, male, 364–365 Gonadotropin-releasing hormone (GnRH) control of testes, 358
hypothalamic–anterior pituitary axis, 257, 258, 259 lactation, 383, 384 menstrual cycle, 368 Granulosa cells, 367, 368, 369 Graves’ disease, 341, 342, 345–346 Gravity, cardiovascular regulation, 102–103 Growth, 349–355 intrauterine, 349 postnatal, 349 puberty, 353 Growth hormone (GH), 254 control of secretion, 352–353 excessive secretion (acromegaly), 354 physiologic actions, 350–352 prepubertal deficiency, 350 stress, 274 thyroid hormones, 339 Growth hormone–releasing hormone (GHRH), 258, 259 Guillain-Barre syndrome (GBS), 32
H H+. See Hydrogen (H+) H2O. See Water (H2O) Hartnup’s disease, 405 Hashimoto’s thyroiditis, 255, 344 Hb. See Hemoglobin (Hb) H band, 55, 56 hCG (human chorionic gonadotropin), 378, 379, 380 HCO3-. See Bicarbonate (HCO3-) hCS (human chorionic somatomammotropin), 380 Heart, electrical activity, 37–51 arrhythmias/ECG alterations, 48–51 cardiac action potentials, 38–42 control of nodal excitability, 42–43 electrocardiology, 43–48 properties of cardiac tissue, 37–38 Heart block, 48–49 first-degree, 48 second-degree, 49 third-degree (complete), 49 Heart failure, 125 Heart rate (HR) cardiac output, 98–99 ECG, 45–46 pumping action, 112 Heart rhythm, ECG, 45–46 Heart sounds, 119, 120–121 Hematocrit, 78 Hemodynamics, 76–80 laminar vs. turbulent flow, 79–80 nephron, 194–196 pressure, flow, resistance, 76–78 series vs. parallel circuits, 80 nephron, 195–196 systemic circulation, 95–96 velocity, 79 Hemoglobin (Hb) concentration effects, 166–167 oxygen content, 164–165
Hemoglobin (Hb) content and oxygen content, 166–167 Hemoglobin-oxygen (Hb-O2) dissociation curves, 165–166 Hemorrhage, pulmonary response, 115 h-gate (inactivation gate), 28 High altitude hypoxemia, 181 respiratory stress, 172–173 High-pressure environment, respiratory stress, 173 Hirsutism, 377 Hormone(s), 251–254 activity, 253 resistance, 254 anabolic, 304 hypothalamic, 257–258, 259 lipid vs. water-soluble, 251–252 measurement of levels, 254 posterior pituitary, 261–263 protein-bound vs. free circulating, 252–253 specificity, 253 steroid, 251, 252 regional synthesis, 272–274 synthetic pathways, 270–272 thyroid. See Thyroid hormones Hormone receptors, 253–254 HPG (hypothalamic-pituitary-gonadal) axis, males, 357–361 hPL (human placental lactogen), 380 HR. See Heart rate (HR) Human chorionic gonadotropin (hCG), 378, 379, 380 Human chorionic somatomammotropin (hCS), 380 Human placental lactogen (hPL), 380 Hydrogen (H+), secretion, 278 Hydrogen-adenosine triphosphatase (H+-ATPase), intercalated cells, 227 Hydrogen/carbon dioxide (H+/CO2) receptors, 171 Hydrostatic pressure, 11, 12 Bowman’s space, 197 glomerular capillaries, 197 11β-Hydroxylase (11β-OH) deficiency, 290–291, 294 17α-Hydroxylase (17α-OH) deficiency, 292–293, 294, 295 21β-Hydroxylase (21β-OH) deficiency, 287–289, 294 17-Hydroxysteroids (17-OH), 271 Hyperaldosteronism with hypertension, 285–286 with hypotension, 286–287 Hyperbaric environment, 173 Hypercalcemia, 324–325 differential diagnosis and treatment, 325 ECG changes, 51 familial hypocalciuric, 224 of primary hyperparathyroidism, 324–325 related causes, 325
417 417
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Pharmacology
Biochemistry
Physiology Physiology
Medical Genetics
Hypercortisolism, 281–283, 285 Hyperfunction, endocrine system, 255 Hyperglycemia, glucagon secretion, 309 Hyperkalemia, 23, 28 consequences, 231 Pathology Behavioral Science/Social Sciences ECG changes, 51 promoters, 231 Hyperosmolar coma, 313 Hyperparathyroidism primary, hypercalcemia of, 324–325 Microbiology secondary renal failure and, 326 vitamin D deficiency and, 327 Hyperpolarization, 22 Hypertension essential, 125 hyperaldosteronism with, 285–286 Hyperthyroidism, primary, 342, 345–346 Hypertonic fluid, net loss, 8 Hypertrophic cardiomyopathy, 92 Hyperventilation, 159, 160 Hypervolemia, 267 Hypoaldosterone states, 229 Hypocalcemia, 325–326 additional causes, 326 ECG changes, 51 of primary hypoparathyroidism, 325–326 Hypocortisolism, 283–285 Hypofunction, endocrine system, 255 Hypogastric nerve, micturition, 193 Hypoglycemia diabetes mellitus, 313 factitious, 311, 314 glucagon secretion, 309 Hypogonadism, male, 364–365 Hypokalemia, 23 consequences, 231 ECG changes, 51 promoters, 231 Hypomagnesemia, 326 Hyponatremia, 266–267 Hypoparathyroidism hypocalcemia of primary, 325–326 pseudo-, 326 vitamin D excess and secondary, 327 Hypophyseal-portal system, 258 Hypopituitarism, 259–260 Hypotension, hyperaldosteronism with, 286–287 Hypothalamic–anterior pituitary axis disorders, 259–260 structure and function, 257–259 Hypothalamic hormones, 257–258 effect on anterior pituitary, 259 Hypothalamic-pituitary-gonadal (HPG) axis, males, 357–361 Hypothyroidism pituitary, 342 postnatal growth, 349 primary, 342, 344–345 Hypoventilation, 159, 160 hypoxemia, 180–181 Hypovolemia, 267
Hypoxemia, 180–184 diffusion impairment, 181–182 high altitude, 181 hypoventilation, 180–181 intrapulmonary shunt, 183–184 ventilation-perfusion mismatch, 182–183 Hypoxic vasoconstriction, 179 H zone, 55, 56
I I band, 55, 56 IC (inspiratory capacity), 133, 134 ICF (intracellular fluid), 3 If (funny current), nodal action potential, 41, 42 IGFs. See Insulin-like growth factors (IGFs) IK1 (inward K+ rectifying) channels, 38 Ileocecal sphincter, 392 Ileum, electrolyte transport, 408, 409 Implantation, 378 preparation, 379 Inactivation gate (h-gate), 28 Incidentaloma, pituitary, 354 Incretin, 307 Infant respiratory distress syndrome, 147 Inferior vena cava, fetal circulation, 115, 116 Inhibin(s), 361 Inhibin B control of testes, 358, 360 menstrual cycle, 369 Inhibitory postsynaptic potential (IPSP), 34 Inotropic state, systolic performance of ventricle, 85 Inspiration cardiovascular changes, 142 lung mechanics at end, 139, 140 lung mechanics before, 138–139 lung mechanics during, 139, 140, 141 muscles of, 137 Inspiratory capacity (IC), 133, 134 Inspiratory center, 171–172 Inspiratory reserve volume (IRV), 133, 134 Inspired air, partial pressure of gas, 157–158 Insulin actions, 303–306 liver, 310 metabolic, 304–305 control of secretion, 307 effects on potassium, 305 synthesis, 302, 303 Insulin-like growth factors (IGFs) intrauterine growth, 349 production and release, 351 specific properties, 352 Insulinomas, 314 Insulin receptor, 303 Insulin resistance, pregnancy, 380 Intercalated cells, 227, 277 Internal sphincter, micturition, 192, 193 Interstitial fluid (ISF), 3 Intestinal villi, 401 Intraalveolar pressure, 139, 140
Intracellular fluid (ICF), 3 Intracellular volume, 6 Intracranial pressure, 113 Intrapleural pressure (IPP) expiration, 140, 141, 142 inspiration, 139, 141, 142 lung recoil, 138 regional differences, 175, 176 Intrapulmonary shunt, hypoxemia, 183–184 Intrarenal renal failure, 232 Intrauterine growth, 349 Intravenous fluids, distribution, 16 Intrinsic factor, 394 Intrinsic regulation, blood flow, 109–110 Inulin clearance curve, 214, 215 nephron tubule concentration, 223 Inward calcium (Ca 2+) current, 41 Inward potassium (K+) rectifying (IK1) channels, 38 Inward sodium (Na+) current, 41 Iodide transport, 333–334 Iodination, 334 Iodine deficiency, 343 Iodine intake, thyroidal response to low, 343 Iodine uptake, 333–334 Ion channels, 20–22 ligand-gated, 20, 21 synaptic transmission, 32, 33 ungated (leak), 20, 21 voltage- and ligand-gated, 21–22 voltage-gated, 20, 21 action potential, 28–29 IPP. See Intrapleural pressure (IPP) IPSP (inhibitory postsynaptic potential), 34 IRV (inspiratory reserve volume), 133, 134 ISF (interstitial fluid), 3 Islets of Langerhans hormones, 301–302 Isometric contraction, 67 maximal, 69 Isotonic contraction, 67 Isotonic fluid loss, 8 net gain, 8 Isovolumetric contraction, 120 Isovolumetric relaxation, 120 Ivabradine, 42
J Jaundice, 400 Jejunum, electrolyte transport, 408, 409 J point, 43 Jugular pulse, 121–123 Juxtaglomerular apparatus, aldosterone secretion, 278–279 Juxtamedullary nephrons, 189, 223
K K+. See Potassium (K+) Kallmann’s syndrome, 365
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Index Kernicterus, 400 Ketoacidosis, diabetic, 313 17-Ketosteroids, 272 Kidney functional organization, 189–190 functions, 189
L Lactase, 404 Lactation, 382–384 Lambert-Eaton syndrome, 36 Lamina propria, 387, 388 Laminar flow, 79–80 LaPlace relationship, 81 Laron dwarfism, 350 Laron syndrome, 350 Latrotoxin, 36 Leak ion channel, 20, 21 Lecithin, bile, 400 Left atrium, fetal circulation, 115, 116 Left-to-right shunts, 184–186 Left ventricle, fetal circulation, 115, 116 Left ventricular end-diastolic pressure (LVEDP), 83, 87 Left ventricular end-diastolic volume (LVEDV), 83, 84 Length-tension curves, skeletal and cardiac muscle, 68–69, 84 Leptin, 315 LES (lower esophageal sphincter), 390 Leydig cells, 358, 359, 360 LH. See Luteinizing hormone (LH) Liddle syndrome, 227 Ligand-gated ion channel, 20, 21 synaptic transmission, 32, 33 Lipase, 404 Lipid absorption, 406–407 Lipid hormones, 251–252 Lipid metabolism cortisol, 275 insulin deficiency, 312 insulin effects, 304–305 thyroid hormones, 339 β-Lipotropin, 276, 277 Lithocholic acid, 400 Liver glucagon actions, 308 insulin actions, 310 Load and velocity, 70 Long QT syndrome, 40 Loop diuretics, 223, 224 Loop of Henle, 189, 190 regional transport, 223–225 Lower esophageal sphincter (LES), 390 Luminal membrane, absorption, 406 Lung diffusing capacity, 161–162 ventilation/perfusion differences, 175–179 “west zones,” 175 Lung capacities, 133–134 Lung compliance, 144–148 components of lung recoil, 146–147 respiratory distress syndrome, 147–148
Lung mechanics, 137–141 end of inspiration, 139, 140 expiration, 140 forces acting on lung system, 138 before inspiration, 138 during inspiration, 139, 140 muscles of respiration, 137 Lung recoil, 138, 146–147 Lung system, forces acting on, 138 Lung volumes, 133–134 mechanical effect, 149 Luteal phase menstrual cycle, 367, 368, 370, 372–373 preparation for implantation, 379 Luteinizing hormone (LH) age-related changes, 361, 362 control of testes, 358, 359 menstrual cycle, 368–374 pregnancy, 378 Luteinizing hormone (LH) surge, 371, 372, 373 LVEDP (left ventricular end-diastolic pressure), 83, 87 LVEDV (left ventricular end-diastolic volume), 83, 84 Lymphatics, 12–13
M Male reproductive system, 357–365 age-related hormonal changes, 361–363 erection, emission, and ejaculation, 363–364 gonadal dysfunction, 364–365 hypothalamic-pituitary-gonadal axis, 357–361 Mammary gland, 382 Mass balance, 206–207 Maturation, thyroid hormones, 339 Maximum force, 70 Maximum velocity (Vmax), 70 Mean arterial pressure (MAP), 78, 95–96 factors affecting, 103, 104–105 gravity, 102–103 Mean electrical axis (MEA), 46 Mean systemic filling pressure (Psf), 97–98 cardiac output, 100, 101 Mechanically altered states, pressurevolume loops, 125 Mechanoreceptors, cardiopulmonary, 94 Medullary centers, 171–172 Meissner’s plexus, 387, 388 α-Melanocyte-stimulating hormone (α-MSH), 276, 277 β-Melanocyte-stimulating hormone (β-MSH), 276, 277 Membrane potential (Em), 19 MEN (multiple endocrine neoplasia), 255 Menses, 367, 368, 372, 373 Menstrual cycle, 367–374 follicular (proliferative, preovulatory) phase, 367–369, 370, 372, 374 luteal phase, 367, 368, 370, 372–373 menses, 367, 368, 372, 373
monitoring, 375 new, 375 ovulation, 367, 369–371 Menstrual irregularities, 376–377 Menstruation, 367, 368, 372, 373 Metabolic acidosis bicarbonate, 237, 240 cause, 246–247 compensation, 238, 241 defined, 236 diagnosis, 240 graphical representation, 244–245 mixed respiratory and, 241, 243 plasma anion gap, 240 with respiratory alkalosis, 241 Metabolic actions cortisol, 275 epinephrine, 297–298 insulin, 304–305 Metabolic alkalosis, 222 bicarbonate, 237, 240 cause, 247 compensation, 238, 242 defined, 236 diagnosis, 240 graphical representation, 244–245 mixed respiratory and, 242 with respiratory acidosis, 242 Metabolic bone disorders, 328–329 Metabolic effects, insulin deficiency, 312–313 Metabolic mechanism, autoregulation of blood flow, 109 Metabolic rate and alveolar PCO2, 159 thyroid hormones, 338 Metabolic syndrome, 311 Metabolites, proximal tubule, 221 Metanephrines, 297 Methyl testosterone, 361 Metyrapone testing, 282 m-gate (activation gate), 28 Micelles, 399–400, 404, 406 Microadenomas, pituitary, 260, 282 Microcirculation, 11–13 Micturition reflex, 192–193 MIF (Müllerian inhibiting factor), 362 Migrating motor complex (MMC), 392 Mineralocorticoids disorders, 285–287 principal cells, 227 Minute ventilation, 136 Mitral auscultation point, 121 Mitral insufficiency regurgitation, 129 Mitral stenosis, 128 Mitral valve closure, 119, 120 opening, 119, 120 MLCK (myosin light-chain kinase), 65, 66 MLC (myosin light-chain) phosphorylase, 65, 66 M line, 56 MMC (migrating motor complex), 392
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Pharmacology
Biochemistry
Physiology Physiology
Medical Genetics
Mobitz type I heart block, 49 Mobitz type II heart block, 49 Motility, gastrointestinal. See Gastrointestinal (GI) motility Motor activity, smooth muscle, 390 Pathology Behavioral Science/Social Sciences Motor neurons, 35 Mouth, digestion, 404, 405 MS (multiple sclerosis), 32 α-MSH (α-melanocyte-stimulating hormone), 276, 277 Microbiology β-MSH (β-melanocyte-stimulating hormone), 276, 277 Mucosa, 387, 388 Mucous neck cells, 395 Müllerian duct, 362 Müllerian inhibiting factor (MIF), 362 Multiple endocrine neoplasia (MEN), 255 Multiple sclerosis (MS), 32 Muscle fibers, 55 Muscle mass, age-related hormonal changes in males, 363 Muscularis externa, 387, 388 Muscularis mucosa, 387, 388 Myasthenia gravis, 36 Myelination, 32 Myelin sheath, 34 Myenteric plexus, 387, 388 Myocardial cells, removal of cytosolic calcium, 63 Myocytes action potentials, 39–40 contraction, 38 Myofibril, ultrastructure, 55–56 Myogenic mechanism, autoregulation of blood flow, 110 Myogenic responses, nephron hemodynamics, 194 Myosin skeletal muscle, 57, 58 smooth muscle, 64 Myosin adenosine triphosphatase (myosin ATPase), 59.60 Myosin filament, 56 Myosin light-chain kinase ( MLCK), 65, 66 Myosin light-chain (MLC) phosphorylase, 65, 66
N Na+. See Sodium (Na+) Natriuresis, 264 Natriuretic peptides, 264 NE. See Norepinephrine (NE) Negative feedback regulation, 10 Nephritic syndrome, 198 Nephrogenic diabetes insipidus, 223, 265 Nephron(s) cortical, 189 function, 191–192 hemodynamics, 194–196 juxtamedullary, 189, 223 structure, 189–190 Nephrotic syndrome, 198 Nernst equation, 22
Net filtration pressure, 197–198 Net force, 19 Net transport, 207 Neural regulation alveolar ventilation, 170–172 gastrointestinal tract, 388–389 Neuromuscular junction (NMJ), 32–33 pathologies, 36 Neuronal excitability/conduction decreased, 36 increased, 36 Neurons, synapses between, 33–34 Nicotinic receptor blockers, 36 Nicotinic synapses, 32, 33, 34 NIS (sodium/iodide symporter), 333 Nitric oxide (NO), cardiovascular regulation, 96 Nitrogen, high-pressure environments, 173 N-methyl-D-aspartic acid (NMDA) receptor, 21–22, 34 NMJ (neuromuscular junction), 32–33 pathologies, 36 NO (nitric oxide), cardiovascular regulation, 96 Nodal cells action potential, 41–42 automaticity, 37 conduction, 37 Nodal excitability, control, 42–43 Non-N-methyl-D-aspartic acid (nonNMDA) receptor, 34 Non-nodal cells action potential, 38–40 resting membrane potential, 39 Non-pitting edema, 13 Norepinephrine (NE), 297 cardiovascular regulation, 96 control of nodal excitability, 42
O O2. See Oxygen (O2) OAT (organic anion transporter), 211 Obstructive pulmonary disease, 150, 152, 153, 154 11β-OH (11β-hydroxylase) deficiency, 290–291, 294 17-OH (17-hydroxysteroids), 271 17α-OH (17α-hydroxylase) deficiency, 292–293, 294, 295 21β-OH (21β-hydroxylase) deficiency, 287–289, 294 Oncotic pressure, 11, 12 Bowman’s space, 197 plasma, 197 OPG (osteoprotegerin), 319, 320 Organic acids/bases, transport, 211–212 Organic anion transporter (OAT), 211 Orthostatic intolerance, 102 Osmolality, 4 Osmolar gap, 5 Osmolarity, 4 changes in body hydration, 9 regulation, 263–264
Osmole, “effective,” 4 Osmoreceptors, 261, 262, 263 Osmoregulation, 261, 262, 263 Osmosis, 4 Osmotic pressure, 11, 12 Osteoblasts, 319, 320 Osteoclasts, 319, 320 Osteomalacia, 329 Osteoporosis, 328 Osteoprotegerin (OPG), 319, 320 Outward potassium (K+) current, 41 Ovarian 17α-OH deficiency, 293 Ovulation, 367, 369–371 Ovum, pickup and fertilization, 377 Oxygen (O2) dissolved, 163–164 high-pressure environments, 173 Oxygenation, coronary circulation, 112 Oxygen consumption (VO2), Fick principle, 107, 108 Oxygen (O2) content of hemoglobin, 164–165 hemoglobin concentration and, 166–167 units, 163 Oxygen (O2) delivery, Fick principle, 109 Oxygen-hemoglobin (O2-Hb) dissociation curves, 165–166 Oxygen (O2) partial pressure. See PO2 Oxygen (O2) transport, 163–168 carbon monoxide effects, 167–168 dissolved oxygen, 163–164 hemoglobin concentration effects, 166–167 hemoglobin O2 content, 164–165 oxygen-hemoglobin dissociation curves, 165–166 oxyhemoglobin, 164 units of oxygen content, 163 Oxyhemoglobin, 164 Oxytocin lactation, 383 parturition, 382 pregnancy, 381
P P50, 166–167 Pacemaker action potential, 41–42 PaCO2 (alveolar pressure of carbon dioxide) acid-base disturbances, 242 and alveolar PO2, 160 PAG (plasma anion gap), 239–240 p-aminohippuric (PAH) acid clearance curve, 214, 215–216 tubular secretion, 209–211 Pancreas endocrine, 301–316 actions of glucagon, 308 actions of insulin, 303–306 control of glucagon secretion, 309–310 control of insulin secretion, 307 diabetes mellitus, 310–313 islets of Langerhans hormones, 301–302
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Index other hormones involved in energy balance and appetite, 315 pancreatic endocrine-secreting tumors, 314 exocrine, control, 398 Pancreatic amylases, 397 Pancreatic endocrine-secreting tumors, 314 Pancreatic lipases, 397 Pancreatic proteases, 397, 404, 405 Pancreatic secretions, 396–398 Parallel circuits, 80 Parasympathetic nervous system, 35 control of nodal excitability, 43 GI tract, 389 Parathyroid hormone (PTH), 321–322 actions, 321 bone remodeling, 320 plasma calcium and, 322 regulation of secretion, 322 Parathyroid hormone–related peptide (PTHrP), 321 Paraventricular nucleus (PVN), 258, 262, 263 Parietal cell secretions, 394 regulation, 395–396 Parotid gland secretions, 393 Partial pressure of carbon dioxide. See PCO2 Partial pressure of gas in ambient air, 157 in inspired air, 157–158 Partial pressure of oxygen. See PO2 Parturition, 381–382 Passive tension curve, 68 Patent ductus, left-to-right shunt, 185 Patm (atmospheric pressure) and alveolar PO2, 159 PCO2, 168 arterial, 237 cerebral circulation, 113 factors affecting alveolar, 158–159 inspired air, 158 PCO2 gradient, 161 PCWP (pulmonary capillary wedge pressure), 84 PEEP (positive end-expiratory pressure), 143 Pelvic nerve, micturition, 193 Pepsin, 394, 404, 405 Pepsinogen, 394 Peptidases, 404 Peptide hormones, 251, 252 Perfusion-limited situation, 161 Peripheral chemoreceptors, 171 Peripheral edema, 13–14 Peripheral nervous system, 35 Peristalsis, 390, 391–392 Permissive action, hormone receptors, 254 Pesticides, 36 PFT. See Pulmonary function testing (PFT) pH acid-base disturbances, 238 arterial blood, 237
Phenylethanolamine-N-methyltransferase (PNMT), 297 Pheochromocytomas, 299 Phosphate (PO-4) absorption, 317 body distribution, 317–318 bone remodeling, 319–321 calcium and, 318–319 disorders, 326–328 hormonal control, 317–329 metabolic bone disorders, 328–329 Phospholipids, bile, 400 Physical conditioning, blood flow, 118 Physiologic dead space, 136 Pinocytosis, thyroid hormone secretion, 336 Pitting edema, 13 Pituitary anterior disorders, 259–260 effect of hypothalamic hormones, 259 structure and function, 257–259 ovulation, 370 posterior, 261–267 hormones, 261–263 hyponatremia, 266–267 pathophysiologic changes in ADH secretion, 264–266 regulation of ECF volume and osmolarity, 263–264 Pituitary adenomas, 260, 282 Pituitary incidentaloma, 354 Placenta, 378, 379 fetal circulation, 115, 116 Plasma, oncotic pressure, 197 Plasma analysis, hormone levels, 254 Plasma anion gap (PAG), 239–240 Plasma volume (PV), 3, 15 Pneumothorax, 144 PNMT (phenylethanolamineN-methyltransferase), 297 PO2, 163–164 ambient air, 157, 158 factors affecting alveolar, 159–160 inspired air, 157, 158 PO2 gradient, 161 PO2 receptors, 171 PO-4. See Phosphate (PO-4) Poiseuille equation, 76 Polycystic ovarian syndrome, 376–377 Polycythemia, 166–167, 168 Polydipsia, primary, 266 Portal vein, fetal circulation, 116 Positive end-expiratory pressure (PEEP), 143 Positive-pressure ventilation, 142–143 Posterior pituitary, 261–267 hormones, 261–263 hyponatremia, 266–267 pathophysiologic changes in ADH secretion, 264–266 regulation of ECF volume and osmolarity, 263–264 Postganglionic neurons, 35
Postnatal growth, 349 Postrenal renal failure, 232 Postsynaptic membrane, 32 Postsynaptic potential excitatory, 34 inhibitory, 34 Potassium (K+) and aldosterone, 281 insulin deficiency, 312 insulin effects, 305 normal values, 5 resting membrane potential, 23 secretion and excretion, 230, 278 Potassium (K+) balance, 229–231 Potassium (K+) channels ungated, 38 voltage-gated, 29 Potassium (K+) current, outward, 41 Potassium (K+) homeostasis, disorders, 229–231 Potassium (K+) sparing diuretics, 227 “Power stroke,” 57 Prader-Willi syndrome, 315 Preganglionic neurons, 35 Pregnancy, 377–382 ectopic, 377 hormonal maintenance of uterine endometrium, 378–379 implantation, 378 maternal compensatory changes, 381–382 ovum pickup and fertilization, 377 peripheral effects of hormonal changes, 379–380 Pregnenolone, conversion of cholesterol to, 272–273 Preload, 67, 68, 69 cardiac output, 99 pumping action, 112 systolic performance of ventricle, 83–84, 88 Preoptic region, 258 Preovulatory follicle, 373 Preovulatory phase, menstrual cycle, 367–369, 370, 372, 374 Prepubertal growth hormone deficiency, 350 Prerenal renal failure, 232 Pressure gradients, 76–77 circulatory system, 97 Pressure overload, 90 Pressure-volume loops, 124–125 Pressure work, 112 Presynaptic membrane, 32 Primary transport, 204–205 Principal cells, 226–227, 277 PR interval, 43, 46 Procarboxypeptidase, 397 Progesterone menstrual cycle, 368, 370, 374 metabolism and excretion, 374–376 parturition, 381 pregnancy, 378, 379, 380
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Pharmacology
Biochemistry
Physiology Physiology
Medical Genetics
Prolactin lactation, 383 pregnancy, 380, 382 Proliferative phase, menstrual cycle, 367–369, 370, 372, 374 Pathology Behavioral Science/Social Sciences Pro-opiomelanocortin, 276 Prostaglandins, parturition, 382 Protein absorption, 405, 406 digestion, 404, 405 Microbiology Protein-bound hormones, 252–253 Protein-mediated transport, 204–206 Protein metabolism cortisol, 275 insulin deficiency, 312 insulin effects, 304 Protein pressure, Bowman’s space, 197 Proteolysis, thyroid hormone secretion, 336 Proximal renal tubular acidosis, 228 Proximal tubule (PT), 189, 190 regional transport, 219–223 Pseudohermaphrodite, 364 Pseudohypoparathyroidism, 326 Psf (mean systemic filling pressure), 97–98 cardiac output, 100, 101 PT (proximal tubule), 189, 190 regional transport, 219–223 PTH. See Parathyroid hormone (PTH) PTM (transmural pressure gradient), 138, 139, 149 Puberty, 353 male reproductive system, 362 Pudendal nerve, micturition, 193 Pulmonary artery, fetal circulation, 115, 116 Pulmonary capillary blood flow, 158 Pulmonary capillary gases, 158 Pulmonary capillary wedge pressure (PCWP), 84 Pulmonary circuit, 75, 114–115 characteristics, 114–115 exercise, 115, 117 hemorrhage, 115 Pulmonary edema, 14 Pulmonary function testing (PFT), 149–155 defined, 133 flow-volume loops, 154–155 obstructive vs. restrictive patterns, 152–153 physiology, 150–151 vital capacity, 149–150 Pulmonary response exercise, 115 hemorrhage, 115 Pulmonary shunt, hypoxemia, 183–184 Pulmonary wedge pressure, 84 Pulmonic auscultation point, 121 Pulse, venous, 121–123 Pulse pressure, factors affecting, 103, 104 Pumping action, coronary circulation, 112 Purkinje cells action potentials, 39–40 automaticity, 37 conduction, 38
PV (plasma volume), 3, 15 PVN (paraventricular nucleus), 258, 262, 263 P wave, 43 Pyloric sphincter, 391
Q QRS complex, 43, 44 QRS deflection, 47–48 QT interval, 43, 44 Quadrant method, ECG, 47–48
R RAAS. See Renin-angiotensinaldosterone system (RAAS) Radial traction, lung volume, 149 RANK-L (receptor activator of nuclear kappa B ligand), bone remodeling, 319, 320 RAP. See Right atrial pressure (RAP) Rapid ACTH stimulation test, 284 Rapture of the deep, 173 RDS (respiratory distress syndrome), 147–148 Reabsorption bicarbonate, 221 glucose, 208–209 metabolites, 221 nephron, 191, 192 rate, 191 sodium, 220 urate (uric acid), 222 water and electrolytes, 221 Receptor activator of nuclear kappa B ligand (RANK-L), bone remodeling, 319, 320 Recruitment, 61, 62 Red muscle, 71 5α-Reductase, 359 Refractory periods, 31, 64 Regional circulations, exercise, 117–118 Regional transport, 219–233 collecting duct, 226–228 disorders of potassium homeostasis, 229–231 distal tubule, 225–226, 228 loop of Henle, 223–225 proximal tubule, 219–223 renal failure, 231–233 renal tubular acidosis, 228–229 Regurgitant valve, 126 aortic, 127 mitral, 129 Relative refractory period, 31, 64 Relaxin, pregnancy, 381 Renal blood flow, exercise, 118 Renal circulation, 114 Renal clearance, 207–208 estimate of glomerular filtration rate, 213–214 free water, 216 sodium and urea, 216–217 Renal corpuscle, 191, 279
Renal cortex, 189, 190 Renal failure, 231–233 and secondary hyperparathyroidism, 326 Renal handling of important solutes, 212 Renal medulla, 189, 190 Renal plasma flow (RPF), 210 Renal processes, 191–192 quantification of, 206–207 Renal system, 189–193 functional organization of kidney, 189–190 function of nephron, 191–192 functions of kidney, 189 insulin deficiency, 312 micturition reflex, 192–193 pregnancy, 381 Renal tubular acidosis, 228–229 Renin, 10 Renin-angiotensin-aldosterone system (RAAS), 10 long-term regulation of blood pressure and cardiac output, 279–281 pregnancy, 381 Reproductive changes, puberty, 353 Reproductive system female, 367–384 lactation, 382–384 menstrual cycle, 367–374 menstrual irregularities, 376–377 pregnancy, 377–382 sex steroid metabolism and excretion, 374–376 male, 357–365 age-related hormonal changes, 361–363 erection, emission, and ejaculation, 363–364 gonadal dysfunction, 364–365 hypothalamic-pituitary-gonadal axis, 357–361 RER (respiratory exchange ratio), 159 Residual volume (RV), 133, 134 Resistance, 76–78 cardiac output, 101 Respiration, muscles, 137 Respiratory acidosis bicarbonate, 237, 240 cause, 246 compensation, 238, 241 defined, 236 diagnosis, 240, 243 graphical representation, 244 metabolic acidosis with, 242 metabolic and, 241 Respiratory alkalosis bicarbonate, 237, 240 cause, 247 compensation, 238, 241 defined, 236 diagnosis, 240, 243 graphical representation, 244 metabolic acidosis with, 241 mixed metabolic and, 242 Respiratory centers, central, 171–172
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Index Respiratory compensation metabolic acidosis with, 241, 243 metabolic alkalosis with, 242, 243 Respiratory distress syndrome (RDS), 147–148 Respiratory exchange ratio (RER), 159 Respiratory quotient (RQ), 159 and alveolar PO2, 160 Respiratory stress, 172–173 Respiratory system, 133 neutral or equilibrium point, 140 Resting membrane potential, 23–25 cardiac, 38 Resting skeletal muscle, blood flow, 111 Restrictive cardiomyopathy, 91 Restrictive pulmonary disease, 150, 152–153, 155 Reverse triiodothyronine (reverse T3), 335, 338 Reynold’s number, 79 Rickets, 329 Right atrial pressure (RAP), 84, 97 cardiac output, 100 mean arterial pressure, 105 Right atrium, fetal circulation, 115, 116 Right-to-left shunt, ventilation-perfusion mismatch, 178 Right ventricle, fetal circulation, 115, 116 RPF (renal plasma flow), 210 RQ (respiratory quotient), 159 and alveolar PO2, 160 RV (residual volume), 133, 134 R wave, 43 Ryanodine (RyR), 59
S S1 heart sound, 119, 120 S2 heart sound, 119, 120–121 abnormal splitting, 121 S3 heart sound, 119, 121 S4 heart sound, 119, 121 Sacubitril, 264 Salivary secretions, 393–394 SA node. See Sinoatrial (SA) node Sarcolemma, 56, 59 Sarcomere, 55, 56 functional proteins, 57 Sarcoplasmic endoplasmic reticulum calcium adenosine triphosphatase (SERCA), 59.60 Sarcoplasmic reticulum (SR) regulation of cytosolic calcium, 59–60 ultrastructure, 56 Saturation kinetics, 204 SCC (sidechain cleavage enzyme), 272 SCN (suprachiasmatic nucleus), 276 Secondary transport, 204–205 Second-degree heart block, 49 Secretin, 389, 396, 398 Secretion(s) gastrointestinal, 393–402 bile, 399–401 gastric, 394–396
pancreatic, 396–398 salivary, 393–394 small intestinal, 401–402 nephron, 191, 192 p-aminohippuric acid, 209–211 potassium, 230 proximal tubule, 222 rate, 191 SERCA (sarcoplasmic endoplasmic reticulum calcium adenosine triphosphatase), 59.60 Series circuits, 80 Serosa, 387, 388 Sertoli cells, 358, 359, 360 Sex steroids, female, 374–376 Sheehan syndrome, 260, 381 Shunt(s) intrapulmonary, 183–184 left-to-right, 184–186 right-to-left, 178 SIADH (syndrome of inappropriate secretion of antidiuretic hormone), 265–266 Sidechain cleavage enzyme (SCC), 272 Simple diffusion, 203 Sinoatrial (SA) node, control of excitability, 42–43 Sinoatrial (SA) node cells action potentials, 41–42 automaticity, 37 Skeletal muscle altering force, 60–62 blood flow, 111 cardiac vs., 63–64 excitation-contraction coupling, 55–62 exercise, 117 mechanics, 67–71 length-tension curves, 68–69 preload and afterload, 67 red vs. white, 69–70 velocity and load, 69 structure-function relationships, 55–58 Slow waves, 389 Small intestinal motility, 392 Small intestinal secretions, 401–402 Small intestine, digestion, 404, 405 Smooth muscle, 64–66 characteristics, 389–390 Sodium (Na+) clearance, 216–217 insulin deficiency, 312 normal values, 5 proximal tubule, 220 reabsorption, 278 resting membrane potential, 24, 25 Sodium (Na+) channels, voltage-gated (fast), 28–29 Sodium chloride (NaCl), distal tubule, 225 Sodium (Na+) current, inward, 41 Sodium/iodide symporter (NIS), 333 Sodium/potassium adenosine triphosphatase (Na+/K+ ATPase), 24
Sodium/potassium adenosine triphosphatase (Na+/K+ ATPase) pump, 205 proximal tubule, 222 Sodium-potassium-chloride (Na+-K+-2Cl-) transporter, 224 Solute(s) concentration, 6 net gain, 8 renal handling of important, 212 transport, 203–206 dynamics of protein-mediated, 204–206 mechanisms, 203 Somatostatin (SST), 258, 259 Somatostatinomas, 314 SO (supraoptic) nucleus, 262, 263 Spermatogenesis, 363 Sperm count, 377 Spirometer, 134 Splanchnic circulation, 113, 114 Splay, 209 Spontaneous pneumothorax, 144 SR (sarcoplasmic reticulum) regulation of cytosolic calcium, 59–60 ultrastructure, 56 SST (somatostatin), 258, 259 StAR (steroidogenic acute regulatory protein), 272, 359 Starling equation, 12 Starling forces, 11 Stenotic valve, 126 aortic, 126 mitral, 128 Stercobilin, 400 Steroid hormones, 251, 252 regional synthesis, 272–274 synthetic pathways, 270–272 Steroidogenic acute regulatory protein (StAR), 272, 359 Stomach digestion, 404, 405 emptying, 392 endocrine and neural control, 391 gastric motility, 391–392 Stress, glucocorticoids, 274 Stress hormones, 274 Stretch receptors, 261, 262, 263 Striated muscles, 63–64 Stroke volume (SV), 89 pulse pressure, 104 systolic pressure, 103 Stroke work, coronary circulation, 112 ST segment, 43, 44 changes, 51 Sublingual gland secretions, 393 Submandibular gland secretions, 393 Submucosa, 387, 388 Submucosal plexus, 387, 388 Subthreshold stimulus, 29 Suckling, lactation, 382–384 Sucrase, 404 Sulfonylurea derivatives, 307 Summation, 61, 62
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Pharmacology
Biochemistry
Physiology Physiology
Medical Genetics
Superior vena cava, fetal circulation, 115, 116 Suprachiasmatic nucleus (SCN), 276 Supraoptic (SO) nucleus, 262, 263 Surface tension, lung recoil, 146 Pathology Behavioral Science/Social Sciences Surfactant, 147, 148 SV. See Stroke volume (SV) SVR (systemic vascular resistance), 78, 86 Swallowing, 390 disorders, 391 Microbiology Swan-Ganz catheterization, 124 S wave, 43 Sympathetic nervous system, 35 GI tract, 388 glomerular filtration, 200–201 Symport, 204 Synapses electrical, 34 between neurons, 33–34 Synaptic buttons, 34 Synaptic cleft, 32 Synaptic transmission, 32–36 electrical synapses, 34 neuromuscular junction, 32–33 neuronal excitability/conduction decreased, 35 increased, 36 peripheral nervous system, 35 synapses between neurons, 33–34 Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 265–266 Syndrome X, 311 Systemic circuit, 75 exercise, 117 hemodynamics, 95–96 pressure, flow, resistance, 76–78 series and parallel circuits, 80 structure-function relationships, 76 Systemic vascular resistance (SVR), 78, 86 Systemic veins, vessel compliance, 81 Systolic blood pressure, factors affecting, 103 Systolic dysfunction, 90–92 Systolic performance, ventricle, 83–86 Systolic sounds, 120–121
T T3. See Triiodothyronine (T3) T4. See Tetraiodothyronine (thyroxine, T4) Tachyarrhythmias, cardiac output, 99 Tachycardia endogenously mediated, 98–99 pathologically mediated, 99 TBG (thyroid-binding globulin), 337 Temperature, spermatogenesis, 363 Temperature regulation, cutaneous circulation, 113–114 Tension pneumothorax, 144 Teriparatide, 328 Terminal cisternae, 56, 59 Testes control, 358–359
cryptorchid, 363, 364 endocrine function, 360–361 Testicular feminizing syndrome, 364 Testicular 17α-OH deficiency, 293 Testosterone, 361 age-related changes, 361, 362 control of testes, 358, 360 deficiency, 364–365 normal male development, 362 synthesis, 272 Tetraiodothyronine (thyroxine, T4) activation and degradation, 337–338 growth and metabolism, 339 structure, 335 synthesis, 334 transport in blood, 337 Tg. See Thyroglobulin (Tg) TGF (tubuloglomerular feedback), 194 Theca cells, 368, 369 Thiazide diuretics, 225 Thick filament, proteins, 57 Thin filament, proteins, 57 Third-degree heart block, 49 Threshold stimulus, 29, 30 Thyroglobulin (Tg), 331, 332 synthesis, 333, 334 thyroid hormone secretion, 336 Thyroid adenomas, toxic, 341 Thyroid-binding globulin (TBG), 337 Thyroid disease, autoimmune, 341, 342 Thyroid follicle, 331, 332 Thyroid function pregnancy, 381 tests, 341 Thyroid gland, 331–332 overall effects of thyrotropin, 341 response to low intake of iodine, 343 Thyroid hormones, 331–347 activation and degradation, 337–338 carbohydrate metabolism, 339 cardiovascular effects, 339 classification, 251, 252 dietary intake, 331 growth and maturation, 339 lipid metabolism, 339 measurement, 254 metabolic rate, 338 physiologic actions, 338–339 secretion, 336 control, 340–342 pathologic changes, 342–347 storage, 334 structure, 335 synthesis, 333–334 transport in blood, 337 Thyroiditis Hashimoto’s, 255, 344 subacute, 341, 346 Thyroid-stimulating hormone (thyrotropin, TSH) overall effects on thyroid, 341 serum, 341 Thyroid storm, 346 Thyroperoxidase (TPO), 334
Thyrotoxicosis, 345–346 Thyrotropin. See Thyroid-stimulating hormone (thyrotropin, TSH) Thyrotropin-releasing hormone (TRH), 258, 259 Thyroxine. See Tetraiodothyronine (thyroxine, T4) Tidal volume (Vt), 133, 134 Titin, 55, 56, 63 TLC (total lung capacity), 133, 134 TM (transport maximum) system tubular reabsorption, 208–209 tubular secretion, 209–212 Torsade de pointes, 40 Total body water, 3 Total lung capacity (TLC), 133, 134 Total peripheral resistance (TPR), 78, 86 mean arterial pressure, 105 Total ventilation, 134, 136 Toxic multinodular goiter, 341 Toxic thyroid adenomas, 341 TPO (thyroperoxidase), 334 TPP (transmural pressure gradient), 138, 139, 149 TPR (total peripheral resistance), 78, 86 mean arterial pressure, 105 Transmural pressure gradient (PTM, TPP), 138, 139, 149 Transport active, 203 dynamics of protein-mediated, 204–206 facilitated, 203 mechanisms, 203 net, 207 organic acids/bases, 211–212 primary and secondary, 204–205 rate, 204 regional, 219–233 collecting duct, 226–228 disorders of potassium homeostasis, 229–231 distal tubule, 225–226, 228 loop of Henle, 223–225 proximal tubule, 219–223 renal failure, 231–233 renal tubular acidosis, 228–229 Transport maximum (TM) system tubular reabsorption, 208–209 tubular secretion, 209–212 Traumatic pneumothorax, 144 TRH (thyrotropin-releasing hormone), 258, 259 Tricuspid auscultation point, 121 Triglyceride(s), digestion, 404 Triglyceride metabolism insulin deficiency, 312 insulin effects, 304–305 Triiodothyronine (T3) activation and degradation, 337–338 growth and metabolism, 339 reverse, 335, 338 structure, 335 synthesis, 334 transport in blood, 337
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Index Tropomyosin, 57, 58 Troponin, 57, 58 Trousseau’s sign, 326 Trypsin, 397, 404 Trypsin inhibitor, 396 Trypsinogen, 397 TSH. See Thyroid-stimulating hormone (thyrotropin, TSH) T-tubule, 56, 59 Tubular reabsorption, 191 glucose, 208–209 Tubular secretion, 191 p-aminohippuric acid, 209–211 Tubuloglomerular feedback (TGF), 194 Turbulent flow, 79–80 T wave, 43, 44
U UES (upper esophageal sphincter), 390 Ultrafiltrate, 191 Umbilical arteries, fetal circulation, 116 Umbilical vein, fetal circulation, 115, 116 Ungated ion channel, 20, 21 Ungated potassium channels, cardiac resting membrane potential, 38 Uniport, 204 Upper esophageal sphincter (UES), 390 Urate, proximal tubule, 222 Urea clearance, 217 Uric acid, proximal tubule, 222 Urinary excretion, steroid hormones, 272 Urine analysis, hormone levels, 254 Uterine endometrium, hormonal maintenance, 378–379
V Valvular dysfunction, 126–129 aortic insufficiency regurgitation, 127 aortic stenosis, 126 mitral insufficiency regurgitation, 129 mitral stenosis, 128 Vanillylmandelic acid (VMA), 297 Vasa recta, 189, 223 Vascular compartment, 3 Vascular function, cardiac output, 98, 100 Vascular resistance (VR), 76–78 cardiac output, 101 Vasoconstriction, 96 cardiac output, 101 hypoxic, 179 Vasodilation, 96 cardiac output, 101 VC. See Vital capacity (VC) Veins, 76 systemic, vessel compliance, 81 Velocity blood flow, 79 and load, 70 maximum, 70 Venae cavae, 76 Venous compliance, mean systemic filling pressure, 97–98 Venous pulse, 121–123
Venous return (VR), 96–98 and cardiac output, 96–97, 99–101 Venous system, exercise, 117 Ventilation, 134–137 alveolar, 136–137, 158 and alveolar PCO2, 158–159 neural regulation, 170–172 assisted control mode, 142 cardiovascular changes, 142 dead space, 134–136 minute, 136 positive-pressure, 142–143 regional differences, 175–176 total, 134, 136 Ventilation/perfusion (V/Q) differences, 175–179 exercise, 179 hypoxic vasoconstriction, 179 regional differences in blood flow, 176 regional differences in intrapleural pressure, 175 regional differences in ventilation, 175–176 ventilation-perfusion relationships, 176–179 Ventilation/perfusion (V/Q) matching, 176–177 Ventilation/perfusion (V/Q) mismatch, 178 hypoxemia, 182–183 Ventilation/perfusion (V/Q) relationships, 176–179 Ventilation/perfusion (V/Q) units, 177, 178 hypoxemia, 182–183 Ventricle, systolic performance, 83–86 Ventricular contractility, systolic pressure, 103 Ventricular function cardiac output, 98, 100 curves, 87–89 Ventricular preload, 88 Ventricular septal defect, left-to-right shunt, 185 Ventricular volumes, 89 Ventromedial nucleus, 258 Venules, 76 Vessel compliance, 81 pulse pressure, 104 Villi, 401 VIPomas, 314 Virilization, 377 Vital capacity (VC), 133, 134 forced, 149–150 pulmonary function testing, 149–150 Vitamin D actions, 323–324 bone remodeling, 320 calcium homeostasis, 322–324 sources and synthesis, 322–323 Vitamin D2, 322 Vitamin D deficiency, and secondary hyperparathyroidism, 327 Vitamin D excess, and secondary hypoparathyroidism, 327 VMA (vanillylmandelic acid), 297
Vmax (maximum velocity), 70 VO2 (oxygen consumption), Fick principle, 107, 108 Voiding phase, micturition, 193 Voltage- and ligand-gated ion channel, 21–22 Voltage-gated ion channel, 20, 21 action potential, 28–29 Volume changes, due to changes in body hydration, 9 Volume measurement, body compartments, 14–15 Volume overload, 90–91 Volume regulation, 261, 262, 263 V/Q. See Ventilation/perfusion (V/Q) VR (vascular resistance), 76–78 cardiac output, 101 VR (venous return), 96–98 and cardiac output, 96–97, 99–101 Vt (tidal volume), 133, 134 v wave, venous pulse, 122, 123
W Wall tension, 81–82 Water (H2O) net gain, 8 net loss, 8 proximal tubule, 221 reabsorption, 278 total body, 3 Water-soluble hormones, 251–252 Waves, ECG, 43–44, 46 Weight-bearing stress, bone remodeling, 320 Weightlessness, effect on ADH secretion, 263 Wenckebach heart block, 49 “West zones,” lung, 175 White muscle, 70 Wolffian duct, 362 Wolff-Parkinson-White syndrome, 50–51
X Xanthine oxidase, 222 x descent, venous pulse, 122, 123
Y y descent, venous pulse, 122, 123
Z Z lines, 55, 56, 58 Zona fasciculata, 269 enzyme deficiency, 289, 290 loss of function, 270 steroid synthesis, 273, 274 Zona glomerulosa, 269 enzyme deficiency, 287–288, 291 loss of function, 270 steroid synthesis, 273 Zona reticularis, 269 enzyme deficiency, 289, 290 loss of function, 270 steroid synthesis, 273, 274
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