Diagnosis and Treatment in Internal Medicine (Oct 16, 2018)_(019956874X)_(Oxford University Press)

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PATRICK DAVEY

DAVID SPRIGINGS

DIAGNOSIS AND TREATMENT IN INTERNAL MEDICINE

DIAGNOSIS AND TREATMENT IN INTERNAL MEDICINE Edited by

Patrick Davey Consultant Cardiologist, Northampton General Hospital NHS Trust, Northampton, UK

David Sprigings Formerly Consultant Physician, Northampton General Hospital NHS Trust, Northampton, UK

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1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2018 The moral rights of the authors have been asserted First Edition published in 2018 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2018941300 ISBN 978–0–19–956874–1 Printed and bound in China by C&C Offset Printing Co., Ltd. Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Preface Diagnosis and Treatment in Internal Medicine came about through our experience on the acute medical take. Here, sick patients present in large numbers with a vast range of problems. What all patients need, as the bedrock of management, is a differential diagnosis, and the central aim of our book is to help doctors formulate this. We asked experts in their field to provide succinct and authoritative guidance across the breadth of internal medicine. The assessment of symptoms or presenting problems is a major element of the book, but there is also comprehensive coverage of disorders of the body systems, including psychological aspects and palliative care. Chapters are structured so that key information can rapidly be found. Doctors need a broad perspective on health and its promotion, and there are sections addressing nutrition, lifestyle, and prevention of disease. This book approaches medicine from the patient’s perspective, through the stories that patients tell us about their illness, and provides the knowledge that turns these narratives into diagnoses, treatment, health, and longevity. Throughout, our focus has been on meeting the needs of doctors in the clinic, in the emergency department, or on the ward. Our eternal thanks go out to our contributors. Some 200 outstanding doctors have produced admirably compact and lucid chapters. Throughout the lengthy gestation of the book, we have been ably supported by the staff at Oxford University Press, who have encouraged us and orchestrated the project. All praise should be directed to the authors, and any mistakes are ours. Please do let us have your suggestions for improvements (you can contact us at [email protected] and [email protected]). Patrick Davey David Sprigings

Contents Normal values  xiii Abbreviations  xv Contributors  xxiii

PART 1  THE APPROACH TO THE PATIENT 1 Diagnostic reasoning  2 2 Dealing with uncertainty  8 3 Taking the history  12 4 The physical examination  15

5 The psychological examination  18 6 Confidentiality  22 7 Consent  24

PART 2  ASSESSMENT OF SYMPTOMS AND PRESENTING PROBLEMS 8 Palpitation  28 9 Acute chest pain  31 1 0 Chronic chest pain  37 1 1 Hypotension  43 1 2 Acute breathlessness  47 1 3 Chronic breathlessness  51 1 4 Peripheral oedema  56 1 5 Murmur  58 1 6 Cough  61 1 7 Wheeze  63 1 8 Haemoptysis  65 1 9 Pleural effusion  67 2 0 Chylothorax  70 2 1 Difficulty swallowing  71 2 2 Haematemesis  73 2 3 Acute abdominal pain  75 2 4 Chronic abdominal pain  78 2 5 Dyspepsia  81 2 6 Abdominal mass  83 2 7 Constipation  85 2 8 Acute diarrhoea  87 2 9 Chronic diarrhoea  89 3 0 Rectal bleeding  91 3 1 Jaundice  93 3 2 Ascites  95 3 3 Chylous ascites  98 3 4 Swelling in the neck  99 3 5 Splenomegaly and other disorders of the spleen  101 3 6 Lymphadenopathy  103

3 7 Anaemia  104 3 8 Bruising and bleeding  106 3 9 Transient loss of consciousness  109 4 0 Coma  112 4 1 Delirium (acute confusional state)  116 4 2 Seizures  120 4 3 Difficulty speaking (including dysphasia and dysarthria)  123 4 4 Weakness  126 4 5 Tremor and other abnormal movements  131 4 6 Gait disorders  134 4 7 Sensory loss  137 4 8 Headache  142 4 9 Loss of vision  146 5 0 The red eye  150 5 1 Hearing loss  153 5 2 Facial pain  155 5 3 Dizziness  157 5 4 Disorders of sleep  159 5 5 Haematuria  161 5 6 Oliguria and anuria  163 5 7 Polyuria  165 5 8 Dysuria  167 5 9 Urinary incontinence  170 6 0 Faecal incontinence  173 6 1 Vaginal discharge  175 6 2 Joint pain  178 6 3 Muscle pain  181 6 4 Low back pain  183 6 5 Painful leg  187

66 Leg ulcers  191 67 Limb ischaemia  193 68 Rashes  195 69 Blistering rashes  197 70 Photosensitive rashes  200 71 Itching  203 72 Lumps and bumps  205 73 Falls  209 74 Immobility (‘Off legs’)  212 75 Suspected anaphylaxis  214

76 Fever  216 77 Hyperthermia  218 78 Hypothermia  221 79 Fatigue  224 80 Unintentional weight loss  226 81 Obesity: differential diagnosis  228 82 Self-​harm  231 83 Alcohol intoxication  234 84 Intravenous drug use  239

Contents

PART 3  CARDIOVASCULAR DISORDERS 85 Normal function of the cardiovascular system  244 86 Risk factors for cardiovascular disease  248 87 Diagnosis and investigation in suspected heart disease  252 88 Congenital heart disease in adults  263 89 Chronic stable angina  271 90 Acute coronary syndromes  275 91 Acute heart failure  280 92 Chronic heart failure  283 93 Aortic stenosis  287 94 Aortic regurgitation  290 95 Mitral regurgitation  292 96 Miscellaneous valvar pathology: Mitral stenosis, pulmonary stenosis, and tricuspid regurgitation  295 97 Percutaneous coronary intervention  299 98 Heart surgery  302 99 Circulatory support therapy  306 1 00 Pulmonary hypertension  308 1 01 Venous thrombosis and pulmonary embolism  312 1 02 Aortic aneurysm  318 1 03 Aortic dissection  320 1 04 Peripheral arterial disease  322

1 05 Raynaud’s phenomenon  325 1 06 Heart muscle disease (cardiomyopathy)  327 1 07 Tumours and the heart  332 1 08 Cardiac infection  335 1 09 Pericardial disease  340 1 10 Extrasystoles  342 1 11 Sinus tachycardia  345 1 12 Focal (ectopic) atrial tachycardia  348 1 13 Multifocal atrial tachycardia  351 1 14 Atrioventricular nodal re-entrant tachycardia  354 1 15 Atrioventricular re-​entrant tachycardia  357 1 16 Atrial fibrillation  361 1 17 Atrial flutter  366 1 18 Ventricular tachyarrhythmias: Ventricular tachycardia and ventricular fibrillation  369 1 19 Bradyarrhythmias  379 1 20 Sudden cardiac death  384 1 21 Cardiac device therapy  395 1 22 Drug-​induced cardiovascular disease  401 1 23 Psychological management of coronary heart disease  403 1 24 Treatment of terminal cardiovascular disease  405

PART 4  RESPIRATORY DISORDERS 1 25 Normal respiratory function  410 1 26 Diagnosis in suspected respiratory disease  412 1 27 Investigation in respiratory disease  415 1 28 Upper respiratory tract infections, including influenza  425 1 29 Pneumonia  427 1 30 Tuberculosis  431

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1 31 Pneumothorax  436 1 32 Cystic fibrosis  439 1 33 Asthma  441 1 34 Chronic obstructive pulmonary disease  445 1 35 Respiratory failure  449 1 36 Obstructive sleep apnoea  454 1 37 Bronchiectasis  456

1 38 Sarcoidosis and other granulomatous lung disease  458 1 39 Interstitial lung disease  460 1 40 Pulmonary vasculitis  464 1 41 Lung cancer (including management of an isolated lung lesion)  467

1 42 Occupational lung disease  472 1 43 Pleural infection and malignancy  475 1 44 Drug-​induced lung disease  477 1 45 Psychology in respiratory disease, including dysfunctional breathing  480 1 46 Terminal care in respiratory illness  482

PART 5  INTENSIVE CARE MEDICINE 1 47 Critical illness  486 1 48 Role of the intensive care unit  488 1 49 ICU treatment of respiratory failure  490 1 50 ICU treatment of cardiovascular failure  493

1 51 ICU treatment of acute kidney injury  496 1 52 ICU treatment of sepsis and septic shock  498 1 53 Terminal care in the intensive care unit  501 1 54 Brain death  503

1 55 Normal renal function  506 1 56 Diagnosis in suspected renal disease  509 1 57 Investigation in renal disease  512 1 58 Urinary tract infection  518 1 59 Glomerulonephritis  521 1 60 Interstitial renal disease  527 1 61 Nephrotic syndrome  529 1 62 Acute kidney injury  533 1 63 Chronic kidney disease  536 1 64 Diabetic renal disease  540 1 65 Urinary tract obstruction   543 1 66 Renal calculi  546 1 67 Renal and bladder cancer  549 1 68 Renal replacement therapy  552

1 69 Inherited renal diseases  556 1 70 The kidney in systemic disease  558 1 71 Renal vascular disease  561 1 72 Management of terminal care in renal disease  563 1 73 Disorders of plasma potassium  565 1 74 Disorders of plasma sodium  568 1 75 Disorders of plasma calcium  570 1 76 Disorders of plasma phosphate  573 1 77 Disorders of plasma magnesium  575 1 78 Disorders of acid–​base balance  577 1 79 Porphyria  580 1 80 Aminoacidopathies, urea cycle disorders, and organic acidurias  582 1 81 Amyloidosis  584

Contents

PART 6  DISORDERS OF THE KIDNEY AND URINARY TRACT, AND ELECTROLYTE AND METABOLIC DISORDERS

PART 7  DIABETES MELLITUS AND ENDOCRINE DISORDERS 1 82 Normal function of the endocrine system  588 1 83 Diagnosis and investigation in endocrine disorders  593 1 84 Diabetes mellitus  596 1 85 Hypoglycaemia  601 1 86 Thyroid disease  603 1 87 Primary hyperparathyroidism  610

1 88 Adrenal disease  612 1 89 Cushing syndrome  617 1 90 Short stature  619 1 91 Infertility  621 1 92 Pituitary disorders: Prolactinomas, acromegaly, and pituitary apoplexy  625

PART 8  GASTROINTESTINAL DISORDERS 1 93 Normal gastrointestinal function  632 1 94 Diagnosis in suspected gastrointestinal disease  635

1 95 Investigation in gastrointestinal disease  637 1 96 Immunology and genetics in gastrointestinal and hepatic medicine  641

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1 97 Gastrointestinal infections  644 1 98 Benign oesophageal disease  648 1 99 Peptic ulcer disease  651 2 00 Gall bladder disease  653 2 01 Pancreatic disease  656

2 02 Malabsorption  660 2 03 Inflammatory bowel disease  663 2 04 Gastrointestinal tumours  667 2 05 Functional gastrointestinal diseases  674 2 06 Psychiatry in gastrointestinal medicine  676

PART 9  DISORDERS OF THE LIVER 2 07 Normal hepatic function  680 2 08 Investigation in liver disease  686 2 09 Acute liver failure  690 2 10 Chronic liver failure  693 2 11 Alcoholic liver disease  697 2 12 Viral hepatitis  700

2 13 Autoimmune hepatitis  709 2 14 Genetic liver disease  713 2 15 Drug-​induced liver disease  718 2 16 Miscellaneous liver diseases  721 2 17 The liver in systemic disease  726 2 18 Liver cancer  731

Contents

PART 10  NEUROLOGICAL DISORDERS 2 19 Normal neurological function  736 2 20 Diagnosis in suspected neurological disease  739 2 21 Investigation in neurological disease  742 2 22 Demographics of neurological disease  752 2 23 Neurogenetic disease  755 2 24 Neurocutaneous syndromes  760 2 25 Congenital neurological disorders  762 2 26 Epilepsy  764 2 27 Stroke  767 2 28 Dementia  777 2 29 Neurological infection  781 2 30 Disorders of movement  787 2 31 Multiple sclerosis  791

2 32 Motor neuron disease  794 2 33 Spinal cord disease  796 2 34 Neuropathy  800 2 35 Myopathy  804 2 36 Vasculitis in neurology  807 2 37 Neurological tumours  812 2 38 Non-​metastatic neurological manifestations of malignancy  815 2 39 Neurosurgery  817 2 40 Drug-​induced neurological disease  821 2 41 Functional and dissociative disorders in neurology  825 2 42 Palliative care in neurological disease  828

PART 11  DISORDERS OF THE SKIN 2 43 Normal skin function  832 2 44 Approach to diagnosing skin disease  836 2 45 Investigation in skin disease  839 2 46 Skin infection and infestation  842 2 47 Cutaneous vasculitis  845 2 48 Acne  847 2 49 Psoriasis  850 2 50 Eczema  853 2 51 Urticaria  855 2 52 Bullous disorders  857 2 53 Hair disorders  860

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2 54 Nail disorders  863 2 55 Mucosal disease  865 2 56 Genital disease  868 2 57 Polymorphic light eruption and actinic prurigo  870 2 58 Disorders of pigmentation  872 2 59 Skin cancer  874 2 60 Skin markers of internal medicine  882 2 61 Drug-​induced skin disease  886 2 62 Psychocutaneous medicine  889

PART 12  DISORDERS OF THE MUSCULOSKELETAL SYSTEM 2 63 Normal function of the musculoskeletal system  892 2 64 Diagnosis in suspected rheumatological disease  894 2 65 Investigation in rheumatological disease  900 2 66 Osteoarthritis  906 2 67 Rheumatoid arthritis  910 2 68 Seronegative spondyloarthropathy  914

2 69 Systemic lupus erythematosus  918 2 70 Crystal arthropathy  921 2 71 Infection of joints and bones  925 2 72 Vasculitis  927 2 73 Osteomalacia  932 2 74 Paget’s disease of bone  933 2 75 Osteoporosis and fragility fracture  935 2 76 Genetic bone and joint disease  938

2 77 Normal blood function  944 2 78 Diagnosis and investigation in haematology  951 2 79 Deficiency anaemias  955 2 80 Haemolytic anaemia  958 2 81 Normal platelet function  967 2 82 Platelet disorders  970 2 83 Normal haemostatic function  975 2 84 Bleeding disorders  979

2 85 Prothrombotic conditions  984 2 86 Acute leukaemia  989 2 87 Chronic leukaemia  992 2 88 Myelodysplasia  995 2 89 Lymphoma  996 2 90 Multiple myeloma and related conditions  999 2 91 Myeloproliferative disorders  1002 2 92 Terminal care in haematological disease  1005

PART 14  DISORDERS OF THE IMMUNE SYSTEM 2 93 Functions of the immune system  1008 2 94 Clinical features and diagnosis of immunological disease  1013 2 95 Neutrophil abnormalities  1017 2 96 Human immunodeficiency virus infection  1020 2 97 Antibody deficiencies  1025

2 98 Combined T-​and B-​cell immunodeficiencies  1028 2 99 Complement deficiencies  1031 3 00 Hypersensitivity diseases  1034 3 01 Immunological support  1038 3 02 Immunosuppressive therapy and therapeutic monoclonal antibodies  1040

Contents

PART 13  HAEMATOLOGICAL DISORDERS

PART 15  INFECTIOUS DISEASES 3 03 Defences against infection  1044 3 04 Nature and demographics: Epidemiology of infective organisms  1048 3 05 Diagnosis in suspected infective disease: The history and examination  1051 3 06 Investigation in infection  1058 3 07 Treatment of infection  1061 3 08 Viral infection  1064 3 09 Sepsis  1068 3 10 Bacterial infection  1071 3 11 Mycobacterial infection other than tuberculosis  1075

3 12 Spirochaetal infection (non-syphilis)  1079 3 13 Syphilis  1082 3 14 Rickettsial infection  1084 3 15 Fungal infection  1086 3 16 Protozoal infection: Gut organisms  1091 3 17 Protozoal infection: Malaria  1094 3 18 Worm infection (including hydatid disease)  1098 3 19 Prion disease  1101 3 20 Sexually transmitted disease (gonorrhoea)  1103

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PART 16 CANCERS 3 21 Cancers related to infection  1106 3 22 Principles of oncogenesis  1109 3 23 Presentations in suspected cancer  1111 3 24 Diagnosis and staging of cancer  1113 3 25 Treatment of cancer  1115

3 26 Prostate cancer  1118 3 27 Breast cancer  1122 3 28 Ovarian and testicular cancer  1126 3 29 Symptom control in cancer  1128 3 30 Dying from cancer  1131

PART 17  DIETARY, LIFESTYLE, AND ENVIRONMENTAL FACTORS AFFECTING HEALTH 3 31 Normal nutritional function  1134 3 32 Starvation and malnutrition  1136 3 33 Vitamin deficiencies  1139 3 34 Nutritional support in the critically ill  1144 3 35 Poor diets  1147 3 36 Obesity: epidemiology, prevention and management  1150

3 37 Physical activity and its role in disease prevention  1155 3 38 Smoking  1158 3 39 Alcohol  1160 3 40 Environmental radiation  1164 3 41 Air pollution  1166 3 42 Non-​prescription drugs  1168

Contents

PART 18  PREVENTION OF DISEASE 3 43 Prevention of cardiovascular disease  1172 3 44 Prevention of respiratory disease  1176 3 45 Prevention of kidney disease  1179 3 46 Prevention of gastrointestinal disease  1181

3 47 Prevention of neurological disease  1183 3 48 Prevention of cerebrovascular disease  1187 3 49 Prevention of infection  1189 3 50 Prevention of cancer  1192

PART 19  SCREENING FOR DISEASE 3 51 Screening for cardiovascular disease  1196 3 52 Screening for respiratory disease  1202 3 53 Screening for kidney disease  1205 Index  1215

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3 54 Screening for gastrointestinal disease  1206 3 55 Screening for neurological disease  1209 3 56 Screening for cancer  1211

Normal values Common haematology values Haemoglobin

men: 130–​180 g/​l women: 115–​160 g/​l

Mean cell volume, MCV

76–​96 fl

Platelets

150–​400 × 109/​l

White cells (total)

4–​11 × 109/​l

• neutrophils

40%–​75%

• lymphocytes

20%–​45%

• eosinophils

1%–​6%

Blood gases pH

7.35–​7.45

PaO2

>10.6 kPa (75–​100 mm Hg)

PaCO2

4.7–​6 kPa (35–​45 mm Hg)

Base excess

±2 mmol/​l

U&ES (urea and electrolytes) Sodium

135–​145 mmol/​l

Potassium

3.5–​5 mmol/​l

Creatinine

70–​120 μmol/​l

Urea

2.5–​6.7 mmol/​l

eGFR

>90

LFTs (liver function tests) Bilirubin

3–​17 μmol/​l

Alanine aminotransferase, ALT

5–​35 IU/​l

Aspartate transaminase, AST

5–​35 IU/​l

Alkaline phosphatase, ALP

30–​150 IU/​l (non-​pregnant adults)

Albumin

35–​50 g/​l

Protein (total)

60–​80 g/​l

Cardiac enzymes Troponin T

20 min) rest pain

Prolonged (>20 min) rest angina, now resolved, with moderate or high likelihood of CAD

Low Risk (No high-​or intermediate-​risk feature but may have any of the following features)

New-​onset CCS Class III or IV angina in the past 2 wk with moderate or high likelihood of CAD

Rest angina (70 y

New or worsening MR murmur S3 or new/​worsening rales Hypotension, bradycardia, tachycardia Age >75 y ECG findings

Angina at rest with transient ST-​segment changes >0.05 mV

T-​wave inversions >0.2 mV

Bundle-​branch block, new or presumed new

Pathological Q waves

Normal or unchanged ECG during an episode of chest discomfort

Sustained ventricular tachycardia Cardiac markers

Markedly elevated (eg, TnT or TnI >0.1 ng/​mL)

Slightly elevated (eg, TnT >0.01 but 40 years Smoker, with >20 pack-​years consumption Gradual onset of symptoms Symptoms including cough present on most days Cough worse in morning Industrial exposure to coal/​ cotton dust Pursed lip breathing/​prolonged expiration Barrel-​shaped chest PEF 2 mm in diameter)

Lower airways (bronchi 600 ml in 24 hours.

Nasal signs: Nasal crusting or dried blood may be found in Wegener’s granulomatosis (granulomatosis with polyangiitis). Superior vena cava obstruction: Swelling of the face and neck with fixed elevation of the jugular venous pressure may be found in lung cancer. Auscultation of the chest: Bronchial breath sounds may be heard in pneumonia or tuberculosis, while coarse crepitations may be heard in bronchiectasis.

Differential diagnosis See Table 18.1 for the differential diagnosis of haemoptysis.

Context

Specific clues to the diagnosis

Haemoptysis is a common and non-​specific symptom. It can vary from blood-​streaked sputum to massive, life-​threatening haemorrhage. Haemoptysis may originate from the bronchial arteries (90%), pulmonary arteries (5%), or non-​bronchial collaterals. Haemoptysis causing haemodynamic instability and/​or respiratory compromise is a medical emergency. Unexplained haemoptysis may herald a ser­ ious underlying lung condition and therefore requires a thorough diagnostic workup. The majority of patients can be safely investigated and managed as outpatients. Urgent workup or inpatient management will be determined by the rate and severity of bleeding, and knowledge of either the source of bleeding and/​or the underlying condition.

See Table 18.2 for specific clues to the diagnosis.

Approach to diagnosis It is important to distinguish haemoptysis from epistaxis or haematemesis. A focused history is the key to diagnosis: Demographics: In patients from the Indian subcontinent or sub-​ Saharan Africa, a diagnosis of tuberculosis or post-​tuberculous bronchiectasis is more likely while, in the West, bronchiectasis or lung cancer is more common. Smoking: A high-​pack-​year history of smoking in the context of haemoptysis and other red-​flag symptoms such as cough, dyspnoea, chest pain, and weight loss is suggestive of lung cancer. Volume of haemoptysis: Bronchiectasis and pulmonary haemorrhage typically present with moderate-​to-​severe bleeding, whereas lung cancer and bronchitis cause mild-​to-​moderate bleeding.

Table 18.1  Differential diagnosis of haemoptysis Primary care

Likely diagnosis

Age

40 years: lung cancer

Fever; rusty-​coloured, purulent sputum

Pneumonia, especially Streptococcal pneumoniae, or tuberculosis

8%

COPD, cachexia, smoker

Lung cancer

6%

History of lung disease: childhood respiratory illness, tuberculosis, pneumonia, etc.

Bronchiectasis

Major risk factors for venous thromboembolism + haemoptysis

Pulmonary embolism

Fever, weight loss, sinus/​nasal symptoms, haematuria, skin rash, eyes, joint, CNS involvement

Vasculitis, e.g. Wegener’s granulomatosis (granulomatosis with polyangiitis).

Bronchiectasis

38%

Lung cancer

25%

Mycetoma/​aspergilloma

16%

Lung cancer

10%

Tuberculosis Pneumonia Pulmonary vasculitis

2%

Others

8%

Note: Twenty per cent of haemoptyses are cryptogenic.

Chest radiograph: This is the first investigation of choice, as it may help localize the bleeding site to, for example, a mass lesion, or regions showing consolidation, bronchiectasis, or diffuse interstitial shadowing in vasculitides. In approximately 20%–​46% of cases, the chest radiograph will be non-​diagnostic. Blood tests: These should be taken to evaluate haemoglobin, platelet count, and clotting profile (full blood count, international normalized ratio, and activated partial thromboplastin time). If vasculitis or a pulmonary–​renal syndrome is suspected, renal and liver function tests as well as antineutrophil cytoplasmic antibodies (ANCAs), autoantibodies, and antiglomerular basement membrane (anti-​GBM) antibodies should be requested. All patients should be grouped and saved. Sputum: In patients at risk for lung cancer, sputum should be sent for cytology; in suspected tuberculosis or pneumonia, it should be sent for Gram stain, stain for acid-​fast bacilli, and culture. CT scan: This is now performed in the majority of unexplained causes of haemoptysis and should be done prior to bronchoscopy, as it directs the bronchoscopist to the likely source of bleeding and therefore increases the potential yield. High-​resolution CT should be requested if bronchiectasis is suspected. Contrast-​enhanced CT may help in identifying vascular lesions such as arteriovenous malformations. Request for a CT with bronchial artery circulation

Clues

60%–​70%

5%

Key diagnostic tests are as follows:

Table 18.2  Specific clues to the diagnosis

Secondary care

Infection bronchitis (25%) • pneumonia (10%) • tuberculosis (8%) • Cardiac haemoptysis (pulmonary venous or arterial hypertension; left ventricular failure, mitral stenosis, pulmonary embolism, and, more rarely, congenital heart disease with Eisenmenger syndrome)

Key diagnostic tests

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will provide a ‘road map’ of dilated tortuous bronchial arteries that may be targeted by an interventional radiologist for embolization if a bronchiectatic cavity or aspergilloma is suspected (see ‘Other diagnostic tests’). Bronchoscopy: Bronchoscopy, pending CT, is useful as both a diagnostic and therapeutic modality. It enables the anatomical source of the haemoptysis to be directly visualized and allows tissue biopsies or bronchial washes to be taken. From a therapeutic perspective, it allows injection of a bleeding tumour with a vasoconstrictor (e.g. adrenaline) or tamponade via a catheter (e.g. a Fogarty catheter). Many clinicians believe bronchoscopy should be performed in all cases of haemoptysis. Urinalysis: Microscopic haematuria in the presence of frank haemoptysis should encourage investigations to confirm or refute pulmonary–​renal syndrome.

Other diagnostic tests

CHAPTER 18 Haemoptysis

Subsequent investigations will depend on the presumed underlying diagnosis: CT pulmonary angiogram: Do this if pulmonary embolism is suspected. Echocardiography: This will identify moderate/​ severe pulmonary hypertension or mitral valve disease if suspected as a cause of haemoptysis. Bronchial artery angiography and embolization (BAE): This technique has both diagnostic and therapeutic benefits. If bleeding is from a bronchial artery, it will identify a mesh of dilated or tortuous vessels surrounding, for example, a bronchiectatic cavity or an aspergilloma. It is best performed during an episode of bleeding in order to maximize the chances of identifying the bleeding source. Abnormal vessel embolization is performed using glue or coils. This technique is only carried out in specialist centres, usually by experienced interventional vascular radiologists, with a success rate in the range of 73%–​98%. Complications include transient chest pain which is often ischaemic in origin and, more seriously, a 1% risk of spinal cord ischaemia if the embolized bronchial artery gives rise to the anterior spinal artery. Pulmonary function tests: In genuine causes of pulmonary haemorrhage, the gas transfer (KCO) will be elevated, reflecting the increased oxygen-​carrying capacity of blood present in the alveoli. This may be useful in confirming haemoptysis, provided the other causes of a raised KCO are excluded.

Introduction to therapy Non-​massive haemoptysis is managed conservatively, provided there is no haemodynamic instability or respiratory compromise. The key is to identify and treat the source. If the haemoptysis is persistent or troublesome, then in the absence of severe renal failure an antifibrinolytic such as tranexamic acid may be prescribed either orally (500 mg three times daily, or 15–​25 mg/​kg two to three times daily) or intravenously (0.5-​1.0 g three times daily). Massive haemoptysis is a medical emergency and must be managed in the same manner as a gastrointestinal (GI) haemorrhage (e.g. variceal bleeding). Resuscitation (intravenous fluids) and airway

66

protection are the first priority. Early anaesthetic input is important, and the patient may need to be admitted to a high-​dependency or intensive care unit. If the bleeding source is known, then the patient should be positioned with the bleeding side down to protect and prevent overspill into the unaffected lung. Nebulized adrenaline (5–​10 ml of 1:10 000) acts as a vasoconstrictor and may be used under these circumstances. Patients with ongoing massive haemoptysis should be intubated with a large endotracheal tube to allow bronchoscopy and suction. Alternatively, a double-​lumen endotracheal tube may be passed to protect the unaffected lung. Early bronchoscopy is advisable as it allows identification of the bleeding source and instillation of topical adrenaline (5–​10 ml of 1:10 000) or lavage with iced 0.9% saline to induce vasoconstriction, or tamponade using a balloon catheter. Rigid bronchoscopy is preferable for balloon tamponade but is often done by thoracic surgeons in tertiary centres in the UK. It also allows laser or electrocautery treatment in endoscopically visible tumours. If haemostasis is achieved, the most effective non-​surgical treatment, depending on the likely cause, is BAE (see ‘Other diagnostic tests’). However, for select cases (e.g. rebleeding despite BAE; localized bronchiectasis; trauma; hydatid cysts; arteriovenous malformations; thoracic aneurysm and aspergilloma) surgery (e.g. by lobectomy) remains the procedure of choice because it is curative.

Prognosis In 20%–​33% of cases, no source of bleeding is identifiable. This is called cryptogenic haemoptysis and has a good prognosis, with resolution of bleeding within 6 months of evaluation. Non-​massive haemoptysis has a mortality ranging from 7%–​ 30%. However, in massive haemoptysis the mortality can reach 80% and such an encounter is often a terrifying experience for both clinician and patient alike.

How to handle uncertainty in the diagnosis of this symptom The majority of cryptogenic haemoptyses can be managed by reassurance; however, it is important to have considered and excluded vasculitides such as Wegener’s granulomatosis, microscopic polyangiitis, or Goodpasture’s if there is any evidence of systemic disease. Patients may occasionally state that ‘blood appeared in my mouth’; if you believe the patient has had a bleed but are unsure if it is haemoptysis, then a thorough history for possible upper respiratory tract (e.g. epistaxis) or upper GI symptoms (dyspepsia, reflux, vomiting, melaena, etc.) should be sought, and referral to either an ENT or a gastroenterologist for possible nasal or upper GI endoscopy should be considered.

Further Reading Larici AR, Franchi P, and Occhipinti M. Diagnosis and management of hemoptysis. Diagn Interv Radiol 2014; 20: 299–​309. Khalil A, Fedida B, Parrot A, et al. Severe hemoptysis: From diagnosis to embolization. Diagn Interv Imaging 2015; 96: 775–88.

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Pleural effusion

Seamus Grundy

Definition of the presentation

Table 19.2  Exudative pleural effusions

A pleural effusion is a collection of fluid within the space between the visceral and parietal pleura. Pleural effusions can be unilateral or bilateral, and differentiation of this can aid with creating a differential diagnosis.

Parapneumonic effusion and empyema • Malignancy • Pulmonary embolism • Congestive heart failure after diuretic therapy • Mesothelioma • Tuberculosis • Rheumatoid arthritis and systemic lupus erythematosus • Esophageal rupture • Pancreatitis • Postcardiotomy syndrome • Drug-​induced • Chylothorax •

Differential diagnosis All unilateral pleural effusions require further investigation within a secondary care setting. Bilateral pleural effusions in the setting of known heart failure can be safely treated without further investigations unless the effusions are markedly asymmetric or there are symptoms suggestive of an alternative aetiology.

Reproduced with permission from Sprigings D, Chambers JB. Acute Medicine, fourth edition, Wiley-​Blackwell, Oxford, UK, Copyright © 2008.

Context Pleural effusion is a common clinical problem which can present both to primary and secondary care. In healthy individuals, the pleural space contains approximately 10–​15 ml of pleural fluid. Pleural effusions can be caused by many different disease processes. However, the process by which fluid accumulates can be divided into transudative or exudative. Transudative effusions (Table 19.1) occur in the presence of normal pleura and are caused by increased oncotic or hydrostatic pressures. Exudative effusions (Table 19.2) are associated with abnormal pleura and are caused by either increased pleural fluid production due to local inflammation or infiltration or by decreased fluid removal which is caused by obstruction of the lymphatic drainage system. Patients may be entirely asymptomatic or they may present with breathlessness, particularly if the effusion is large. Other symptoms include a cough and systemic symptoms such as weight loss, an­orexia, and fever. Chest pain is suggestive of inflammation/​infiltration of the parietal pleura and points towards malignancy or empyema. It is crucial to illicit the underlying diagnosis rapidly with a minimum of invasive tests in order to allow appropriate management of the causative disease process.

Approach to diagnosis The initial assessment of a patient with a pleural effusion requires a thorough medical history with particular attention to the following: Systemic symptoms: High fevers are suggestive of parapneumonic effusion/​empyema or tuberculosis. Weight loss/​anorexia points towards malignancy or empyema. Past medical history: In particular, look for previous malignancy or systemic diseases which can be associated with pleural effusion. Occupational history: Asbestos exposure can cause both malignant mesothelioma and benign asbestos-​related pleural effusion. The

temporal relationship with the asbestos exposure is important, with mesothelioma often having a lag time of decades whereas benign asbestos-​related effusion normally presents within 10 years of asbestos exposure. The patient should be examined with close attention being paid to the presence of any palpable lymph nodes, cachexia, and peripheral oedema suggestive of either congestive cardiac failure or a low-​protein state. Auscultation of the lungs will reveal diminished breath sounds over the pleural effusion, with stony dullness to percussion.

Specific clues to the diagnosis Specific clues to the diagnosis are as follows: Exudate vs transudate:  Pleural fluid can be defined as exudative or transudative, according to the concentration of protein and/​or lactate dehydrogenase (LDH) within the fluid. Light’s criteria have a sensitivity of 97% and a specificity of 80% for diagnosing an exudate (Table 19.3). Unilateral vs bilateral pleural effusion:  A unilateral pleural effusion invariably requires further investigation to determine the underlying pathological process. Bilateral pleural effusions in the presence of a history consistent with left ventricular dysfunction can safely be managed with medical treatments for heart failure without further tests. However, if the effusions are treatment resistant, further investigations should be pursued. Pleuritic chest pain: The presence of pleuritic chest pain implies involvement of the parietal pleura. This almost invariably suggests that the effusion is exudative in nature and most likely infectious or malignant, although pulmonary embolism with associated lung infarction is an important differential.

Key diagnostic tests Table 19.1  Transudative pleural effusions Congestive heart failure • Cirrhosis • Nephrotic syndrome • Peritoneal dialysis • Hypothyroidism • Pulmonary embolism (in 10−20% of cases) • Malignancy (in 5% of cases) • Reproduced with permission from Sprigings D, Chambers JB. Acute Medicine, fourth edition, Wiley-​Blackwell, Oxford, UK, Copyright © 2008.

The diagnostic workup of a patient with a pleural effusion should be systematic and based upon clinical judgement and results of initial investigations (see Figure 19.1).

Pleural fluid In most cases, a sample of pleural fluid should be obtained. This should be analysed for the following: Biochemistry: Protein and LDH should be measured to define whether the effusion is transudative or exudative. The pH of the fluid should

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Pleural effusion Use ultrasound to confirm if in doubt

Known systemic cause of transudate? No

Yes Asymmetric effusions, chest pain or fever?

Yes

Pleural aspiration

Transudate

Exudate

No Further tests to establish diagnosis

CHAPTER 19  Pleural effusion

Treat underlying cause Repeat chest X-ray to confirm resolution

Seek advice from chest physician

Figure 19.1  Management of pleural effusion. Reproduced with permission from Sprigings D, Chambers JB. Acute Medicine, fourth edition,Wiley-​Blackwell, Oxford, UK, Copyright © 2008.

be measured, particularly when pleural infection is suspected. If the pH is 80% is suggestive of tuberculosis. If initial tests are non-​ diagnostic, a repeat cytology sample can improve the sensitivity for malignant effusions.

Table 19.4  Pleural fluid analysis (2): Additional tests for exudative pleural effusion Test

Comment

Pleural fluid pH and glucose (check these if a parapneumonic or malignant pleural effusion is suspected. Send sample in heparinized syringe for measurement of pH in blood gas analyzer)

Low pH (70% positive in adenocarcinoma, 25–​50% in lymphoma, 10% in mesothelioma

Microbiology (Gram stain and culture; markers of tuberculosis (TB))

Send fluid for markers of TB if TB is suspected or there is a pleural fluid lymphocytosis

Other tests depending on the clinical setting (e.g. amylase, triglyceride)

Elevated pleural fluid amylase is seen in acute pancreatitis and esophageal rupture

See Tables 19.3 and 19.4 for overview of pleural fluid analyses.

Table 19.3  Pleural fluid analysis (1) Test

Comment

Visual inspection

Blood-​stained effusion (pleural fluid hematocrit 1−20% of peripheral hematocrit) is likely to be due to malignancy, pulmonary embolism or trauma Purulent fluid signifies empyema

Protein and lactate dehydrogenase (LDH)

These are the only tests needed if the effusion is likely to be a transudate Pleural fluid LDH correlates with the degree of pleural inflammation Exudative pleural effusions have a protein concentration >30 g/​L If the pleural fluid protein is around 30g/​L, Light’s criteria are helpful in distinguishing between a transudate and exudate. An exudate is identified by one or more of the following: • Pleural fluid protein to serum protein ratio >0.5 • Pleural fluid LDH to serum LDH ratio >0.6 • Pleural fluid LDH more than two-​thirds the upper limit of normal for serum LDH

Reproduced with permission from Sprigings D, Chambers JB. Acute Medicine, fourth edition, Wiley-​Blackwell, Oxford, UK, Copyright © 2008.

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Check triglyceride level if chylothorax is suspected (opaque white effusion); chylothorax (triglyceride >1.1 g/​L) is due to disruption of the thoracic duct by trauma or lymphoma CABG, coronary artery bypass graft. Reproduced with permission from Sprigings D, Chambers JB. Acute Medicine, fourth edition, Wiley-​Blackwell, Oxford, UK, Copyright © 2008.

If the initial tests do not provide a firm diagnosis, then a pleural biopsy should be obtained. This can be taken ‘blind’ with an Abrams needle; under radiological guidance, with a cutting biopsy needle; or at thoracoscopy. The only indication for Abrams biopsy is a suspected tuberculous effusion, as the sensitivity for malignant effusions with a blind biopsy is almost half that with either radiologically guided biopsy or thoracoscopy.

Introduction to therapy The management strategy for a pleural effusion is aimed at relieving symptoms and treating the underlying pathology. In the case of transudative effusions, effective treatment of the causative process is normally all that is required. Removal of pleural fluid can be achieved in two ways: therapeutic thoracocentesis or intercostal drain insertion. An intercostal drain should only be inserted once a diagnosis has been achieved, as complete drainage of the pleural space may inhibit the ability to perform thoracoscopy. The only urgent indication for intercostal drain is empyema or parapneumonic effusion with a pleural fluid pH 110 mg/​dl is diagnostic of chylothorax. A  low pleural-​fluid cholesterol level, the presence of chylomicrons, and a high lymphocyte count support the diagnosis. The appearance of the fluid may be misleading, resulting in under-​diagnosis of chylothorax: the classic milky appearance is seen in around 50% of cases.

Other diagnoses that should be considered Empyema is an important differential requiring early recognition and treatment. The pleural-​fluid pH will be low (200 mg/​dl, although it may exceed 1000 mg/​dl). The effusion is usually sterile and requires no treatment unless large enough to cause respiratory

21 

Difficulty swallowing

Satish Keshav and Alexandra Kent

Definition of the symptom Dysphagia is a difficulty in the process of swallowing.

Common causes Dysphagia is an alarm symptom, and therefore requires referral to secondary care for investigation. There are multiple causes, divided into oesophageal, neurological, surgical, and extrinsic obstruction, as shown in Table 21.1. Investigation and treatment of non-​oesophageal causes is not covered in detail in this section.

Context Swallowing is a complex process involving coordination of many nerves and over 50 pairs of muscles and can be divided into oral, pharyngeal, and oesophageal phases. It is important to ascertain whether patients have a problem initiating the swallow (suggesting

Incidence Oesophageal

Tumours Oesophagitis Eosinophilic oesophagitis Peptic stricture Diverticulum Rings and webs Motility disorders Scleroderma Functional

Most common causes are peptic stricture and oesophagitis; with increasing age, the incidence of dysmotility increases; dysphagia in juveniles and young adults is more likely to be due to eosinophilic oesophagitis

Extrinsic compression

Aberrant subclavian artery Cervical osteophytes Enlarged aorta Enlarged left atrium Mediastinal mass

Rare

Surgical

Laryngectomy Pharyngectomy Oesophagectomy Head and neck surgery

Rare

Stroke or traumatic brain injury Multiple sclerosis Myasthenia gravis Myopathy (dermatomyositis, myotonic dystrophy) Poliomyelitis Cervical brace Cervical spondylosis Motor neuron disease (e.g. amyotrophic lateral sclerosis) Parkinson’s disease and other degenerative disorders Cerebral palsy

Increasing with age

Other

Age, ventilator dependency

Approach to diagnosis The cornerstone to diagnosing the cause of dysphagia is a careful medical history. It is important to assess whether dysphagia is intermittent or progressive, and ask for associated symptoms, including heartburn, weight loss, haematemesis, coffee-​ ground emesis, anaemia, regurgitation of food particles, and respiratory symptoms. Furthermore, it is important to determine the type of food that produces dysphagia (solid vs liquid) and the temporal association to symptoms. For example, motility disorders may produce intermittent symptoms, whereas obstructing lesions (cancer, peptic strictures) will be progressive, involving solids before liquids.

Specific clues to the diagnosis

Table 21.1  Causes of dysphagia

Neurological

a neurological cause) or describe a sensation of ‘food sticking’ (suggesting oesophageal causes). Dysphagia can lead to weight loss and malnutrition; it also predisposes to aspiration pneumonia. Acute dysphagia has an annual incidence of ~13 per 100 000 population and is usually due to food impaction in obstructing lesions or eosinophilic oesophagitis.

Specific clues to the diagnosis are as follows: • Cancers causing obstruction will cause progressive dysphagia, from liquids to solids, with no relief from symptoms. Patients often have associated systemic symptoms including weight loss, anaemia, and chest pain, and risk factors such as smoking. • Patients with peptic strictures will have an underlying history of gastro-​oesophageal reflux. • Achalasia is a progressive disease often developing over months to years, and may be associated regurgitation or chest pain. • Motility disorders often have an intermittent history, and associated symptoms including chest pain, heartburn, and regurgitation. There may be symptoms of underlying disease, such as scleroderma, dermatomyositis, Sjögren’s syndrome, and so on. • Pharyngeal pouches are slowly progressive and have associated regurgitation and gurgling. • Patients with eosinophilic oesophagitis are often younger with a history of atopy.

Key diagnostic tests Any patient suffering dysphagia requires an upper gastrointestinal (GI) endoscopy, to rule out obstructing lesions. Furthermore, this provides the opportunity to obtain oesophageal biopsies to exclude eosinophilic oesophagitis.

Other diagnostic tests Patients who are felt to be at risk of complications from endoscopic procedures (comorbidities, such as severe heart or lung disease) should undergo a barium swallow, which will identify mucosal lesions and motility disorders such as achalasia. Oesophageal biopsies taken at the time of endoscopy are fundamental to the diagnosis of eosinophilic oesophagitis. In cases of a normal endoscopy and biopsies, patients should undergo oesophageal manometry to identify a motility disorder. Patients who have a problem initiating swallowing may have a neurological cause. These patients should undergo CT head, assessment by speech and language therapists (SALT) and video fluoroscopy. Assessment by SALT is important to reduce the risk of aspiration.

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Introduction to therapy Therapy is dictated by the underlying diagnosis: • Strictures can be treated with endoscopic balloon dilatation, although cancerous strictures have a significantly higher risk of perforation, compared to benign peptic strictures. Patients suffering with oesophageal cancers unsuitable for surgical resection or curative procedures may gain symptomatic relief from placement of an oesophageal stent. • Oesophagitis and peptic strictures require high-​dose therapy with proton-​pump inhibitors. • Achalasia is treated with smooth muscle relaxants, botulinum toxin, balloon dilatation, or surgical myotomy. • Eosinophilic oesophagitis responds to elimination diets and/​or topical steroids in the majority of patients.

Prognosis

CHAPTER 21  Difficulty swallowing

Overall prognosis is highly dependent on the underlying diagnosis. However, in most conditions, relief of dysphagia is achievable.

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How to handle uncertainty in the diagnosis of this symptom It is important to take a detailed history, as patients may misinterpret their symptoms, for example, describing ‘difficulty in swallowing’ when their main symptom is pain on swallowing (odynophagia). Standard tests may yield no clear diagnosis. Dysmotility in the early stages can be subtle, and tests may be negative. However, with time, symptoms may worsen, and subsequent testing may reveal a diagnosis previously not established. Rarely, pseudoachalasia, which is caused by an infiltrating tumour in the gastric cardia, may be misdiagnosed or missed.

Further Reading Johnston BT. Oesophageal dysphagia: a stepwise approach to diagnosis and management. Lancet Gastroenterol Hepatol 2017; 2: 604–09.

22 Haematemesis Satish Keshav and Alexandra Kent

Definition of the symptom Haematemesis is the vomiting of fresh or altered blood.

Common causes Haematemesis is almost exclusively dealt with in the hospital setting, as it is a medical emergency (see Box 22.1). Mallory–​Weiss tear, which typically occurs after prolonged vomiting and retching, usually is of small volume, without haemodynamic compromise, and is usually self-​limiting, may be recognized as such and not always referred to secondary care. Rare causes of haematemesis are unlikely to be encountered by most general practitioners. No cause for the haematemesis is found in 17% of cases, despite investigation. Endoscopy in the emergency setting can be difficult, and lesions may be missed. The Mallory–​Weiss tear may have healed by the time endoscopy is performed, and Dieulafoy lesions may only be transiently visible. Haemoptysis and vomiting of red-​stained food can be mistaken for haematemesis, possibly accounting for some cases where a diagnosis is not established.

Context Upper gastrointestinal haemorrhage (UGIH) has an incidence of 50–​150 cases per 100 000 population. Upper gastrointestinal bleeds have a 10% mortality rate, and as such should be treated as a medical emergency. The airway, breathing, and circulation (ABC) should be immediately assessed in all patients, as this reflects intravascular volume and the presence of ongoing bleeding. However, the physiological response to blood loss can mask signs and symptoms until >40% of the intravascular volume has been lost. Despite the use of proton-​pump inhibitors (PPIs), admission rates for peptic ulcer haemorrhage have increased in older age groups, probably related to increased use of antiplatelet agents and anticoagulants. Further reductions in mortality and morbidity may be prevented by the rising age of the population. The commonest cause of haematemesis is peptic ulceration, accounting for nearly 50% of cases. Risk factors include the use of NSAIDs, including aspirin; Helicobacter pylori infection; smoking; and alcohol use. Ninety per cent of duodenal ulcers, and 70% of gastric ulcers, are associated with H. pylori, and eradication is integral to treatment. Excess alcohol consumption has doubled the incidence of variceal bleeding over the past 10  years; this condition carries a high mortality that is related to underlying portal hypertension and liver disease/​cirrhosis.

Box 22.1  Causes of haematemesis

Common

duodenal ulcer* • • gastric ulcer • oesophageal varices* • Mallory–​Weiss tear

Infrequent

• vascular malformations: • Dieulafoy lesions • gastric antral vascular ectasia (GAVE) • angiodysplasia • upper gastrointestinal cancer oesophagitis* • gastroduodenal erosions

Rare

haemobilia • • aortoenteric fistula * Common with excess alcohol.

Rapid access to specialist care and emergency endoscopy are desirable, although this standard of care is not yet universally available in the United Kingdom. Integrated management by the acute medical and gastroenterology teams is, however, critically important, whatever the local service structure.

Approach to diagnosis History and examination will often give clues to the underlying cause of bleeding. If possible, be certain that the blood was vomited rather than coughed up. Was it a large or small volume, and was there evidence of volume depletion, such as feeling faint, weak, sweaty, or unwell? The list of medications can identify precipitants (e.g. aspirin, NSAIDs), medications likely to worsen bleeding (e.g. aspirin, warfarin, clopidogrel), and medications that may mask signs of intravascular depletion (e.g. beta blockers). Examination should ascertain the level of cardiovascular compromise: level of consciousness, breathing, pulse rate, blood pressure, and postural hypotension. It should also include a rectal examination to check for melaena, the presence of which confirms significant UGIH. Signs of chronic liver disease suggest that variceal bleeding is more likely. This can be torrential and life-​threatening and therefore enhanced care is appropriate: for example, early referral to gastroenterology, rapid replacement of blood, attention to comorbidity such as sepsis, and intensive nursing care. Nonetheless, peptic ulceration remains a major cause of haemorrhage even in those with portal hypertension, accounting for 20%–​40% of bleeding episodes. It is important to remember that the circulating haemoglobin level will not fall after haematemesis until the patient has replaced their lost circulating volume with plasma. Therefore, the first test in the emergency setting may be completely or nearly normal. This should not be regarded as reassuring!

Specific clues to the diagnosis Establishing that haematemesis has occurred may require endoscopy if non-​invasive tests are negative. There is no wholly satisfactory alternative to this, although passage of a nasogastric tube, followed by gastric lavage with a few hundred millilitres of saline, may be helpful in some circumstances. A negative lavage may allow the medical team to search more efficiently elsewhere for the cause of hypotension and anaemia, for instance. Endoscopy also allows a diagnosis to be made of the cause of haematemesis. Clues to the underlying diagnosis are shown in Table 22.1. The advantage of rapid or immediate endoscopy is that it also enables therapy to be administered. Table 22.1  Causes of upper gastrointestinal haemorrhage Diagnosis

Symptoms, signs, clues

Peptic ulcer disease

Dyspepsia Smoking/​alcohol/​caffeine Medications: aspirin, NSAIDs

Varices

Excess alcohol consumption Signs of chronic liver disease or portal hypertension

Mallory–​Weiss tears

Vomiting prior to haematemesis

Upper gastrointestinal cancers

Weight loss, dysphagia, early satiety, anaemia, older age (>50 years)

Haemobilia

Recent endoscopic retrograde cholangiopancreatography Gallstones

Aortoenteric fistula

Aortic aneurysm surgery, signs of endovascular infection

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Table 22.2 Rockall score Variable

Score 0

1

2

Age

80

3

Shock

No shock Systolic BP >100 Pulse 100 Pulse >100

Systolic BP 100 mOsm/​ kg being consistent with osmotic diarrhoea. The false-​positive rate of stool microscopy and culture means that at least three stool samples should be examined. An abdominal X-​ray should be performed in patients who are unwell, to exclude perforation, to assess the extent of colitis, and for toxic dilatation. In patients with persistent symptoms and negative stool examinations, a lower gastrointestinal (GI) endoscopy examination can be performed to obtain mucosal biopsies, although these are more useful when performed in the first 72 hours of infection.

Introduction to therapy Fluid replacement Fluid and electrolyte replacement is the cornerstone of therapy. Glucose-​based oral rehydration solutions are extremely effective, taking advantage of the active carrier-​mediated sodium–​glucose co-​transport. The ideal solution should have a low osmolarity (210–​250 mmol/​l) and a sodium content of 50–​60 mmol/​l. This means that the majority of commercially available drinks are far less suitable as rehydration agents. In more extreme cases, intravenous fluids can be given and will usually reverse any metabolic acidosis associated with the illness.

Antibiotics The use of antibiotics in GI infections is controversial. In infections that are improving with conservative therapy, antibiotics will often

88

be avoided. Antibiotic therapy should be considered for patients with immunosuppression, malignancy, or cardiac disease; with valvular, vascular, or orthopaedic prostheses; or at the extremes of age. Antibiotics are indicated in shigellosis, V.  cholerae infections, pseudomembranous enterocolitis, and parasitic infection. However, they should be considered in cases of persistent yersinia infections and early in the course of campylobacter, aeromonas, and plesiomonas infections. Antibiotic therapy, in general, reduces the severity and length of symptoms.

Probiotics The evidence for the use of probiotics is limited. They have been shown to shorten the length of rotavirus illnesses and bacterial illnesses in children by 1 day.

Antidiarrhoeal therapy The use of anti-​motility agents (usually loperamide) is contentious, associated with fears of increasing the risk of toxic dilatation and increasing the faecal carriage of enteropathogens. Studies have usually used loperamide in combination with antibiotic therapy with some success, and few doctors would be prepared to treated infective diarrhoea with loperamide alone. New antisecretory agents are in development.

Prognosis The majority of patient will recover from acute diarrhoeal illnesses with no long-​term complications. However, it is well recognized that GI infections can precipitate irritable bowel syndrome. Yersinia enterocolitica and C.  jejuni have been associated with Reiter’s syndrome, which may present with painful swollen joints. C. jejuni infection is the commonest cause of Guillain–​Barré syndrome. Haemolytic uraemic syndrome is an important although uncommon complication of shigellosis and EHEC infection.

How to handle uncertainty in the diagnosis of this symptom Infectious diarrhoea will often have signs or symptoms of underlying infection (fever, leucocytosis, raised inflammatory markers), and a combination of stool samples and mucosal biopsies will often pinpoint a pathogen. In patients with worsening symptoms, empirical antibiotics can be given after liaison with the local microbiologist. However, the majority of patients will improve with conservative therapy.

Further Reading DuPont HL. Acute infectious diarrhea in immunocompetent adults. N Engl J Med 2014; 370: 1532–40. Leffler DA and Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372: 1539–48.

29 

Chronic diarrhoea

Satish Keshav and Alexandra Kent

Definition of the symptom

rectal bleeding, loss of weight, or abnormal blood tests, it is unlikely to be due to a serious illness.

Diarrhoea is defined as the passage of more than three stools per day or a stool weight >400 g/​day, and duration ≥4 weeks is regarded as chronic.

Approach to diagnosis

Differential diagnosis The list of possible causes of chronic diarrhoea is long, and likely to be incomplete as many rare conditions may present unusually with diarrhoea as part of the symptom complex (Table 29.1). The key to the diagnostic process is to consider the context in which the presentation occurs, and the most likely causes. Colorectal cancer rarely presents only with diarrhoea, although this is frequently the diagnosis which is most feared and the one which might prompt attendance in primary and secondary care. Most patients will be referred to secondary care for investigations, but their ongoing care will be provided by the GP.

Context Four to five per cent of the Western population suffers from diarrhoea, with irritable bowel syndrome (IBS) being the commonest cause in 20–​40  year-​old patients. It is the commonest reason for referral to secondary care gastroenterology clinics. In the absence of Table 29.1  Causes of chronic diarrhoea Common

Irritable bowel syndrome Post-​infectious irritable bowel syndrome Diet related: excessive fruit, non-​digestible carbohydrate sweeteners, excessive caffeine intake Iatrogenic drug related: e.g. proton-​pump inhibitors, metformin, antibiotics Coeliac disease Microscopic colitis Diverticular disease Giardiasis

Uncommon

Inflammatory bowel disease Lactose intolerance Pancreatic insufficiency Small bowel bacterial overgrowth Chronic infection, e.g. cryptosporidiosis, microsporidiosis, parasitic worm infestation (especially in immunocompromised) Autonomic neuropathy (e.g. diabetes mellitus, alcohol, uraemia, amyloid) Colonic or ileal resection Bile acid malabsorption Post-​cholecystectomy diarrhoea Endocrine disease (e.g. hyperthyroidism, Addison’s disease, hypoparathyroidism)

Rare

Factitious diarrhoea and laxative abuse Colorectal cancer (rarely presents with diarrhoea) Villous adenoma of the colon Ischaemic colitis Hormone-​secreting tumours (e.g. carcinoid, VIPoma, gastrinoma) Villous adenoma of the colon Factitious diarrhoea and laxative abuse Fabry’s disease

The patient’s age helps in deciding the direction of investigation. Patients who are ≥50  years old should undergo colonic imaging to check for colorectal cancer. Although colorectal cancer is unlikely to present with diarrhoea only, this is an anxiety for patients and referrers and, with the likely introduction of colorectal cancer screening in asymptomatic adults over the age of 50 years, it seems prudent to screen those who have symptoms. The history will give clues to the likely diagnosis. It is important to compare current symptoms to what the patient considers to be their usual bowel habit. Specific triggers should be sought; commencing new medications, recent surgery, travel, food poisoning or infection, and stress should all be checked. The help of a dietician examining the patient’s food diary can be invaluable in identifying excessive or inadequate fibre intake, excessive caffeine, and potential dietary triggers such as lactose or gluten. Examination should include the perineum, anus, and rectum, checking for evidence of inflammatory bowel disease; constipation and faecal impaction with paradoxical diarrhoea; and corroborative evidence of diarrhoea with excoriation of the perianal skin. Is the patient malnourished or dehydrated? Is there evidence of hyperthyroidism?

Specific clues to the diagnosis Specific clues to the diagnosis are as follows: Weight loss/​rectal bleeding: These are alarm symptoms irrespective of the patient’s age, necessitating urgent investigations due to their association with inflammatory bowel disease and colorectal cancer. Previous surgery: Bowel resection can lead to diarrhoea due to reduced water absorption (colonic resection), bile salt or fat malabsorption (terminal ileal resection), decreased transit time, or small bowel bacterial overgrowth. Ten per cent of patients develop diarrhoea post cholecystectomy. Systemic disease: Multiple diseases can be associated with diarrhoea, through various mechanisms. Such diseases include dia­ betes, thyrotoxicosis, vasculitis, scleroderma, hypoparathyroidism, Addison’s disease, and amyloidosis. Pancreatic disease: Diarrhoea in a patient with a history of excess alcohol consumption or pancreatitis may be due to pancreatic exocrine insufficiency, and resultant fat malabsorption. Recent travel: Giardiasis is more common following travel to the USA or Eastern Europe, whereas amoebiasis is endemic to western and southern Africa, South Asia, South America, and Mexico. Family history: There is a strong familial association recognized in colorectal cancer, inflammatory bowel disease, and coeliac disease. Medication history: Four per cent of cases are drug related, and symptoms may develop some weeks or months after commencing new medications.

Key diagnostic tests The key test in this diagnosis rests entirely on the context. IBS accounts for the majority of presentations, and it is helpful to be able to make this clinical diagnosis confidently and positively without recourse to excessive testing that can serve to heighten anxiety and reaffirm the patient’s suspicion that ‘they still can’t find what is wrong’. In other contexts, it is critically important to check for inflammatory bowel disease or colorectal cancer, and here either colonic

89

CHAPTER 29  Chronic diarrhoea

imaging or colonoscopy and biopsy are the key tests. Coeliac disease and thyrotoxicosis frequently present with diarrhoea. In both cases, the key test can be performed on a blood sample, with no need for colonoscopy, although many physicians consider it necessary to confirm the diagnosis of coeliac disease with duodenal biopsy.

Condition

Treatment options

Inflammatory bowel disease

5-​ASA, steroids, immunosuppression, anti-​TNFα therapy

Coeliac disease

Gluten-​free diet

Other diagnostic tests

Irritable bowel syndrome

Other diagnostic tests are as follows:

Dietary modification, optimized fibre intake, antidiarrhoeals

Diverticular disease

High fibre diet, colonic resection

Giardia, amoebiasis

Antibiotics

Microscopic colitis

Budesonide, bismuth, 5-​ASA

Post-​cholecystectomy syndrome

Cholestyramine, loperamide

Bile acid malabsorption

Cholestyramine

Pancreatic insufficiency

Pancreatic enzyme supplements

Bacterial overgrowth

Antibiotics

Vasculitis

Steroids, immunosuppression

Hormone-​secreting tumours

Resection, octreotide, chemotherapy

Faecal fat levels: Steatorrhoea can be confirmed from a 3-​day stool collection or on spot stool samples, although further tests are required to determine the underlying cause. Faecal elastase levels: Pancreatic insufficiency can be diagnosed by the finding of reduced faecal elastase levels. SeHCAT nuclear medicine scan: Bile salt malabsorption can be diagnosed with this test, which checks for reduced retention of an exogenously administered labelled bile acid. Glucose or lactulose hydrogen breath tests: These test for small bowel bacterial overgrowth. Gut hormone levels: This test requires a fasting blood sample and tests for levels of gastrin, vasoactive intestinal peptide, pancreatic polypeptide, glucagon, and neurotensin. For accurate gastrin levels, H2 antagonists should be stopped 24 hours prior to the test, and proton-​pump inhibitors stopped 6 days prior to the test. Barium follow-​through/​MRI small bowel: This can identify small bowel diverticula, entero-​enteric fistulae, or terminal ileal disease. Enteroscopy: This is not often required; it is usually reserved for identifying small bowel lesions seen on radiological examination. Urinary 5-​hydroxyindoleacetic acid: This is raised in patients with carcinoid syndrome. Lactose hydrogen breath test: This can be used to diagnose lactose intolerance.

Introduction to therapy Therapy is dictated by the underlying diagnosis, and dealt with in the appropriate section. Symptomatic relief of diarrhoea can be readily achieved using loperamide, diphenoxylate, or codeine phosphate. Codeine is best avoided because of its sedating and potentially addictive properties. Loperamide is well tolerated and can be used in the long term if needed. Table 29.2 gives a summary of treatment strategies for each condition. Advice from a dietician can be extremely helpful for patients requiring dietary modification in IBS, and for those with coeliac disease and therefore needing to follow a strict gluten-​free diet.

Prognosis Organic causes of diarrhoea usually respond to therapy, while IBS can be harder to treat. Patients often learn to cope with their symptoms,

90

Table 29.2  Treatment of diarrhoeal conditions

Abbreviations: 5-​ASA, 5-​aminosalicylic acid; TNFα, tumour necrosis factor alpha.

using loperamide and other antidiarrhoeals to maintain social and professional lives.

How to handle uncertainty in the diagnosis of this symptom Care should be taken not to over-​ investigate patients with IBS. However, patients with continuing weight loss, anaemia, or persistently raised inflammatory markers may require intensive investigation, and referral to specialist and tertiary care. Changes from microscopic colitis and inflammatory bowel disease can be patchy, and systemic inflammatory conditions can remit spontaneously temporarily, so that repeated investigation may be necessary when the first tests are normal. In difficult cases, in-​hospital assessment of diarrhoea may be necessary to quantify stool volume and to determine if diarrhoea is dependent on oral intake or not. Secretory diarrhoea due to endocrinopathy and secretory tumours of the bowel continues even when the patient does not eat or drink, while diarrhoea due to malabsorption or inflammation tends to be improved when oral intake ceases.

Further Reading Ford AC, Lacy BE, and Talley NJ. Irritable bowel syndrome. N Engl J Med 2017; 376: 2566–78. Schiller LR. Definitions, pathophysiology, and evaluation of chronic diarrhoea. Best Pract Res Clin Gastroenterol 2012; 26: 551–​62.

30 

Rectal bleeding

Satish Keshav and Alexandra Kent

Definition of the symptom

Table 30.2  Clues to the diagnosis of rectal bleeding

Rectal bleeding (haematochezia) refers to the passage of bright red blood per rectum.

Differential diagnosis The differential diagnosis of rectal bleeding, ordered by probability, is shown in Table 30.1.

Context Rectal bleeding is a common symptom, affecting all age groups, with the highest incidence in the sixth and seventh decades and associated with a higher mortality and morbidity with increasing age. Epidemiological studies have shown rectal bleeding to occur in nearly 1% of hospital admissions. Bleeding stops spontaneously in 80% of cases, although rebleeding occurs in 25%. The majority of patients will present to their general practitioner and will be referred to colorectal or gastroenterology outpatient clinics. Massive lower gastrointestinal (GI) bleeding is a medical emergency.

Approach to diagnosis The initial approach to patient care should be assessment of their haemodynamic stability, including vital signs. The most important diagnosis to be excluded is colorectal cancer, especially in older (>50 years) patients. Associated GI symptoms may narrow the differential diagnosis (weight loss, abdominal pain), although many causes of bleeding may be otherwise asymptomatic (angiodysplasia, polyps). A concise history and examination should significantly narrow the differential diagnosis.

Specific clues to the diagnosis

Diagnosis

Comorbidities and background

Symptoms and signs

Diverticular disease

Diverticulitis

Left iliac fossa pain, constipation

Inflammatory bowel disease

Family history

Diarrhoea, abdominal pain, fatigue, weight loss, extra-​intestinal manifestations

Neoplasia

Family history, smoker

Weight loss, constipation, change in bowel habit

Arteriovenous malformations/​ angiodysplasia

Aortic stenosis

Asymptomatic

Ischaemic colitis

Ischaemic heart disease, peripheral vascular disease, diabetes, hypertension, hyperlipidaemia

Severe abdominal pain, bloody diarrhoea

Radiation proctitis

Previous pelvic radiotherapy

–​

Solitary rectal ulcer

Constipation, straining, mucus per rectum

Haemorrhoids

Constipation

Pruritus ani, mucus, palpable lump

Anal fissure

Constipation

Pain on defaecation

Fistula-​in-​ano

Previous anorectal abscess, inflammatory bowel disease

Visible fistula, perianal discharge, pain, swelling

Upper gastrointestinal bleed

Recent NSAID/​aspirin use, excess alcohol

Haematemesis, dyspepsia

Clues to the diagnosis of rectal bleeding are given in Table 30.2.

Key diagnostic tests Endoscopic evaluation by flexible sigmoidoscopy or colonoscopy is the key test and allows biopsies to be taken from abnormal lesions. Bleeding lesions can be treated endoscopically by sclerotherapy or cauterization; in these instances, biopsies are usually deferred until active bleeding has settled. Brisk lower GI bleeding usually precludes effective endoscopy and treatment, and CT scanning with or without angiography may be necessary in the acute situation. In elderly patients in whom rectal bleeding is not causing haemodynamic

Table 30.1  Causes of rectal bleeding Common

Infrequent

Rare

Haemorrhoids (affects 4% of the population) Anal fissure Diverticular disease Neoplasia (distal colorectal cancer, polyps)

Inflammatory bowel disease Fistula-​in-​ano Arteriovenous malformations/​ angiodysplasia Massive upper gastrointestinal bleed

Radiation proctitis Ischaemic colitis Solitary rectal ulcer

compromise, a CT scan may be preferable, to identify possible causes (e.g. diverticular disease) or exclude serious pathologies (e.g. malignancy).

Other diagnostic tests Brisk bleeding may obscure endoscopic views. Diagnostic tests can usually be deferred until bleeding has settled and patients have received pre-​endoscopic bowel purgatives. In cases where bleeding is torrential with associated haemodynamic compromise, mesenteric angiography may identify the bleeding site, and allow embolization of the responsible vessel. Each patient should be assessed individually; many patients presenting with lower GI bleeding are elderly and/​or frail, and endoscopy may be difficult. In such cases, radiological imaging (abdominal CT, barium enema) may exclude diagnoses such as neoplasia or diverticular disease, with more invasive tests avoided unless bleeding persists.

Introduction to therapy The stability of the patient and rate of bleeding dictate the initial approach to patient care, with restoration of intravascular volume

Note: In ~10% of cases, the cause of bleeding is not found.

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being the most important objective. Patients require surgery more often when bleeding is due to a lower GI source than when it is due to an upper GI source, and patients requiring ≥4 units of blood in the first 24 hours have a 50% chance of requiring surgery. Specific therapeutic options are as follows:

CHAPTER 30  Rectal bleeding

Haemorrhoids: stool softeners, high-​fibre diet, band ligation, local injection Solitary rectal ulcer: endoscopic treatment of active bleeding ulcer using endoscopic adrenaline injection or cauterization Diverticular disease: The majority of cases will stop bleeding spontaneously; some centres advocate endoscopic adrenaline injection, although endoscopic therapy does incur a higher risk of colonic perforation. Persistent bleeding usually leads to surgical resection. Arteriovenous malformation: usually endoscopically cauterized using argon plasma coagulation Radiation proctitis: Bleeding points can be treated endoscopically using argon plasma coagulation. Other rectal therapies, including steroids, 5-​aminosalicylic acid (5-​ASA), or sucralfate, are less effective. Inflammatory bowel disease and colorectal cancer: see Chapters  203 and 204, respectively.

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Prognosis Rectal bleeding is a common symptom and as such has a poor positive predictive value for diagnoses such as colorectal cancer. The majority of patients will have a benign diagnosis.

How to handle uncertainty in the diagnosis of this symptom Since rectal bleeding is associated with colorectal cancer, all patients age ≥50 years, or 40 μmol/​l.

Differential diagnosis

Approach to diagnosis The initial approach is to determine if the jaundice is pre-​hepatic, intra-​hepatic, or post-​hepatic.

Pre-​hepatic jaundice Causes of pre-​hepatic jaundice include conditions such as sickle cell anaemia, spherocytosis, glucose-​6-​phosphate dehydrogenase deficiency, and haemolytic uraemic syndrome, which associated with an increased rate of haemolysis and thus lead to an increased production of unconjugated bilirubin. Serum bilirubin will be unconjugated and, since unconjugated bilirubin is not water soluble, there will be no bilirubin in the urine. Table 31.1  Causes of jaundice Common

Infrequent

Rare

Gilbert’s syndrome Drug-​induced jaundice Viral hepatitis Alcoholic hepatitis/​alcoholic liver disease Cirrhosis of the liver Cholelithiasis

Hepatic metastases from cancer Pancreatic cancer Haemolysis

Inherited disorders of bilirubin metabolism Cholangiocarcinoma Pancreatic cysts/​ pseudocysts

Hepatic impairment It is important to determine the extent of hepatic impairment associated with jaundice by measuring serum transaminases, prothrombin time, and albumin, and by checking clinically for evidence of hepatic dysfunction. This can vary from virtually none, for example, in Gilbert’s syndrome or massive haemolysis, to fulminant liver failure in other instances. Management is very much guided by the degree by the degree of hepatic impairment.

Specific clues to the diagnosis As described in ‘Context’, changes in urine and stool colour can be used to predict whether hyperbilirubinaemia is pre-​or post-​ conjugation:  unconjugated bilirubin is not water soluble and therefore the bilirubin will pass into the GI tract, and the urine will not change colour; in contrast, conjugated bilirubin is water soluble, and the excess bilirubin passes into the urine as it cannot drain out of the liver, so stool becomes paler, and urine darker. The following factors also give clues as to the underlying diagnosis: Pain: Impacted gallstones causing biliary obstruction will be associated with biliary colic and classically right upper quadrant abdominal pain. Alcohol intake: This suggests liver injury and raises the possibility of more chronic liver damage and cirrhosis. Weight loss: Pancreatic tumours classically present as painless obstructive jaundice, and may well have associated symptoms such as weight loss and cachexia. Viral symptoms: The viral illnesses which most commonly cause acute jaundice are hepatitis A  and infectious mononucleosis (glandular fever). Hepatitis A often presents with fever, fatigue, diarrhoea, anorexia, nausea, and abdominal pain. Glandular fever presents with fatigue, sore throat, fever, arthralgia, and lymphadenopathy. Many other viruses can cause jaundice, including the hepatitis B virus, the hepatitis E virus, cytomegalovirus, and so on. Medications: The commonest causes of drug-​induced hepatitis are co-amoxiclav, flucloxacillin, chlorpromazine, and drugs used for antituberculosis therapy. Any recent changes to medications should be noted, as liver derangement is a common side effect.

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Key diagnostic tests With respect to liver chemistry, classically, the alkaline phosphatase and gamma-​glutamyl transferase levels are elevated in post-​hepatic (obstructive) causes of jaundice, whereas the transaminases are elevated in hepatic causes. Acute cholelithiasis and cholangitis can, however, be associated with markedly raised transaminases. The most important test is to perform is an ultrasound scan of the biliary tract, to determine if there is biliary obstruction. Ultrasonography can diagnose biliary obstruction, gallstones, pancreatic masses, biliary tree dilatation, and liver echogenicity. Prothrombin time and albumin concentration provide a measure of hepatic synthetic function, which is particularly important in acute jaundice where there is concern about liver failure.

Other diagnostic tests

CHAPTER 31 Jaundice

The following blood tests may give further information regarding the cause of jaundice:

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Unconjugated and conjugated bilirubin: This test can ascertain whether the rise in bilirubin occurs before or after conjugation in the liver. Tests for haemolysis: Haemolysis can be confirmed from a blood film, a reticulocyte count, haptoglobin levels, the lactate dehydrogenase test, and/​or the Coombs test. Viral serology: Hepatitis A  IgM is positive in acute hepatitis A  (IgG is not diagnostic). Infectious mononucleosis is diagnosed by the presence of Epstein–​Barr virus IgM, or the heterophile antibody test (the monospot test). Infectious mononucleosis may also be associated with thrombocytopaenia, raised transaminases, and a raised erythrocyte sedimentation rate. If an ultrasound is inconclusive, magnetic resonance cholangiopancreatography (MRCP) can provide clear views of the biliary tree, and is safer than endoscopic retrograde cholangiopancreatography (ERCP). However, ERCP may be required to allow removal of obstructing stones, or relief of a stricture by stenting, and to aid diagnosis by obtaining biopsies or biliary brushings.

Introduction to therapy Treatment of jaundice is dependent on the underlying cause. ERCP involves passing an endoscope into the duodenum and intubating the sphincter of Oddi; the test is used to identify the site and cause of obstruction, and potentially to relieve it by removal, stenting, and, or sphincterotomy. Treatment of pancreatic cancer and

cholangiocarcinoma will be decided by a multidisciplinary team, including oncologists and gastroenterologists. Non-​obstructive jaundice requires treatment aimed at the underlying disease. Viral illnesses are usually self-​limiting. Treatment of drug-​induced jaundice depends on the causative medication. The majority of drug-​induced jaundice require removal of the offending agent and close monitoring for signs of liver failure. Alcoholic liver disease and alcoholic hepatitis require supportive treatment with laxatives, nutrition, and an investigation into underlying precipitant of decompensation (e.g. toxins, infection, constipation, GI bleed).

Prognosis The prognosis is as follows: • The overall prognosis of a patient with jaundice depends on the underlying disease process. • Patients with obstructive jaundice from gallstones usually respond well to ERCP treatment, with further episodes being prevented by a cholecystectomy. • The presence of ascending cholangitis worsens the prognosis, but the early institution of antibiotics can resolve sepsis. • The elderly, and patients with cardiovascular disease, always have a poorer prognosis from cases of obstructive jaundice. • Pancreatic and cholangiocarcinoma have an overall poor prognosis. • Viral causes of jaundice usually recover with conservative treatment. • Drug-​induced jaundice, if caught late, can be fatal due to the associated liver failure.

How to handle uncertainty in the diagnosis of this symptom The most important diagnosis to exclude is obstructive jaundice, as patients can rapidly deteriorate due to associated ascending cholangitis. In the setting of fever and obstructive jaundice, it is safer to advocate early antibiotics if ascending cholangitis is a possible diagnosis. A combination of blood tests and radiological investigations usually provides a clear diagnosis, and the commonest cause in patients with no additional symptoms or signs is Gilbert’s syndrome.

Further Reading Addley J and Mitchell RM. Advances in the investigation of obstructive jaundice. Curr Gastroenterol Rep 2012; 14: 511–​19. Kathpalia P and Ahn J. Assessment of jaundice in the hospitalized patient. Clin Liver Dis 2015; 19: 155–​70.

32 Ascites Ehoud Shmueli

Definition of the symptom Ascites is the accumulation of fluid within the peritoneal cavity.

Differential diagnosis The differential diagnosis of a swollen abdomen includes obesity, large bowel obstruction, and huge liver, ovarian, or mesenteric cysts. Differentiation from ascites is by physical examination and imaging. Most patients with ascites usually have a known diagnosis of cirrhosis, malignancy, or heart failure.

Table 32.1  High serum–​ascites albumin gradient (11 g/​l or greater, denoting portal hypertension) Cause

Comment

Cirrhosis (about 80% of patients)

Stigmata of chronic liver disease Clear yellow fluid Albumin concentration usually 11 g/​l indicates portal hypertension, and therefore probably cirrhosis. A  SAAG 300–​350 mg/​ mmol

Pancreatitis

Protein concentration is usually >30 g/​l, and there is a high amylase concentration often >1000 IU/​l

Meigs syndrome

Benign solid ovarian tumour associated with ascites and pleural effusion that disappear after tumour removal

Chylous ascites

Disruption of the lymphatic system Ascitic triglycerides should be >2.26 mmol/​l, or twice serum levels

titrated upwards to a maximum of 400 mg spironolactone and 160 mg furosemide per day. Amiloride 10–​40 mg can be substituted for spironolactone if gynaecomastia is a problem but it is less effective. There is no limit to the daily weight loss of patients who have significant oedema. Once the oedema has resolved, 0.5 kg is probably a reasonable daily maximum. NSAIDs, beta blockers, angiotensin-​converting-​enzyme inhibitors, and angiotensin receptor II blockers can all impair the effect­ iveness of diuretic treatment in ascites by reducing renal perfusion and function. Hyponatraemia (11 g/​l = portal hypertension 25 g/​l and an SAAG of >11 g/​l suggests heart failure

Glucose (not required routinely)

A low glucose occurs with malignancy An undetectable glucose may occur with bowel perforation

Ascitic fluid:serum LDH ratio (not required routinely)

1000 IU/​ml in pancreatic ascites

Abbreviations: SAAG, serum–​ascites albumin gradient; LDH, lactate dehydrogenase. *SAAG = [ascitic fluid albumin] –​[serum albumin].

thrombosis, and heart failure are contraindications to TIPS. Hepatic encephalopathy occurs in up to 30% of patients who receive a TIPS; hence, it is used mostly as a last resort and usually in younger patients with less severe liver dysfunction and who are thus less likely to become encephalopathic.

Ascites from peritoneal carcinomatosis This is treated with repeated large-​ volume paracentesis. Unlike the case for patients with ascites due to portal hypertension, in patients with peritoneal carcinomatosis, large volumes of fluid can be removed without fear of haemodynamic problems, and HAS infusion is not required. Diuretics do not work unless there is also portal hypertension from hepatic metastases.

Prognosis This depends on the cause but, in general, malignancy-​associated ascites carries a prognosis of 1–​4  months. Patients who develop ascites as a complication of cirrhosis have a 50% 2-​year mortality. However, patients with alcoholic cirrhosis who stop drinking can do surprisingly well.

How to handle uncertainty in the diagnosis The diagnosis of newly presenting ascites is often unclear. The stigmata of liver disease can be subtle, an alcoholic history may be hidden, malignancy may not be apparent on CT, and the admitting

Table 32.5  Microbiology and pathology Cell count

>500 WBCs or >250 neutrophils/​mm3 suggests infection. A predominance of lymphocytes suggests TB or malignancy

Gram stain

Rarely positive

Culture (not required routinely)

A repeat sample of 20 ml ascitic fluid in blood culture bottles (10 ml/​bottle) before antibiotics are stated gives the best chance of obtaining a culture

Cytology (not required routinely)

If malignancy is suspected, send 50 ml

Table 32.3 Appearance

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Clear or straw-​coloured

Uncomplicated ascites; deeply jaundiced patients will have a darker coloured ascites

Cloudy

Infection

Milky

Chylous ascites

Bloody

Traumatic tap causes a heterogeneously bloody specimen Malignancy causes a homogenously bloody specimen

Abbreviations: WBC, white blood cell.

Further Reading Pericleous M, Sarnowski A, Moore A, Fijten R, and Zaman M. The clinical management of abdominal ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: a review of current guidelines and recommendations. Eur J Gastroenterol Hepatol 2016; 28: e10–18.

CHAPTER 32 Ascites

clinician may have forgotten to request an ascitic albumin concentration. A  high Ca-​125 can lead clinicians in the wrong direction. The SAAG is the key test. A high-​SAAG ascites will usually indicate cirrhosis. A low-​SAAG ascites most commonly indicates a malignancy. About 5% of patients may have a combination of causes for the ascites, such as cirrhosis plus malignancy or tuberculosis, and it is important to be open to that possibility.

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33 

Chylous ascites

Ehoud Shmueli

Definition of the symptom

Context

Chylous ascites is ascites that has a cloudy or milky appearance due to a high level of triglycerides (>2.26 mmol/​l).

Chylous ascites is very rare and is due to disruption of the lymphatic system. The cause may be clear from the history; in developed countries, the differential rests between cirrhosis and malignancy, especially lymphoma. In developing countries, tuberculosis or filariasis is more likely.

The causes of chylous ascites The causes of chylous ascites are given in Table 33.1.

Table 33.1  The causes of chylous ascites Cause

Comment

Cirrhosis

Due to rupture of serosal lymphatics spontaneously or due to hepatocellular carcinoma; SAAG > 11 mg/​l

Neoplastic: lymphoma, and any malignancy disrupting the lymphatics

The diagnosis may be obvious from the history; SAAG < 11 mg/​l

Complex surgery or trauma: involving the retroperitoneum, e.g. abdominal aortic aneurism repair or retroperitoneal node dissection

Lymphatic disruption during surgery or following trauma causes chylous ascites in the first post-​operative week; chylous ascites occurring weeks/​months after surgery is due to adhesions or other extrinsic lymphatic compression

Congenital: yellow nail syndrome; primary lymphatic hypoplasia, or hyperplasia; intestinal lymphangiectasia

The most common cause in children

Infection: Tuberculosis, filariasis

The most common cause in developing countries

Inflammatory causes: Radiotherapy, pancreatitis, retroperitoneal fibrosis

Causing fibrosis of the lymphatics

Right heart failure, constrictive pericarditis

Impaired drainage of lymph; SAAG > 11 mg/​l

Nephrotic syndrome

Unknown pathogenesis

HIV associated

Kaposi’s sarcoma, mycobacterium avium intracellulare

Abbreviations: SAAG, serum–​ascites albumin gradient.

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Key diagnostic tests Check triglycerides (should be >2.26 mmol/​l, or twice serum levels) and exclude infection. Lymphocytes should predominate; neutrophils indicate infection. Request culture, cytology, and albumin concentration. The serum–​ascites albumin gradient (SAAG) is calculated as follows: SAAG = [ascitic fluid albumin] − [serum albumin]. A SAAG >11 g/​l indicates portal hypertension. A SAAG 110 fl) is characteristic of megaloblastic erythropoiesis (B12 or folate deficiency). An MCV greater than 120 fl is usually an artefact due to red-​cell clumping in vitro, which can occur in autoimmune haemolytic anaemias.

Normocytic anaemias As the MCV is an average of the red-​cell size distribution, there is considerable overlap between micro-​and macrocytic anaemias, and anaemias with a normal MCV. Causes include blood loss, renal failure, anaemia of chronic disease, haemolytic anaemia, bone marrow failure, myelodysplasia, and haematological malignancies.

Specific clues to the diagnosis A full blood count will be a routine investigation in a wide range of clinical situations, and will reveal anaemia if it is present. In individuals with unexplained tiredness, fatigue, or pallor, the result will often be reassuring.

The key diagnostic test for anaemia is the full blood count (see Chapter 278), and the important parameters are the Hb level, red-​cell count, and MCV. Other red-​cell parameters—​packed cell volume, or haematocrit; mean cell Hb levels, and mean cell Hb concentration—​ are calculated from these but are of relatively little use clinically. The reference range for Hb varies slightly between laboratories but, for adults in developed countries, Hb levels between 120 and 160 g/L would generally be considered normal in females, and between 140 and 180 g/L for males. The difference in Hb levels between adult males and females reflects higher levels of androgens (which stimulate erythropoiesis) in males.

Other diagnostic tests Specific tests for specific anaemias are described in the relevant chapters.

Introduction to therapy The principles of treatment in anaemia are to correct any deficiencies if present, treat any underlying conditions, and, as a last resort, to consider red-​cell transfusion, but only if the anaemia is moderate or severe, symptomatic, and unlikely to respond to the first two approaches. In selected situations, for example, renal disease and cancer, administration of recombinant erythropoietin may be useful.

Prognosis The prognosis in anaemia is dependent on the cause and the prognosis of any underlying condition. Simple deficiency anaemias are usually easily corrected. On the other hand, congenital anaemias such

as sickle cell disease and thalassaemias are essentially incurable, and homozygous forms are life shortening. More details are available in the relevant chapters.

How to handle uncertainty in the diagnosis of anaemia The diagnosis of anaemia is based on the Hb concentration, which is normally accurate and reproducible. However, there are situations where this may give an inaccurate or misleading picture. In addition, the Hb concentration may vary in an individual by as much as 10 g/L from day to day. Blood for the full blood count should be taken with care:  prolonged tourniquet pressure may give rise to slight haemoconcentration and an artefactual rise in the Hb level, while taking blood from an arm that also has a running intravenous infusion in place commonly leads to haemodilution and an abnormally low Hb level. Samples may deteriorate if delayed in transit to the laboratory. The clinical context is important: for example, Hb levels are commonly slightly reduced in the elderly for no easily discernible reason. It is unwise to label such patients as anaemic on the basis of a single Hb estimation.

Further Reading DeLoughery TG. Microcytic anemia. New Engl J Med 2014; 371: 1324–​31. Gangat N and Wolanskyj AP. Anemia of chronic disease. Semin Hematol 2013; 50: 232–​8. Lopez A, Cacoub P, Macdougall IC, and Peyrin-Biroulet L. Irondeficiency anaemia. Lancet 2016; 387: 907–16.

CHAPTER 37 Anaemia

Key diagnostic tests

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38 

Bruising and bleeding

Nicola Curry and Raza Alikhan

Definition of the symptom The amount of blood that leaks from a blood vessel into the subcutaneous tissue will determine the size and description of a lesion. Minute amounts of blood producing pin-​point red lesions 1 cm.

Differential diagnosis in primary care and secondary care Box 38.1 gives examples of the causes of bruising and bleeding that are likely to present in primary and secondary care, as well as causes relating specifically to neonates and children.

Context Bruising is extremely common and a normal response to injury. Perception of what is a normal level of bruising is subjective and it can be difficult to differentiate a patient with ‘normal’ bruising from a patient who has bruising due to a mild bleeding disorder. However, spontaneous bruising or bruises that seem incongruent to the degree of injury experienced must be taken seriously. Therefore, it is important that you assess your patient globally before providing reassurance that their symptoms are not worrying.

Approach to the diagnosis, and specific clues to the diagnosis It can be helpful to categorize patients with bruising/​bleeding into two clinical groups: those who have no other symptoms, in whom the cause is likely to be either a normal response to injury, or an isolated platelet disorder or clotting factor deficiency; and those who have additional symptoms, in whom haematological disease (e.g. thrombocytopenia due to bone marrow infiltration) or systemic disease (e.g. connective tissue disorder) is more likely. The history is the most important part of the assessment of a patient who presents with bruising or bleeding. The main considerations to make are: the accompanying symptoms • • the timescale of the symptoms • the site of bruising or bleeding • the severity of the problem

Accompanying symptoms Try to get a feel for whether the patient has an isolated bleeding problem, or whether their symptoms are a manifestation of a wider problem. Ask about accompanying fatigue (anaemia), increased infection (leucopenia), lymphadenopathy, joint pains, and so on. Be guided by the history.

Timescale of the symptoms It is important to determine whether the problem has been a lifelong one or whether it started recently, to differentiate between inherited or acquired disease. If the history suggests an inherited disease, ask whether there is a family history of bleeding. Inherited bleeding disorders can be X-​linked (haemophilia), autosomal dominant (some forms of von Willebrand’s disease), or autosomal recessive (some factor deficiencies

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Box 38.1  Causes of bruising and bleeding likely to present in primary and secondary care, and causes relating specifically to neonates and children

Primary care

• ‘easy bruising’ • no underlying diagnosis • elderly • steroid therapy • drugs • antiplatelet agents • anticoagulants • systemic disease • liver disease, including alcoholic liver disease • uraemia • thyroid disease • Cushing’s disease • autoimmune disease • thrombocytopenia • in particular, immune thrombocytopenia purpura • von Willebrand’s disease • haemophilia A • haemophilia B

Secondary care

• drugs • antiplatelet agents • anticoagulants • heparin • systemic disease • liver disease • uraemia • sepsis/​disseminated intravascular coagulopathy • thrombocytopenia • platelet destruction • immune thrombocytopenia purpura • disseminated intravascular coagulopathy • thrombotic thrombocytopenia purpura • haemolytic uraemic syndrome • reduced production of platelets • marrow failure • marrow infiltration • von Willebrand’s disease • haemophilia A • haemophilia B • vasculitis • collagen disorders

Causes relating specifically to neonates and children Neonates • sepsis/​disseminated intravascular coagulopathy • congenital infection (TORCH): • toxoplasmosis • other (syphilis) • rubella • cytomegalovirus • herpes simplex virus • vitamin K deficiency • immune thrombocytopenia purpura

neonatal alloimmune thrombocytopenia • • haemophilia

Childhood

immune thrombocytopenia purpura • • leukaemia • inherited bleeding disorders • non-​accidental injury

dilatation and curettage, iron therapy, and/​or hysterectomy needs to be documented.

Haemarthroses Spontaneous joint bleeds are a feature of haemophilia (see Chapter 284).

Umbilical stump bleeding Delayed bleeding from the umbilical stump is a feature suggestive of Factor XIII deficiency, but may also occur in haemophilia.

and various platelet diseases). It may therefore, in some circumstances, be important to ask whether the patient’s parents are related other than by marriage. If the problem started recently, ask whether the symptoms relate temporally to any new medications, or new activities.

Severity of the problem

Site of bruising or bleeding Epistaxis

• recurrent bleeding (i.e. more than three times at one site of the body) • more than two sites of the body affected at one time • unusual bleeding following a routine operation/​childbirth, particularly if a blood transfusion is required • iron deficiency anaemia secondary to blood loss • bleeding lasting more than 30 minutes and requiring intervention (such as nasal packing)

Bleeding from the nose is one of the most common symptoms of platelet disorders and von Willebrand’s disease. It is also a common symptom of hereditary haemorrhagic telangiectasia. However, a large number of the population also suffer from nosebleeds. If the bleeding is confined to a single nostril, it is more likely due to a localized abnormality rather than a coagulopathy. Epistaxis during childhood is also common and tends to disappear after puberty. The need to seek medical advice, nasal packing, cautery, or transfusions must be sought from the history.

Gums Spontaneous bleeding from the gums is another common symptom of a platelet disorder or von Willebrand’s disease. Bleeding from the gums after tooth brushing may be normal or abnormal, depending on the presence or absence of gingival disease and the type of toothbrush employed.

Skin Is the bleeding response excessive or in keeping with the degree of trauma to the skin? Spontaneous bruising is likely to be pathological. It is sometimes difficult to elicit a history of trauma from a patient; therefore, the location of a bruise can help in deciding if bruising is traumatic. In general, bruises following trauma arise at bony surfaces and on the arms and legs. Bruising arising on the back or trunk are likely to be spontaneous or due to minimal trauma.

Tooth extraction This is often the first and only significant haemostatic challenge a person faces. The need for packing, suturing, or transfusions may be significant and indicate the presence of an underlying bleeding disorder.

Haematemesis It is important to look for an anatomical cause. Defects in haemostasis may arise in patients with liver disease or oesophageal varices, or who are on aspirin.

Haemoptysis

As a general rule, the more severe the symptom, the more severe is the bleeding disorder. The following points suggest further investigation is required:

Key diagnostic tests The following tests should be performed as a screen for patients with increased bruising and bleeding symptoms: full blood count and film • • coagulation profile (prothrombin time, activated partial thromboplastin time, fibrinogen) Any abnormality that arises in these tests can then guide you to your next investigation. If the history suggests a systemic cause for the bleeding, consider checking: urea and electrolytes • • liver function tests • thyroid function tests • an autoantibody screen

Other diagnostic tests

CHAPTER 38  Bruising and bleeding

Box 38.1  (Continued)

If you have a patient with a suspected bleeding disorder, it is often best to refer them to a haematologist. The specialized testing is often only available in haemophilia centres (see Chapter  273). These tests include: coagulation factor assays (Factor VIII, Factor IX, and Factor XI) • • von Willebrand’s disease screen (FVIII:C, vWF:Ag, vWF:RiCof ) • platelet analysis: • platelet aggregometry and nucleotide testing • electron microscopy • flow cytometry • DNA analysis

As with haematemesis, it is important to look for an anatomical cause.

Menorrhagia Menorrhagia is defined as the loss of more than 80 ml of blood per cycle. It is often difficult to assess the severity of blood loss from the history or by the number of sanitary towels used. Pictorial menstrual charts have been found to be useful in quantifying blood loss. If no gynaecological cause is present, it is important to look for platelet disorders and, specifically, von Willebrand’s disease.

Pregnancy It is important to take a detailed history of bleeding both during pregnancy and in the post-​partum period. The need for transfusions,

Introduction to therapy Treatment for patients with symptoms of bruising will depend on the underlying diagnosis. Many patients will require simple reassurance that their bruising is not clinically concerning and that no active intervention is required. For those patients that are bruising because of a systemic disorder, symptoms can be ameliorated by treating the underlying disease. When drugs such as aspirin or warfarin are the cause of the symptoms, the risks and benefits of continuing or stopping the drug must be weighed up.

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Whatever the cause of the bleeding, simple instructions can be given to reduce risks of further bleeding: avoidance of intramuscular injections • • avoidance of antiplatelet/​anti-​inflammatory/​anticoagulant drugs, if possible • avoidance of contact sports in severe bleeding disorders • informing any physician/​dentist, prior to an invasive procedure, of the bleeding history and, if possible, seeking advice from a haematologist Patients with inherited bleeding disorders, and those with significant acquired bleeding disorders, should be treated by a haemophilia centre so that, at times of significant haemostatic challenge (such as childbirth or surgery), they are managed appropriately and safely.

Prognosis It is impossible to provide specifics regarding prognosis, as this will entirely depend on the underlying cause of the bleeding and the severity of the disease.

How to handle uncertainty in the diagnosis of this symptom

CHAPTER 38  Bruising and bleeding

Bruising is a very difficult symptom to diagnose with accuracy. Therefore, uncertainty is common.

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The simple rule to follow is, don’t ignore bruising/​bleeding if: a patient has systemic symptoms • • it is spontaneous or recurrent • it has required active intervention to halt it • it has led to the need for iron replacement or blood transfusion These types of symptoms require urgent attention. Less convincing evidence of disease can be investigated at a more leisurely pace and, indeed, underlying pathology may not be found.

Further Reading British Society for Haematology: Haemostasis and Thrombosis Guidelines. Available at: http://www.b-s-h.org.uk/guidelines/?category=Haemostasis+and+Thrombosis&p=1&search=#guidelin e-filters__select__status. Rydz N and James PD. Why is my patient bleeding or bruising? Hematol Oncol Clin North Am 2012; 26: 321–​44. World Federation of Hemophilia: About Bleeding Disorders (http://​ www.wfh.org/​en/​page.aspx?pid=1282)

39 

Transient loss of consciousness

Jonathan Timperley and Sandeep Hothi

Definition of the symptom Transient loss of consciousness (TLoC) is characterized by a rapid, transient, and complete loss of consciousness of short duration with spontaneous, complete recovery. Syncope is a specific type of TLoC caused by transient, global, cerebral hypoperfusion.

Differential diagnosis TLoC may be traumatic or non-​traumatic. Causes of non-​traumatic TLoC include syncope, epilepsy, psychogenic causes, and other, rarer causes. Causes of syncope are shown in Box 39.1.

Context TLoC is common and affects up to half the population at some point in their lives. It accounts for approximately 3% of A & E attendances and 1% hospital admissions; with etiologies ranging from benign conditions and clinical courses on the one hand, and up to 33% mortality on the other when there is underlying cardiac structural disease. The incidence of TLoC rises with age, particularly beyond the age of 70  years. The diagnostic process can be difficult, investigations can be costly, and even potentially serious conditions may be difficult to diagnose early.

Approach to diagnosis The first aim is to confirm a diagnosis of TLoC (see ‘Definition of the symptom’), and then to determine if there are features predictive

Box 39.1  Causes of syncope

Reflex (neurally mediated)

• vasovagal • emotional stress • orthostatic • situational • micturition • coughing, sneezing • post-​exercise • carotid sinus hypersensitivity

Orthostatic hypotension

drug induced • • hypovolaemia • primary autonomic failure • secondary autonomic failure

Cardiovascular

• arrhythmia • bradyarrhythmias (sinus node dysfunction; atrioventricular block) • supraventricular and ventricular tachyarrhythmias • structural heart disease • stenotic valve disease • cardiomyopathies • acute major pulmonary embolism • severe pulmonary hypertension Data from Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC), volume 30, p. 2631, Copyright © 2009 Eur Heart Journal

Box 39.2  History taking after syncope Questions regarding circumstances prior to the attack: position (supine, sitting, or standing) • • activity (rest, change in posture, during or after exercise, during or immediately after urination, defaecation, cough, or swallowing) • predisposing factors (e.g. crowded, warm, prolonged standing, postprandial) and precipitating factors (fear, pain, neck movements) Questions about the onset of the attack: • nausea, vomiting, abdominal discomfort, feeling cold, sweating, aura, neck or shoulder pain, blurred vision, dizziness • palpitations Questions about the attack (eyewitness): • way of falling, skin colour, duration of loss of consciousness, breathing pattern, movements, duration of movements, onset of movements in relation to fall, tongue biting Questions about the end of the attack: • nausea, sweating, feeling cold, confusion, muscle aches, skin colour, injury, chest pain, palpitations, urinary or faecal incontinence Questions about the background: family history of sudden death, cardiomyopathy, or fainting • • previous cardiac disease • neurological history • metabolic disorders • medication and other drugs, including alcohol • if recurrent syncope, information about recurrences including time from first event and frequency of events Data from Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC), volume 30, p. 2631, Copyright © 2009 Eur Heart Journal

of a high risk of cardiovascular events or death. The presence of the following features makes syncope highly likely: complete loss of consciousness; rapid loss of consciousness; spontaneous and full recovery; and loss of postural tone. If any of these features are absent, a non-​syncopal cause of TLoC should be considered. The account of a witness, if available, is of importance. This, together with the patient’s account, will be required to build a description of events from before the episode through to the recovery. Thus, the features in the Box 39.2 should be elicited.

Specific clues to the diagnosis History The duration of TLoC due to syncope is typically in the region of 20 seconds, and rarely up to a few minutes. A  previous history of episodes of TLoC and their descriptions may help confirm the diagnosis as well as establishing the frequency and impact upon the patient’s life. Myoclonic jerks can occur after the onset of syncope, but only last for seconds; in contrast, during epilepsy, they occur simultan­ eously with the onset of loss of consciousness and usually last minutes.

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Neurally mediated syncope is suggested by the absence of cardiac disease; multiple episodes; and onset after prolonged standing or after exertion, head rotation, or specific situational triggers. Orthostatic hypotension is suggested by TLoC after standing; the recent start of drugs causing hypotension; TLoC in hot, crowded places; autonomic neuropathy; Parkinson’s disease; and TLoC associated with standing after the cessation of exercise. Cardiac syncope is suggested by structural cardiac disease, exertional symptoms, palpitations, or an abnormal ECG. Features suggesting epilepsy include prodrome, tongue biting, unilateral head rotation during the event, prolonged jerking of the limbs, and postictal confusion. Tongue biting (especially of the lateral tongue) is very rare in syncope. Its presence strongly suggests the diagnosis of epilepsy. The previous medical history may reveal conditions predisposing to TLoC, such as known heart disease, Parkinson’s disease, and epilepsy. The drug history may identify a cause, for instance, antihypertensives, diuretics, antiarrthymic drugs, QT-​prolonging drugs, or alcohol. The family history may reveal a familial predisposition to a specific cause for TLoC, such as inherited cardiac or neurological diseases. A family history of sudden death or syncope is therefore important, whether the diagnosis is certain or not.

CHAPTER 39  Transient loss of consciousness

Physical examination Measurement of vital signs may identify abnormalities of heart rate and/​or blood pressure. A  postural blood pressure should be checked: a decrease in systolic pressure of 20 mm Hg or more, or 10 mm Hg diastolic, within 3 minutes of standing, is significant and represents orthostatic hypotension. Cardiovascular examination may reveal an irregular pulse, a diminished pulse volume in severe aortic stenosis, a bradycardia, or a tachycardia. On auscultation there may be a mid-​systolic murmur with aortic stenosis or hypertrophic cardiomyopathy; there may be a malar flush and diastolic murmur with mitral stenosis. Neurological examination should, by definition, demonstrate no permanent de novo neurological abnormalities causing TLoC. There may, however, be neurological deficits secondary to neurological injury sustained during injury caused by the loss of consciousness. There may also be features of Parkinson’s disease or autonomic neuropathy and its causes (multiple system atrophy, diabetes mellitus, Lewy body dementia, amyloidosis, renal failure, spinal cord lesions).

Key diagnostic tests Key diagnostic tests are:

Introduction to therapy

ECG: conduction abnormalities, ventricular pre-​excitation, ventricular or atrial arrhythmias, long or short QT intervals, ST-​or T-​wave changes, pathological Q waves, Brugada syndrome Blood tests: full blood count, to exclude anaemia, and blood glucose, to exclude hypoglycaemia

Patients must be advised not to drive while awaiting specialist review; the relevant driving guidelines must be consulted. Depending on the patient’s occupation, modification of working patterns may be needed, such as working at height or operating machinery. Lifestyle advice should be given, including avoidance of triggers, and modification of behaviours that might be dangerous.

Other diagnostic tests

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sinus hypersensitivity as the cause of TLoC. Complications include a small risk of stroke. CSM should be avoided in patients with a history of TIA, recent stroke (3 months), or carotid bruits. ECG monitoring:  Cardiac monitoring (in hospital) is appropriate in patients considered high risk for cardiac arrhythmia as the cause of TLoC in the immediate phase after presentation. Other forms of monitoring include Holter monitoring (up to 48 hours recording), external event recorder (applied by the patient when palpitations occur), or implantable event recorder (over 3 years monitoring). The selection of these forms of monitoring is based on the frequency of episodes of TLoC. Short Synacthen test:  This test is done when adrenal insufficiency is suspected to cause orthostatic hypotension. Orthostatic challenging:  A change in posture from supine to upright results in venous pooling and reduced venous return. In the normal situation, compensatory mechanisms act to minimize consequent hypotension and syncope. Abnormalities may be cardioinhibitory response (reflex bradycardia), vasodepressor response (reflex hypotension), or both, in such patients. Two forms of test exist to identify significant hypotension and syncope caused by a change in posture. The first involves a change from supine to standing, where the blood pressure is measured in the supine position and then on standing (commonly known as postural blood pressure, described in ‘Physical examination’. The second method is known as tilt-​table testing. In this test, the patient has blood pressure and heart rate monitoring while being put into a head-​up tilt, to assess for neurally mediated syncope. It is thus useful in assessing for neutrally mediated orthostatic hypotension. False positives may be seen in other forms of neurally mediated syncope as well as sinus node dysfunction. EEG: This is useful in suspected epilepsy rather than as a test for the investigation of syncope. CT head:  This is performed to exclude injury secondary to TLoC when there is suspected head injury, and to exclude structural brain abnormality where a new diagnosis of epilepsy is considered. CT pulmonary angiogram:  This is done where pulmonary embolism is suspected. Transoesophageal echocardiography/​CT/​MR aorta: These are done to exclude aortic dissection. Exercise testing:  This is done to assess syncope during or post exertion. Cardiac catheterization: This is done to exclude myocardial ischaemia or ischaemia-​induced arrhythmias.

Other diagnostic tests are:

Neurally mediated syncope and orthostatic hypotension

TSH level: Where tachyarrhythmias or bradyarrhythmias are identified, the TSH level should be checked to exclude hyperthyroidism and hypothyroidism (bradycardia). Urea and electrolytes: These must also be checked; hypokalaemia is associated with tachyarrhythmias and acquired long-​QT syndrome; hyperkalaemia may also cause ventricular arrhythmias. Echocardiography: This test may reveal aortic or mitral stenosis, aortic dissection, or left ventricular systolic dysfunction. Carotid sinus massage: Carotid sinus massage (CSM) is performed by applying pressure to the carotid sinus (the point of bifurcation of the common carotid artery) while recording the heart rate and blood pressure to identify symptomatic bradycardia or hypotension. Carotid sinus hypersensitivity (CSH) is diagnosed when CSM causes a pause of 3 or more seconds or a reduction in systolic blood pressure of 50 mm Hg or more. This must be performed with resuscitation facilities to hand in case of asystole. CSH in the presence of a history of syncope is highly suggestive of carotid

In terms of lifestyle advice, education and reassurance should be given that the condition is quite benign. Advice of the identification and avoidance of triggers is also important. Cessation of exacerbating factors, such as specific drugs, should be advised. Education in recognizing prodromal symptoms will enable the patient to perform manoeuvres to prevent progression to TLoC (e.g. physical counterpulsation manoeuvres that cause a rise in blood pressure). Tilt training may reduce TLoC caused by reflex orthostatic hypotension. An adequate intravascular volume should be aimed for by sufficient fluid intake (2–​3 l/​day) and ~10 g salt per day, in the absence of hypertension. Compression stockings can help reduce gravitational venous pooling. Physical counterpressure may be useful if patients have prodromal symptoms that can be used as warnings. Midodrine (an alpha agonist) may be of help in chronic autonomic failure, and the mineralocorticoid fludrocortisone may also be helpful.  Especially if the patient is unable to addequately increase their fluid and salt intake. In

Carotid sinus syndrome In carotid sinus syndrome, when TLoC is caused by a predominant cardioinhibitory response, permanent cardiac pacing is the treatment of choice.

Cardiac arrhythmia Permanent pacing is indicated in sinus node dysfunction causing bradycardia as well as atrioventricular block with symptoms. Syncope caused by atrioventricular reentrant tachycardia, atrioventricular nodal reentrant tachycardia, or atrial flutter is ideally treated by ablation. Antiarrhythmic therapy is used while awaiting ablation or following failed ablation. For ventricular tachycardia (VT) or ventricular fibrillation (VF), any proarrhythmic drugs must be stopped. An implantable cardioverter defibrillator (ICD) is indicated in VT with a reduced ejection fraction, or VT/​VF without reversible causes. Ablation may be considered in a structurally normal heart. Revascularization should be considered in ischaemic arrhythmias.

Structural heart disease Where TLoC is secondary to underlying structural heart disease, treatment is aimed at the specific abnormality as well as an aim to reduce the risk of future events. Treatment thus varies but includes, for instance, surgery for severe aortic stenosis, revascularization, and secondary prevention for myocardial ischaemia and anticoagulation for pulmonary embolism. An ICD may be indicated where the risk for arrhythmia remains high despite optimum management (see ‘Further reading’).

Epilepsy Treatment should be directed by an expert and includes antiepileptic drugs and driving advice.

Prognosis Situational and vasovagal syncope usually follow a benign course. The EGSYS 2 (Guidelines in Syncope 2)  study demonstrated that, in patients presenting to the emergency department with TLoC, a higher mortality was observed in those with an abnormal ECG and/​ or heart disease, seen in 82% of those who died. In general, features suggestive of a serious condition need rapid assessment, include an abnormal ECG, signs of heart failure, exertional TLoC, cardiac murmur, family history of sudden cardiac death or cardiac disease, and unexplained or new breathlessness.

How to handle uncertainty in the diagnosis of this symptom Where the diagnosis remains unclear despite appropriate investigations, psychogenic pseudosyncope and psychogenic non-​ epileptic seizures should be considered. These are particularly likely if TLoC events are variable in their nature, prolonged, or accompanied by other unexplained physical features. In addition, an implantable loop recorder will determine if a cardiac arrhythmia is the underlying causes in cases of recurrent, unexplained TLoC.

Further Reading National Institute for Health and Clinical Excellence: Transient Loss of Consciousness (‘Blackouts’) Over 16s. Clinical Guideline CG109 https://www.nice.org.uk/guidance/cg109) Shen W-K, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2017; 70: e39–110. Wieling W, Thijs RD, van Dijk N, et al. Symptoms and signs of syncope: A review of the link between physiology and clinical clues. Brain 2009; 132: 2630–​42.

CHAPTER 39  Transient loss of consciousness

severe cases of TLoC due to reflex syncope with a cardioinhibitory response revealed on tilt testing, permanent pacing may be indicated.

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40 Coma David Sprigings

Definition Coma is a pathological state of unconsciousness from which a patient cannot be roused to wakefulness by stimuli. The comatose patient has closed eyes and no speech, and lacks both wakefulness and awareness, the two clinical dimensions of consciousness. The level of consciousness can be graded using the Glasgow Coma Scale (GCS), based on eye-​opening, verbal, and motor responses to stimuli (Table 40.1). Coma is defined as a score of 8 or below on the GCS.

Differential diagnosis Coma reflects dysfunction of the brainstem reticular system and its thalamic projections (the neuronal basis of wakefulness), or diffuse injury of both cerebral hemispheres. A unilateral lesion of a cerebral hemisphere (e.g. haemorrhagic stroke) will not cause coma unless there is secondary compression of the contralateral hemisphere or brainstem. Coma may be due to systemic or primary intracranial disease. Often both mechanisms and both etiologies are involved (e.g. alcohol intoxication complicated by head injury; opioid poisoning complicated by respiratory arrest with resultant hypoxic-​ischaemic brain injury). Excluding head trauma, the commonest causes of coma are poisoning, stroke, and metabolic disorders. Box 40.1 summarizes the causes of coma (defined in this study as a GCS score of 10 or below for >30 minutes) in a series of 938 medical patients presenting to two urban emergency departments in Sweden; the data are probably representative of the case in the UK as well. Over half the cases of poisoning involved alcohol, either alone or in combination with sedative drugs. Poisoning was the cause of coma in 80% of patients under 40, but only 11% of those over 60.

Box 40.1  Causes of non-​traumatic coma seen in an emergency department poisoning (38%) • • focal neurological lesion (24%) • metabolic or diffuse cerebral disturbance (21%) • seizures or postictal state (12%) • psychogenic (1%) • cause not defined (4%) Adapted by permission from BMJ Publishing Group Limited. Forsberg S, et al. Coma and impaired consciousness in the emergency room: characteristics of poisoning versus other causes, Emerg Med Journal, volume 26, pp.100-​2, copyright © 2009.

of diseases. The common causes of coma by context are given in Table 40.2.

Approach to diagnosis Coma is a medical emergency, because a comatose patient is at high risk of permanent brain injury or death, caused either by the

Table 40.2  Causes of coma by context Patient group

Causes to consider*

Emergency department patient under 40

Poisoning with alcohol and/​or other psychoactive substances Postictal state Hypoglycaemia Traumatic brain injury Carbon monoxide poisoning

Emergency department patient over 40

Stroke Subdural haematoma Hypoxic-​ischaemic brain injury following cardiac arrest Postictal state Hypoglycaemia Respiratory failure Traumatic brain injury Poisoning with alcohol and/​or other psychoactive substances Carbon monoxide poisoning

Medical inpatient

Respiratory failure Stroke Subdural haematoma (e.g. following fall in hospital) Liver failure Septic encephalopathy

Surgical inpatient

Respiratory failure Opioid intoxication Septic encephalopathy

Patient with cancer

Raised intracranial pressure due to brain or meningeal metastases Opioid intoxication Hypercalcaemia Hyponatraemia

Context Over 70 causes of coma are recognized, ranging from the common disorders in Box 40.1 to rarities such as cerebral fat embolism following long-​bone fracture or hyperammonaemic coma complicating ornithine transcarbamylase deficiency (an X-​linked urea cycle disorder). However, the age of the patient, the comorbidities present, the setting in which coma occurs, and the examination findings generally limit the differential diagnosis to a handful

Table 40.1  Grading of level of consciousness using the Glasgow Coma Scale* Points

Eye opening (E)

Best verbal response (V)

Best motor response (M)

6

–​

–​

Obeys commands

5

–​

Orientated

Localizes pain

4

Spontaneous

Confused

Withdraws to pain

3

To speech

Words

Flexes to pain

2

To pressure

Sounds

Extends to pain

1

None

None

None

* The score is expressed both as its components (e.g. E2, V1, M4) and sum (e.g. Glasgow Coma Scale (GCS) 7). By definition, a patient in coma will have a score of E < 3, V < 3, and M < 5. In a patient with an endotracheal tube in place, preventing assessment of verbal response, the modifier ‘T’ is attached to the score (e.g. E2, M4; GCS 6T). The accuracy and reliability of the measurement of the GCS score are influenced by technique and experience. Adapted from Teasdale G, Maas A, Lecky F, et al. The Glasgow Coma Scale at 40 years: Standing the test of time Lancet Neurol 2014; 13: 844–54, with permission from Elsevier.

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*This is not an exhaustive list, but highlights those causes which are commonly seen in the given context.

The neurological examination The neurological examination should include documentation of the level of consciousness using the GCS, examination of the eyes and fundi, testing for neck stiffness, and examination of the limbs.

Examination of the eyes The position of the eyes; the size and symmetry of the pupils; the response of the pupils to bright light; the corneal reflex; and the oculocephalic response should be observed (Table 40.3).

The fundi The fundi should be examined for spontaneous venous pulsation (which, if present, excludes raised intracranial pressure), papilloedema, and retinal haemorrhages. Subhyaloid and vitreous haemorrhage may be seen in aneurysmal subarachnoid haemorrhage.

Testing for neck stiffness Neck stiffness is an important sign of meningeal irritation, and may be seen in bacterial meningitis, meningoencephalitis, subarachnoid haemorrhage, cerebral or cerebellar haemorrhage with extension into the subarachnoid space, and cerebral malaria. In any of these conditions, neck stiffness may be lost with increasing depth of coma.

The limbs Limb tone, response to painful stimuli, tendon reflexes, and plantar responses should be examined. Consistent asymmetry between right-​and left-​sided findings usually indicates a structural cause for coma, although symmetrical findings do not exclude this. Limb tone is generally normal or reduced in toxic/​metabolic coma (an exception is neuroleptic malignant syndrome, which is characterized by bilateral limb rigidity). An extensor plantar response usually indicates a structural lesion in the motor pathway (cerebral cortex, subcortex, brainstem, or spinal cord). However, bilateral extensor plantar responses

The history The history is the richest source of information relevant to the diagnosis and needs to be gathered from all available sources, including ambulance personnel, family and friends, GP and hospital records, and the patient’s belongings. The patient’s age and comorbidities, and the setting and time course of loss of consciousness provide the most important clues. Current medications, history of previous or recent alcohol/​substance abuse, and travel history (to determine whether infectious diseases acquired abroad (e.g. malaria) should be included in the differential diagnosis) must be established. Additional questions may of course be relevant in particular circumstances.

The examination The examination of the comatose patient has general and neuro­ logical aspects. Findings on neurological examination contribute to diagnosing the mechanism and cause of coma, determine immediate management, and serve as a reference point against which neurological progress can be measured.

Table 40.3  Diagnostic significance of eye signs in the comatose patients Sign

Significance

Conjugate deviation of the eyes

Seen with cerebral hemisphere lesions (eyes and head deviated away from the hemiplegic side) and pontine lesions (towards the hemiplegic side); also a feature of focal epilepsy

Dysconjugate deviation of the eyes

Indicates brainstem dysfunction (either primary brainstem lesion or secondary compression) or III/​VI nerve lesion

Roving eye movements

Seen in toxic/​metabolic coma (may be absent in deep coma); indicate an intact brainstem

Pupillary size and response to light

Small unreactive pupils are seen in opioid poisoning and pontine lesions, and fixed mid-​ point pupils in midbrain lesions; fixed dilated pupils are seen with central herniation and severe hypoxic-​ischaemic brain injury; asymmetric pupillary size and response to light indicate brainstem dysfunction or III nerve lesion (compression of III nerve by uncal herniation results in ptosis, pupillary dilatation, reduction, and eventual loss of light reflex and deviation of the eye laterally and downwards)

Corneal reflex

A normal response bilaterally (eyelid closure and upward deviation of the eyes) indicates normal function of the midbrain and pons; the corneal reflex may be lost in deep coma due to a toxic/​ metabolic cause; loss of the corneal reflex is associated with loss of the cough reflex

Response to rotation of the head

Normal reflex eye movements (both eyes rotate counter to movement of the head) indicate normal brainstem function; abnormal eye movements may be seen in brainstem lesions and Wernicke’s encephalopathy

The general examination The general examination begins with assessment of airway, breathing, and circulation, and measurement of body temperature. Severe hypertension suggests raised intracranial pressure (or, rarely, hypertensive encephalopathy) as the cause of coma. A rapid comprehensive examination should then be done, including checking for signs of head injury (e.g. scalp laceration or bruising; bleeding from an external auditory meatus or from the nose) and possible complications of coma (e.g. pressure injury of skin or muscle; corneal abrasions; inhalation pneumonia). If there are signs of head injury, additional cervical spine injury should be suspected until proven otherwise:  the neck must be immobilized in a collar and X-​rayed before testing for neck stiffness and the oculocephalic response.

CHAPTER 40 Coma

underlying disorder or the secondary effects of coma. Stabilization of the airway, breathing, and circulation, and exclusion of hypoglycaemia, are the first priorities before diagnosis is explored further. In coma, the reflexes which protect the airway (pharyngeal (gag) and tracheal (cough) reflex, mediated via cranial nerves IX and X) are impaired or lost, and endotracheal intubation to protect the airway should be discussed with an anaesthetist. It is particularly important that the patient’s airway is protected during neuroimaging, when supine positioning of the patient and relative isolation during scanning increase the risk of airway compromise. Blood glucose should be checked by stick test at the bedside, and hypoglycaemia corrected. Seizures should be treated. If Wernicke’s encephalopathy is suspected (e.g. coma with eye signs in the setting of chronic alcohol abuse and malnutrition, recurrent vomiting or after gastrointestinal surgery), give thiamine intravenously (before the administration of glucose). When opioid poisoning or the use of benzodiazepine in hospital (e.g. for procedural sedation) is suspected as the cause of coma, the appropriate antidote (naloxone/​flumazenil) should be given. Having dealt with these priorities, the cause of coma must be determined, as the quicker this is treated, the better is the outcome. Clinical assessment together with neuroimaging will usually identify the likely cause or causes. As a general rule, the absence of meningeal signs or focal neurological abnormalities indicates a systemic cause of coma (usually toxic or metabolic). However, some intracranial diseases (e.g. hypoxic-​ischaemic brain injury, bilateral subdural haematomas) may not give rise to meningeal or focal signs. Conversely, focal signs do not necessarily indicate a primary intracranial cause of coma: they may be the consequence of secondary pathology (e.g. cerebral herniation with brainstem compression complicating cerebral oedema due to fulminant hepatic failure), may reflect previous unrelated disease (e.g. stroke) or may be seen in certain metabolic disorders (e.g. hyperglycaemic or hyperammonaemic states).

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may be seen transiently after tonic–​clonic seizures. Hemiplegia with a contralateral III palsy may be seen with a unilateral cerebral hemisphere mass lesion complicated by uncal herniation and brainstem compression.

Other signs Other signs are as follows: • Multifocal myoclonus (brief, random, asynchronous jerks in limb, trunk, or facial muscles) suggests a toxic/​metabolic cause. • Myoclonic twitches of facial muscles and fingers may be seen in non-​convulsive status epilepticus. • Focal or general seizures may complicate many systemic and primary intracranial diseases causing coma.

Specific clues to the diagnosis The cause of coma may be obvious (e.g. documented ingestion of alcohol and psychoactive medication in a young patient; coma following prolonged cardiorespiratory arrest). However, in many cases, the cause or causes of coma are less clear. The neurological signs allow patients to be placed in one of three subsets (Box 40.2) which constrain the differential diagnosis and establish priorities in management and therapy (e.g. urgency of neuroimaging; need for empirical antimicrobial therapy).

Key diagnostic tests

CHAPTER 40 Coma

Key diagnostic tests are: Blood glucose:  This should be checked immediately at the bedside, and confirmed by laboratory testing. CT: This should be done urgently in all patients, unless there is a clear toxic cause of coma in a younger patient, with no features pointing

Box 40.2  Clues to the diagnosis of coma from the neurological findings (less common or rare causes are placed in parentheses)

No meningeal or focal signs

toxic/​metabolic disorders • • hypoxic-​ischaemic brain injury • postictal state • septic encephalopathy • (cerebral venous sinus thrombosis) • (bilateral subdural haematomas) • (cerebral vasculitis) • (cerebral fat embolism)

Meningeal but no focal signs subarachnoid haemorrhage • • bacterial meningitis • meningoencephalitis • (cerebral malaria)

Focal signs Cerebral hemisphere signs • trauma • cerebral infarction • mass lesion (haematoma, neoplasm, abscess) • (cerebral venous sinus thrombosis) • (acute demyelinating encephalomyelitis)

Brainstem signs

trauma • • brainstem infarction or haemorrhage • cerebellar infarction or haemorrhage • posterior fossa mass lesion causing hydrocephalus • Wernicke’s encephalopathy • (brainstem encephalitis) • (central pontine myelinolysis) • (basilar artery thrombosis)

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to additional disease. CT is very sensitive for intracranial haemorrhage (sensitivity for subarachnoid haemorrhage, 95%; for other intracranial haemorrhage, >95%) and will identify mass lesions, hydrocephalus, marked cerebral oedema, and large cerebral hemisphere ischaemic strokes. Non-​contrast CT may be normal in patients with meningitis or meningoencephalitis; early ischaemic stroke, especially of the brainstem or cerebellum; diffuse axonal injury from trauma; hypoxic-​ischaemic brain injury; and white matter disorders (e.g. central pontine myelinolysis). Examination of the cerebrospinal fluid: This test (assuming no contraindication to lumbar puncture) should be done in patients with a normal CT scan and in whom coma remains unexplained, to rule out intracranial infection. Other key tests: Other key tests are measurement of arterial blood gases and pH; full blood count; a coagulation screen; and a biochemical profile. A toxicology screen and measurement of plasma paracetamol and salicylate levels should be done if poisoning is possible.

Other diagnostic tests Other diagnostic tests are: MRI: This should be done if CT and other tests do not establish the cause of coma, or a cause to which CT is insensitive is suspected. EEG: This is indicated if the clinical findings suggest non-​convulsive status epilepticus or if the cause of coma remains unclear after neuroimaging and other tests. Other tests: Other tests such as blood culture, measurement of adrenal and thyroid function, measurement of plasma osmolality (raised in poisoning with ethanol, ethylene glycol, isopropyl alcohol, or methanol), measurement of plasma ammonia (raised in hepatic encephalopathy, valproate poisoning, and ornithine transcarboxylase deficiency), and measurement of red-​cell transketolase level (reduced in Wernicke’s encephalopathy due to thiamine deficiency) may be helpful in specific circumstances.

Introduction to therapy Patients with coma should be nursed in a high-​dependency or intensive care unit. As well as specific treatment directed at the underlying cause, supportive care of the comatose patient, including stabilization of the airway, breathing, and circulation, correction of hypoglycaemia or hyperglycaemia, treatment of seizures if present, correction of fever or hypothermia, and anticipation and prevention of the complications of coma (e.g. use of pressure mattress and positioning/​ turning to prevent pressure injury of skin and muscle) should be performed. Induced hypothermia can improve the neurological prognosis for coma after cardiac arrest. Thiamine and other B vitamins should be given intravenously (before the administration of glucose) if Wernicke’s encephalopathy is possible (e.g. in the setting of chronic alcohol abuse, hyperemesis, or refeeding syndrome). If bacterial meningitis or viral meningoencephalitis is possible (because of fever and meningism), empirical antimicrobial therapy (with cefotaxime (plus ampicillin in patients over 55 or at increased risk of Listeria infection) and aciclovir) should be started immediately, after taking blood for culture. An urgent neurosurgical opinion should be sought if CT shows a structural cause for coma.

Prognosis Patients in coma may make a complete recovery (e.g. after poisoning with psychoactive drugs), survive with varying degrees of brain injury (including the vegetative state), or die from brain death or systemic disease. The prognosis largely depends on the cause of coma, and is poor when due to major structural brain disease. For a given cause, the depth of coma and the status of brainstem reflexes influence prognosis (better with normal brainstem function). In patients with coma after cardiac arrest, the neurological findings in the first 24 hours do not allow a firm prognosis to be made. However, if pupillary or corneal reflexes are absent at 24 hours, or motor responses are absent at 72 hours, the prognosis is very poor.

Coma versus psychogenic unresponsiveness Psychogenic unresponsiveness should be considered if there is a resistance to passive eye opening, the avoidance of stimuli, a response to stimuli discordant with the assessed level of consciousness, and a history of non-​epileptic seizures or other functional disorders. The diagnosis should not be made simply because the existing investigations are normal. Appropriate consideration should always be given to the possibility of additional organic pathology, which should be assessed and investigated according to the principles discussed in this chapter.

Coma versus brain death Brain death may follow coma because of the primary and secondary effects of the underlying disease or diseases. In brain death,

brainstem reflexes and respiratory function (response to arterial carbon dioxide level >8.0 kPa) are absent. There are no motor reflexes. In the UK, brainstem death can be confirmed on the basis of clinical examination by two experienced doctors. When performed, EEG shows electrocerebral silence, and evoked potentials are absent. A PET scan or a functional MRI shows absent cortical metabolism.

Further Reading Edlow JA, Rabinstein A, Traub SJ, et  al. Diagnosis of reversible causes of coma. Lancet 2014; 384: 2064–​76. Teasdale G, Maas A, Lecky F, et  al. The Glasgow Coma Scale at 40  years:  Standing the test of time Lancet Neurol 2014; 13: 844–​54.

CHAPTER 40 Coma

How to handle uncertainty in the diagnosis

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41 

Delirium (acute confusional state)

David Sprigings

Definition Delirium (from the Latin delirare, to deviate from the furrow when ploughing, and hence to be crazy or rave) is a functional brain disorder characterized by disturbances of consciousness, attention, and cognition which develop over a period of hours to days, and often fluctuate during the day. Delirium can reflect a primary neurological disorder, substance intoxication or withdrawal, an adverse effect of drugs (especially those with an anticholinergic effect), or a systemic disorder such as sepsis. The term ‘acute confusional state’ is often used synonymously with delirium, although delirium is preferred (as confusion is not specific to delirium, and its definition is imprecise). Delirium may be associated with a range of associated clinical features including increased or decreased psychomotor activity (hyperactive and hypoactive variants), hallucinations and delusions, and efferent sympathetic hyperactivity. Delirium with pronounced psychomotor and sympathetic hyperactivity is more often seen in younger patients with alcohol or substance intoxication/​withdrawal (delirium tremens), but no cause is specific to a clinical subtype. Delirium is distinguished from dementia (with which it may coexist, as dementia is a major risk factor for delirium) by its speed of onset (over hours or days), and its reversibility with correction of the underlying cause. In some patients, however, delirium may be followed by long-​term cognitive impairment, suggesting that the pathophysiology of delirium overlaps with that of dementia.

Differential diagnosis Several neuropsychiatric disorders may give rise to abnormal consciousness, language, memory, or behaviour, and thus enter the differential diagnosis of delirium (Table 41.1).

Context Delirium is present on hospital admission in around 15% of older patients (age over 65), and develops after admission in a further 20%, making it the commonest complication of hospitalization in this age group. In patients of all ages, delirium may reflect a primary neurological disorder, or substance intoxication/​withdrawal. In older patients, it can be caused by a wide range of systemic disorders (most commonly infection) or medications, especially those with an anticholinergic effect. Delirium predisposes to injury, falls, dehydration, malnutrition, incontinence, and pressure ulceration, and thus

Box 41.1  Major risk factors and precipitants of delirium

Major risk factors

dementia • • age over 65 • current hip fracture • severe illness

Common precipitants

infection • • medications, especially with those with an anticholinergic or psychoactive effect • electrolyte disorders • alcohol intoxication or withdrawal • major surgery • urinary retention or faecal impaction • sleep deprivation Data from NICE, Delirium: prevention, diagnosis and management, 2010 nice.org.uk/​ guidance/​cg103

significantly increases morbidity and mortality. Given these adverse consequences, prevention of delirium is of high importance; studies suggest that 30%–​40% of cases are preventable, and multicomponent intervention (see ‘Introduction to therapy’) has been shown to reduce the incidence in vulnerable patients. Delirium can be conceived as the interaction between risk factors which predispose to delirium (brain vulnerability), and precipitants which trigger it. Common risk factors and precipitants are shown in Box 41.1; the interval between onset of precipitant and delirium is typically >24 hours. A  postulated model of the neuronal pathophysiology underlying delirium is illustrated in Figure 41.1. In highly vulnerable patients, such as those with dementia, a relatively minor precipitant such as a urinary tract infection may cause delirium. Often, several precipitants act in concert. Causes of delirium to consider in particular patient groups are summarized in Table 41.2. Major surgery is a common precipitant of delirium in older patients, with rates of up to 50% after cardiac surgery and surgery for hip fracture. Delirium typically appears 2–​7  days post-​operatively, when plasma levels of inflammatory and catabolic mediators reach their peak, consistent with these having a causal role.

Table 41.1  Differential diagnosis of delirium

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Diagnosis

Comment

Dementia

Delirium and dementia often coexist, as dementia is a major risk factor for delirium; dementia is characterized by the gradual onset of impairment of memory, impairment of the execution of activities of daily living, and impairment of social behaviour; there is no clouding of consciousness

Acute functional psychosis (manic or schizophrenic)

In acute functional psychosis, hallucinations, if present, are typically auditory, whereas in delirium they are typically visual or tactile; assume a diagnosis of delirium rather than acute functional psychosis if the patient is older than 40 with no previous psychiatric history, there is a history of alcohol or substance abuse, there are major medical comorbidities, there is disorientation, clouding of consciousness, or decreased alertness, or if physiological observations are abnormal

Non-​convulsive status epilepticus

In non-​convulsive status epilepticus, there are often mild clonic movements of the eyelids, face, or hands, or simple automatisms; the EEG is abnormal

Transient global amnesia

In transient global amnesia, there is an abrupt onset of antegrade amnesia without clouding of consciousness or loss of personal identity; cognitive impairment is limited to amnesia, and there are no focal neurological or epileptic signs; symptoms resolve within 24 hours

Fluent (receptive) dysphasia

Speech is fluent but with meaningless words, unnecessary phrases, and nonsensical grammar; there is no clouding of consciousness

(A) Normal situation

(B) Old age, incipient neurodegenerative disease, or anticholinergic drug treatment 4

Systemic infection

Resting microglia

Cholinergic inhibition of microglia

Systemic infection

3

Reduced cholinergic inhibition of microglia 2

primed microglia

Delirium of limited duration and severity

1

Neurodegeneration

Overactivated microglia

Severe, prolonged delirium

Dementia

Figure 41.1  Neuronal pathophysiology underlying delirium: A postulated model based on clinical and research observations. (A) In the normal situation, peripherally produced pro-​inflammatory cytokines, such as tumour necrosis factor alpha (TNFα) can enter the brain and activate microglia that produce inflammatory mediators affecting neuronal functioning, thus causing delirium. However, cholinergic inhibition controls microglial activation and thereby limits the severity and duration of delirium. (B) In old age, incipient neurodegenerative disease, or anticholinergic drug treatment, microglia might already be primed, which leads to overactivation on new stimuli. If cholinergic inhibition also fails, because of either preexisting neurodegeneration or use of drugs with anticholinergic effects, neuroinflammation could spin out of control, leading to severe prolonged delirium that can become associated with dementia. The green arrows indicate four ways in which control could be re-​established over activated microglia: (1) direct inhibition of microglial activation by anti-​inflammatory treatment (e.g. minocycline); (2) inhibition of the effects of cytokines (e.g. anti-​TNFα); and augmentation of inhibitory cholinergic control by (3) nicotine-​receptor ligands (e.g. anabasine) or (4) other cholinomimetic drugs (e.g. cholinesterase inhibitors). Reprinted from The Lancet, Volume 375, Gool WA, van de Beek D, Eikelenboom P. , Systemic infection and delirium: when cytokines and acetylcholine collide, pp.73-​75, Copyright 2010, with permission from Elsevier.

Approach to diagnosis There are two aspects to the diagnosis of delirium: recognition of the syndrome, and identification of its cause or causes. Any patient with an abnormal mental state may have a disease which is an immediate threat to life (e.g. respiratory failure), and therefore exploration of the diagnosis should be preceded by a rapid assessment of the patient to Table 41.2  Causes of delirium by context Patient group

Causes to consider*

Older patient in the emergency department

Acute infection Adverse effect of medication Electrolyte disorder Stroke Subdural haematoma

Younger patient in the emergency department

Alcohol intoxication Poisoning with cocaine, amphetamine, or other psychoactive drugs Primary neurological disorder (e.g. encephalitis)

Older patient with delirium after surgery

Acute infection Adverse effect of medication Urinary retention Faecal impaction

Patient from psychiatric hospital

Neuroleptic malignant syndrome Primary neurological disorder (e.g. encephalitis)

Patient with alcohol dependence

Alcohol intoxication or withdrawal Wernicke’s encephalopathy Liver failure Acute infection (e.g. pneumonia, spontaneous bacterial peritonitis)

Patient with cancer

Adverse effect of medication (e.g. opioid toxicity) Brain or meningeal metastases Electrolyte disorder (e.g. hyponatraemia, hypercalcaemia) Paraneoplastic effect

* This is not an exhaustive list, but highlights those causes which are commonly seen in the given context.

ensure that the airway, breathing, and circulation are not compromised. Blood glucose should be measured and hypoglycaemia excluded. Recognition of delirium requires examination of the mental state and establishing the antecedent history by talking to family members, carers, or hospital staff. Mental state examination should include tests of attention, orientation, and memory and can be done in a few minutes with the 10-​item abbreviated mental status examination, or equivalent (Box 41.2). The Confusion Assessment Method (CAM) instrument is an alternative and simpler method of confirming a diagnosis of delirium, with a sensitivity and specificity of >90% when compared to a diagnosis based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (a recognized standard) (see Inouye et al., 1990). Using CAM, the diagnosis of delirium requires an acute onset and fluctuating course, with evidence of reduced attention together with disordered thinking or an altered level of consciousness. Given the broad range of disorders which may underlie delirium, identification of the cause requires a comprehensive assessment of the patient. Of particular importance in the history are the presence

CHAPTER 41  Delirium (acute confusional state)

Activated microglia

Box 41.2  Examination of the mental state in suspected delirium (abbreviated mental status examination) Age • • Time (to nearest hour) • Address for recall at end of test—​this should be repeated by the patient to ensure it has been heard correctly:  42 West Street. • Year • Name of hospital • Recognition of 2 people (e.g. doctor, nurse) • Date of birth (day and month sufficient) • Year of 2nd World War • Name of present monarch • Count backwards 20–​1 Each correct answer scores one mark. The healthy elderly score 8–​10. Reproduced with permission from Qureshi KN, Hodkinson HM., Evaluation of a ten-​question mental test in the institutionalized elderly, Age and Ageing, volume 3. pp.152-​7, copyright © 1974 Oxford University Press

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of other systemic or neuropsychiatric symptoms; comorbidities which may be systemic (e.g. chronic obstructive pulmonary disease, diabetes, chronic liver disease), neurological (e.g. dementia, parkinsonism), or psychiatric; a complete list of current and recent medications; and enquiry about alcohol or substance abuse. In addition to assessment of the mental state and conscious level, the examination should include assessment of the airway, breathing, and circulation; measurement of body temperature; abdominal findings; and testing for neck stiffness, lateralized weakness, tendon reflexes, and plantar responses. Blood glucose should be checked at the bedside by stick test.

Specific clues to the diagnosis

CHAPTER 41  Delirium (acute confusional state)

Delirium is under-​diagnosed in hospital, particularly in patients with the hypoactive variant. Patients with major risk factors for delirium (Table 41.2) should be screened on admission by mental state examination. Delirium should also be suspected in patients with: • abnormal cognitive function (confusion, impaired concentration, slow responses to questions—​the patient described as a ‘poor historian’) • abnormal mood (‘depression’ developing in hospital) • abnormal perception (visual or auditory hallucinations) • abnormal behaviour (hyperactivity or hypoactivity (restlessness, agitation, or reluctance to mobilize); unwillingness to eat or drink; abnormal sleep–​wake cycle) • abnormal social behaviour (withdrawal from social contact; unwillingness to cooperate with care—​the patient described as ‘uncooperative’ or ‘difficult’)

Key diagnostic tests Delirium is a diagnosis based on clinical findings. There is no laboratory test for delirium, although investigation is usually needed to establish the cause or exclude other diagnoses (Table 41.1). As a

general rule, all patients with delirium should have a full blood count, a biochemical profile, a C-​reactive protein test, and urinalysis.

Other diagnostic tests Other diagnostic tests are: Neuroimaging (by CT or MRI): This is indicated if delirium followed a fall or head injury; if there are new focal neurological signs; if there is papilloedema or other evidence of raised intracranial pressure; if the patient has cancer or HIV–​AIDS; if the patient’s behaviour prevents adequate neurological examination; or if no systemic cause for the delirium is apparent. Examination of the cerebrospinal fluid: This should be done (assuming no contraindication to lumbar puncture) if meningitis or encephalitis is suspected; if the patient is febrile and no systemic focus of infection is found; or if the cause of delirium remains unclear. Electroencephalography: This is indicated if non-​convulsive status epilepticus or encephalitis is suspected, or no cause for delirium is apparent. It may be useful in distinguishing delirium from psychosis.

Introduction to therapy The major elements in the therapy of delirium are: identification and treatment of the underlying cause • • comprehensive supportive care (summarized in Table 41.3), with avoidance of physical restraint, and anticipation and prevention of complications of delirium • avoidance of unnecessary medications, especially those with anticholinergic effect Short-​term (1 week or less) therapy with haloperidol (in a dose of 30 minutes or recurring repeatedly without recovery of consciousness.

Differential diagnosis Paroxysmal neurological symptoms occur in a large number of conditions, and the differential diagnosis depends on the type of presentation (see Table 42.1).

Context Seizures will affect between 5% and 10% of the population at some time in their life. This can be in the form of isolated or acute symptomatic seizures during an acute medical or neurological illness, or as part of an epilepsy syndrome. Epilepsy has a point prevalence of 5–​10/​1000 persons. Some people with epilepsy also have non-​ epileptic, psychologically mediated attacks (dissociative seizures), although most people with non-​ epileptic attacks do not have epilepsy. Common presentations in the acute medical take include: • seizures or other paroxysmal events in a patient with known epilepsy • first seizure • seizure in the context of an acute medical or neurological illness

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Table 42.1  Differential diagnosis of seizures and other paroxysmal events Loss of consciousness

Syncope reflex • orthostatic hypotension • cardiac arrhythmia • obstruction to the circulation • Metabolic disturbance (e.g. hypoglycaemia) Intoxication Daytime sleep attacks Non-​epileptic/​psychogenic

Paroxysmal motor disorder

TIA basal ganglia ischaemia • shaking TIAs • Movement disorders tics • myoclonus • chorea • tremor • Tonic spasms (e.g. in MS) Sleep disorders hypnagogic jerks • periodic limb movements • REM parasomnia •

Paroxysmal sensory disorder

TIA Migraine with aura

Paroxysmal behaviour disturbance

Psychiatric disease panic attacks • hysterical fugue • episodic dyscontrol • acute psychotic episode • Acute encephalopathy (metabolic/​toxic) Transient global amnesia Basilar migraine Sleep disorders

Drop attacks without loss of consciousness

Spinal cord disease Cataplexy Third ventricular colloid cyst Idiopathic drop attacks

Approach to diagnosis Step 1: Establish whether or not the paroxysmal event was a seizure. For past events, this distinction lies solely in the history taken from the patient and, whenever possible, from an eyewitness. If no witness is with the patient, a telephone call to a person who saw what happened is more useful than any diagnostic test. Step 2: Further define the type of seizure by analysis of the seiz­ ure semiology and use of the EEG (see ‘Key diagnostic tests’). Is there more than one seizure type? Aim to define a syndrome. Step 3: Establish the underlying aetiology. Demographic features can point to a likely cause, but investigations are needed to establish the cause of seizures (see ‘Key diagnostic tests’).

Specific clues to the presence of seizures Ask the patient and witnesses what happened before, during, and after the event, bearing in mind that no single feature in the history is completely specific for the presence of a seizure. A common difficulty is to distinguish between epileptic seizures, syncope (loss of consciousness due to a global reduction in cerebral blood flow), and non-​epileptic events (Table 42.2).

Timing

Feature

Seizure

Syncope

Non-​epileptic attack

Before

Precipitating factors

Uncommon Sleep deprivation, alcohol Specific trigger in reflex epilepsies (rare)

Pain, emotion, standing, Valsalva Exercise or none (cardiac)

Stressful circumstance

Prodrome

Non-​specific warning in some Aura (part of seizure)

Tiredness, sweating, nausea, visual disturbance (brief hallucinations and tunnel vision), muffled hearing

None or symptoms of anxiety

During

After

Onset

Sudden

Often gradual

Gradual

Duration

1–​3 minutes

1–​30 seconds

Minutes to hours

Facial appearance

Blue/​cyanosed Frothing at mouth

Pale

Normal

Eyes

Open, or clonic eyelid movements

Open, turned up

Closed, resists eye opening

Movement

Synchronous rhythmic limb movements

None, can have brief convulsion (less than 15 seconds), myoclonus, and tonic flexion or extension

Asynchronous, waxing and waning, pelvic thrusts

Tongue biting

Common, lateral tongue biting

Rare

Occasionally, tip of tongue

Incontinence

Common

Uncommon

Uncommon

Recovery

Slow Headache, myalgia, fatigue

Rapid

Variable

Injury

Common

Uncommon

Uncommon

Confusion

Prolonged

Brief

None (maybe emotional)

Specific clues to the nature of seizures

Key diagnostic tests

Specific clues to the nature of seizures are as follows:

Key diagnostic tests are as follows:

• Is this an acute symptomatic seizure? Ask about preceding febrile illness and look for meningism and rash (meningitis, encephalitis?), trauma (head injury), and signs of alcohol or substance intoxication or withdrawal. • If patients present with generalized tonic–​clonic seizures, search for additional seizure types suggestive of a generalized epilepsy syndrome. For example, a young adult with absences and myoclonus in addition to generalized tonic–​clonic seizures might have juvenile myoclonic epilepsy. There might be a family history. • Are seizures preceded by other symptoms (motor, sensory, autonomic, psychic) that could represent focal seizures? For example, a rising sensation from abdomen to chest before a convulsion would indicate medial temporal lobe focal seizures. • Does the physical examination show features of a syndrome known to be associated with epilepsy, for example, a neurocutaneous syndrome, or focal signs such as weakness or reflex asymmetry, which point towards an underlying structural lesion? • The age of onset will narrow the differential diagnosis (Table 42.3).

Blood tests: In the acute setting, rule out hypoglycaemia, electrolyte abnormalities (Na+, Ca2+, Mg2+), and infection (full blood count, C-​reactive protein). Check renal and liver function to look for precipitant factors and guide therapy. The creatine kinase is often raised. Perform a toxicology screen. ECG: Rhythm disturbance can mimic seizures. In particular, look at the PR interval (heart block) and QTc time. Neuroimaging: MRI of the brain is the imaging modality of choice to detect epileptogenic lesions and should be performed in any patient with suspected epilepsy unless contraindicated. A CT brain is not sufficiently sensitive, but can be helpful in emergency presentations to rule out gross underlying pathology. EEG: An EEG may be helpful to make an accurate diagnosis of the epilepsy type and to distinguish between focal and generalized epilepsies. Epileptiform discharges (sharp waves, spikes, spike-​and-​ wave forms, polyspikes) are present in ~55% of interictal EEGs in patients with epilepsy, so a negative EEG does not rule out epilepsy. The sensitivity is higher in the sleep EEG. Normal people may have non-​specific abnormalities (10%) and rarely epileptiform changes (CUI.,.,_, sewnl)' on meNHS. ~ p.utyrepot1. )uly 1012. Royal Colege

airway obstruction leads to noisy breathing and is common if consciousness is impaired. Partial obstruction may occur at several levels within the airway and lead to characteristic sounds, such as snoring (tongue obstructing the oropharynx), stridor (obstruction at larynx by oedema, a foreign body, or a tumour), and wheeze (bronchospasm of small airways). Obstruction of the oropharynx by the tongue in an unconscious patient can be relieved by simple airway manoeuvres, such as a chin lift or jaw thrust. The oropharynx should be inspected and any foreign body such as dentures, food, vomit, or blood removed. If airway patency cannot be restored by these simple measures, then experienced help should be sought. The inappropriate insertion of airway adjuncts or suction catheters into semiconscious patients can precipitate laryngospasm and complete airway obstruction. Endotracheal intubation or surgical airway placement should only be performed by appropriately trained staff. Complete airway obstruction is uncommon; there is no movement of air at the mouth, and paradoxical movement of the chest and abdomen. It requires immediate intervention by an individual trained in airway management, as cardiac arrest and death will occur within minutes. High-​flow oxygen should be applied to all patients to avoid hypoxia.

it allows arterial samples to be drawn easily for blood gas analysis. A rapid infusion of fluid is a prerequisite when circulatory failure exists (fluid challenge). The fluid should be given as a bolus of 250–​500 ml over a period of 10–​15 min. Response to treatment is judged against improvements in blood pressure, pulse, capillary refill, urine output, GCS score, lactate levels, and cardiac output, if this is being measured. Further aliquots may be given if there is a response to therapy. Even in cardiogenic shock, fluid may result in improved tissue perfusion; however, it should be avoided if there is evidence of pulmonary oedema.

Breathing

Exposure

Observation is the most rewarding aspect of examining the breathing system. The respiratory rate should be recorded. Tachypnoea (>20 breaths/​min) is the most frequent physiological abnormality amongst patients admitted to the ICU. Patient may also have a reduced respiratory rate (90%. Oxygen is administered by using a mask with a reservoir bag and a non-​ rebreathing valve and at high flow (15 l/​min), as this will achieve an inspired oxygen of >80%. An arterial blood gas should be performed on oxygen to assess the adequacy of oxygenation (as determined by the oxygen saturation (SaO2), the partial pressure of oxygen (PaO2), and the alveolar–​arterial oxygen gradient) and ventilation (as determined by the partial pressure of carbon dioxide (PaCO2) and by pH). It may also provide information about the acid–​base balance and the circulation (via the base deficit, pH, and lactate level). Lactate is frequently raised in critical illness often long before other indices, usually reflecting an inadequate circulation and a switch to anaerobic metabolism. Removal of oxygen to perform an arterial blood gas is dangerous, as it may precipitate cardiorespiratory arrest, and is therefore avoided. In patients with COPD and type II respiratory failure, a small proportion of individuals retain carbon dioxide on oxygen. In these patients, it is acceptable to initiate a fixed-​performance oxygen mask delivering inspired oxygen of 40%. The amount of oxygen delivered can be titrated upwards if oxygen saturations fall to 93% or consciousness decreases. Oxygen saturations 20  mm Hg, and new organ failure). Despite general supportive measures, AKI may fail to improve or may even deteriorate; in these circumstances, RRT may be required. Currently, there is controversy as to the timing and type of RRT that should be used. Conventional indications for RRT include refractory hyperkalaemia, fluid overload, severe metabolic acidosis, and overt uraemic symptoms such as encephalopathy or pericarditis. Broadly, there are two types of RRT:  continuous RRT (CRRT) and intermittent RRT (IRRT). Currently, there is no data to support the superiority of either of these modalities, and both are commonly used for AKI in the ICU. Doses of RRT that have been associated with increased survival in ICU patients are at least 35 ml/​ kg hour−1 of haemofiltration or haemodiafiltration, and daily IRRT (dialysis).

Further Reading Hertzberg D, Ryde L, Pickering JW, et al. Acute kidney injury—an overview of diagnostic methods and clinical management. Clin Kidney J 2017; 10: 323–31. doi:10.1093/ckj/sfx003 Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Inter Suppl 2012; 2: 1–​138. National Institute for Health and Care Excellence. Acute Kidney Injury: Prevention, Detection and Management. 2013. Available at https://​ www.nice.org.uk/​guidance/​cg169?unlid=8859070520174952738 (accessed 28 Apr 2017).

CHAPTER 151  ICU treatment of acute kidney injury

Prognosis and how to estimate it

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ICU treatment of sepsis and septic shock Matt Wise and Paul Frost

Definition of the disease The Third International Consensus definitions for sepsis and septic shock (Sepsis-​3) were published in 2016; sepsis is defined as ‘life-​threatening organ dysfunction caused by a dysregulated host response to infection’ (Singer et  al., 2016, p.  801). Organ dysfunction can be assessed using the Sequential Organ Failure Assessment (SOFA) score (see Table 152.1). SOFA utilizes clinical findings, laboratory data, and therapeutic interventions to quantify organ dysfunction in six organ systems (Table 152.1). Organ dysfunction is indicated by an acute change in the SOFA score of ≥2 points consequent to the infection. (The SOFA score is assumed to be 0 in patients without preexisting organ dysfunction.) Patients with suspected infection who are at risk of poor outcomes can be promptly identified at the bedside by the quick SOFA score (qSOFA). The criteria for qSOFA are a respiratory rate of >22 breaths/​min; altered mentation; and a systolic blood pressure of ≥100 mm Hg. Patients with suspected infection and any two of these three variables are at high risk of death or prolonged intensive care stay. Septic shock, which is a subset of sepsis, is defined by the presence of particularly profound circulatory, cellular, and metabolic abnormalities and is associated with a greater risk of mortality than sepsis alone. Clinically, septic shock patients are sepsis patients who require vasopressors to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg and have a serum lactate level >2 mmol/​l despite adequate volume resuscitation.

Aetiology of sepsis Bacteria are the most frequent causes of sepsis and septic shock, while viruses, fungi, and parasites are implicated less often. Positive cultures are found in only 60% of cases; this may be the result of previous antibiotic therapy or of inadequate sampling or testing. The aetiology of sepsis is constantly changing; whereas Gram-​negative

organisms used to make up the majority of cases, Gram-​positive bacteria now predominate. Sepsis due to fungal disease has also seen a dramatic rise. These changes may be explained by alterations in patient demographics, such as an increasingly elderly population with multiple comorbidities; an increased frequency of indwelling catheters or devices; and greater numbers of patients with immunosuppression as a result of disease or drug therapy. The causative organisms depend on the patient population in question; for example, patients with a haematological malignancy and who have prolonged neutropenia following chemotherapy have a high prevalence of invasive fungal disease. The organism type will also depend on whether the infection is acquired in the community or the hospital setting, where antimicrobial resistance is more common. In European ICUs, one-​third of all patients either present with or develop sepsis; in two-​thirds of these cases, the sepsis is present on admission. The commonest sites of infection are lung (68%), abdomen (22%), blood (20%), and urinary tract (14%). The most common microorganisms are Staphylococcus aureus (30%), Pseudomonas species (14%), and Escherichia coli (13%). Roughly half of the Staphylococcus aureus organisms identified were methicillin resistant (i.e. MRSA).

Typical symptoms of the disease, and less common symptoms Symptoms of sepsis and septic shock are protean and depend on the site of infection as well as patient factors such as age, immune status, and presence of comorbidity. Altered mental status, such as anxiety or confusion, is a consistent feature while constitutional symptoms such as malaise, loss of appetite, fatigue, and fever are common. The site of infection may be localized by symptoms such as dysuria and frequency for the urinary tract; cough and purulent sputum for the lung; and diarrhoea and vomiting for bowel infection. Localized symptoms may diminish and constitutional symptoms predominate at extremes of age or if the patient is immunosuppressed.

Table 152.1  The Sequential Organ Failure Assessment (SOFA) score System

0

1

2

3

4

Respiration PaO2/​FiO2 mm Hg

>400

10 µg/​l. Neuromuscular blocking agents can mimic coma and respiratory failure and it is important to exclude their presence. This can be done by demonstrating the presence of deep tendon reflexes or by using a nerve stimulator. Metabolic disturbances and circulatory instability that arise as a direct consequence of brainstem injury should be distinguished from similar, primary disturbances that may cause coma. Hypernatraemia may occur as a consequence of DI complicating BSD or be due to gross dehydration, unrelated to BSD. It is important to emphasize that the establishment of an unequivocal, irreversible cause of the coma outweighs any contribution that minor deviations from normal homeostasis might theoretically make to the comatose state.

Definitions

Natural history, and complications of the disease Cerebral injury following trauma, haemorrhage, or infection causes the brain to swell (cerebral oedema). Usually, deleterious rises in intracranial pressure are prevented by compensatory reductions in CSF and intracranial blood volumes. However, following severe injury, these mechanisms are exhausted, and intracranial pressure rises, often exponentially. This causes a deteriorating cycle of further cerebral ischaemia, neuronal injury, and oedema. In these circumstances, brain tissue is displaced downwards towards the foramen magnum. Ultimately, the cerebellar tonsils may be forced through the foramen magnum (tonsillar coning), compressing the brainstem and causing BSD. Crucial functions of the brainstem include control of consciousness via the reticular activating system, and control of cardiorespiratory homeostasis. Additionally, all sensory and motor tracts pass through the brainstem and cranial nerves 3–​ 12 emerge from it. Therefore, clinical signs of coning include coma; apnoea; cardiovascular instability and absence of receptivity; movement; and brainstem reflexes. Following BSD, characteristic pathophysiological changes arise. These include hypotension; cardiac arrhythmias; pulmonary oedema; diabetes insipidus (DI) and other endocrine disturbances; disseminated intra-​vascular coagulopathy (DIC); and hypothermia. Cardiovascular instability occurs in around 80% of brain dead patients; its causes are multifactorial and include loss of sympathetic tone; vasodilatation; and myocardial depression. The mechanism of myocardial depression is uncertain but is characterized by evidence of myocardial ischaemia and even infarction. Pulmonary oedema may arise as a result of myocardial dysfunction secondary to massive sympathetic over activity, occasionally seen at the onset of BSD (neurogenic pulmonary oedema). Following BSD, production of antidiuretic hormone is low to non-​ existent; consequently, DI occurs in up to 65% of affected

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CHAPTER 154 Brain death

Nonetheless, as far as it is possible, metabolic, endocrine, and circulatory contributions to the internal milieu must be normalized prior to BSD testing. So, profoundly abnormal electrolyte levels, for example, sodium 160 mmol/​l, potassium 60 mm Hg, and blood gases should be normal. Rarely, myxoedema, thyroid storm, and Addisonian crisis can present with coma, and appropriate hormone assays should be requested if there is any suspicion that these conditions are present. Several neurological disorders, for example, acute inflammatory polyneuritis, cause profound neuromuscular weakness resembling loss of brainstem reflexes. Although it would be extremely unlikely for such conditions to coexist with the primary, known cause of irreversible brain damage, nonetheless, these conditions should be considered and excluded. Finally, in the context of traumatic coma, it is essential to exclude a high cervical spinal injury, as this could cause quadriparesis and invalidate the apnoea test. Once the preconditions have been fulfilled, BSD can be confirmed by clinical examination. In the UK, this examination is undertaken by two doctors, experienced in the procedure, who have been registered for at least 5  years, one being a consultant. These clinicians must confirm the absence of all brainstem reflexes as follows: pupils are fixed in diameter and do not respond to light • • no response (i.e. eyelid movement) to direct stimulation of the corneas (corneal reflex) • no eye movements following direct stimulation of the tympanic membranes with iced water (vestibulo-​ocular reflex) • there should be no motor response in the cranial or somatic distribution to supraorbital pressure • no contraction of the soft palate when the uvula is stimulated (gag reflex) • no response to tracheal suctioning as far as the carina (cough reflex) • no respiratory response to an apnoea test; this means that no breathing movements should be seen following disconnection of the patient from the ventilator; when the partial pressure of carbon dioxide (PaCO2) is above the threshold for maximal stimulation of the respiratory centres in the medulla oblongata (i.e. PaCO2 > 6.65 kPa); during this time, hypoxaemia is prevented by the provision of oxygen at 5 l/​min via a catheter placed down the endotracheal tube In order to reassure the family and remove the risk of observer error, the BSD tests are carried out twice. In the UK, there is no prescribed interval between tests.

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Other diagnoses that should be considered The ‘locked-​in’ syndrome usually arises as a result of destruction of the base of the pons, for example, following haemorrhage, infarction, or trauma. Characteristically, these patients are cognitively intact, retain vertical eye movements, but are otherwise totally paralysed. Guillain–​Barré syndrome involving all of the peripheral and cranial nerves could mimic BSD. It is vitally important to appreciate that adherence to the preconditions prior to clinical examination will always protect against the misdiagnosis of BSD.

‘Gold-​standard’ diagnostic test Clinical neurological examination remains the gold-​standard method for diagnosing BD.

Other relevant investigations Various neurophysiological and imaging tests are available that can be helpful in the diagnosis of BSD. EEG shows electrocerebral silence, and somatosensory evoked potentials show loss of all cortically generated components. Imaging, such as magnetic resonance angiography, four-​vessel angiography, and CT angiography will all demonstrate absence of intracranial blood flow. All of these tests require further validation studies before they can be recommended as a routine part of the diagnosis of BSD. Until that time, the diagnosis remains a clinical one.

Treatment and its effectiveness Following the diagnosis of BSD, the grim news is imparted to the family. During this time, it is always reasonable to consider whether the patient is eligible to be an organ donor. In addition to the benefits for organ recipients, grieving families often report some comfort resulting from this act of altruism. If organ donation is not an option, then the patient should be disconnected from the ventilator.

Further Reading Lewis A and Greer D. Current controversies in brain death determination. Nature Reviews Neurology 2017; 13: 505–9. Magnus DC, Wilfond BS, and Caplan AL. Accepting brain death. N Engl J Med 2014; 370: 891–​4. Simpson P, Bates D, Bonner S, et al. A Code of Practice for the Diagnosis and Confirmation of Death, 2008. Academy of Medical Royal Colleges. Available at: http://aomrc.org.uk/wp-content/uploads/2016/04/ Code_Practice_Confirmation_Diagnosis_Death_1008-4.pdf

PART 6 Disorders of the kidney and urinary tract, and electrolyte and metabolic disorders

155 

Normal renal function

Aron Chakera, William G. Herrington, and Christopher A. O’Callaghan

The kidney is a vital organ with multiple functions. Without kidney function, death will occur in a matter of days. Fortunately, several forms of effective renal replacement therapy are available.

as blood passes through the glomerulus. The filtrate (urine) is modified along the course of the tubules, where substances may be reabsorbed or secreted. Urine present at the end of the nephron drains into the renal pelvis and from there passes down the ureters to the bladder, leaving through the urethra.

Urinary tract structure

Kidney function

There are normally two kidneys that are 9–​11  cm in length, and each weigh about 150 g. They lie in the retroperitoneum below the levels of the liver and spleen, respectively (see Figure 155.1) The blood supply to the kidneys comes from the renal arteries, which are branches of the aorta. The kidneys receive 20% of cardiac output (approximately 1100 ml/​min), and blood is first delivered to the glomeruli in the outer part of the kidney. Inflow to the glomerulus is via the afferent arteriole, with outflow through the efferent arteriole, which then supplies blood to the tubules. Blood then returns to the renal veins, which drain into the inferior vena cava. The glomerulus, tubules, and collecting ducts make up the functional unit of the kidney: the nephron (see Figure 155.2). Each kidney contains approximately 1 million nephrons. Urine is formed by a process of filtration,

The kidneys have several important functions:

Introduction

• they are organs of excretion:  they remove metabolic products such as urea, organic acids, and unwanted electrolytes • they are critical to homeostasis: they regulate body water content, as well as blood electrolyte and acid–​base balance • they have endocrine functions: they sense hypoxia and produce erythropoietin in response, promoting red blood cell formation; they are also responsible for vitamin D activation by hydroxylation and thus have a central role in calcium, phosphate, and bone metabolism; lastly, they secrete renin in response to decreased blood flow, thus activating the renin–​angiotensin system, which regulates the salt and water balance; the kidneys are thus central to blood pressure control The kidneys do not act in isolation. A careful balance of hormones released from other organs act on the kidneys to maintain the body’s fluid and electrolyte balance. These include aldosterone, vasopressin, parathyroid hormone, and atrial natriuretic peptide.

Glomerulus function Each glomerulus is composed of a network of capillaries, supplied by muscular arterioles. The amount of vasoconstriction in the afferent and efferent arterioles determines the pressure within the glomerulus. This intra-​glomerular pressure drives filtration of water and solutes through the glomerular filtration barrier, which is composed of three layers: the fenestrated capillary endothelial cells, the basement membrane, and a layer of epithelial cells with foot processes (podocytes) (see Figure 155.3). The epithelium makes up the Bowman’s capsule and continues as the tubules. The three layers of the filtration barrier act to limit the passage of large proteins, but allow water and solutes to pass freely. Blood leaves the glomerular capillaries through the efferent arteriole. By modifying tone in the afferent and efferent arterioles, intra-​glomerular pressure and, therefore, glomerular filtration rate and the production of urine are regulated. Angiotensin II acts predominantly on the efferent arterioles to cause vasoconstriction, which increases intra-​glomerular pressure and filtrate formation.

Tubular function The tubular system can be divided into four main parts on the basis of function: the proximal tubes, the loop of Henle, the distal tubules, and the collecting ducts.

Proximal tubules

Figure 155.1  CT demonstrating the urinary system. Please see colour plate section. image courtesy of Nigel Cowan.

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The proximal tubules perform the bulk of the reabsorption. Significant amounts of water and solutes are returned to the blood from the filtrate. This is the main site of glucose and amino acid reabsorption. These cells are highly metabolically active and are thus susceptible to hypoxic damage (acute tubular necrosis).

Cortical collecting duct

Connecting tubule

Distal convolution Macula densa Renal corpuscle Proximal tubule Outer medullary collecting duct OUTER MEDULLA

Descending thin limb

Inner medullary collecting duct INNER MEDULLA

Ascending thin limb

Figure 155.2  The basic organization of short-​looped (cortical) and long-​looped (juxtamedullary) nephrons; note that the early distal tubule of each type of nephron is in contact with the afferent arterioles of its own glomerulus. Reproduced with permission from Pocock G et al., Human Physiology, Third Edition, Oxford University Press, Oxford, UK, Copyright © 2006.

Loop of Henle

Distal tubules

The loop of Henle plays a critical role in concentrating urine through the countercurrent system, which depends on the differing permeability of parts of the loop to water and electrolytes.

The distal tubules fine tune the urinary acid and electrolyte composition, influenced by the actions of aldosterone.

CHAPTER 155  Normal renal function

Ascending thick limb

Figure 155.3  Normal glomerulus and glomerular filtration barrier under light and electron microscopy; note the glomerular basement membrane (G), with endothelial cells (E) at its upper edge, and the foot processes of the podocytes (P) abutting its lower edge. Please see colour plate section. image courtesy of Ian Roberts

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Collecting ducts Collecting ducts modify urinary water content (and therefore osmolality) in response to vasopressin.

degree of renal impairment in the elderly is, thus, very common and may not require investigation. However, associated cardiovascular risk factors should still be addressed.

Assessment of kidney function

Further Reading

The main assessment of kidney function is by measurement of the serum creatinine. This can be used to provide an estimate of the glomerular filtration rate. This is discussed in detail in Chapter 157.

Elger M and Kriz, W. ‘The renal glomerulus: The structural basis of ultrafiltration’, in Davison A, Cameron JS, Grünfeld JP, et al., eds, Oxford Textbook of Nephrology (3rd edition). Oxford University Press.

Natural history of kidney function

CHAPTER 155  Normal renal function

Kidney function may deteriorate with age. On average, there is a fall of 1 ml/​min year−1. However, this is extremely variable. A mild

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156 

Diagnosis in suspected renal disease

William G. Herrington, Aron Chakera, and Christopher A. O’Callaghan

Introduction

Box 156.1  Pulmonary renal syndromes

Renal dysfunction can be easily and, in most cases, unambiguously diagnosed from an elevation in serum creatinine and/​or abnormal urinalysis. The clinical challenges lie in first suspecting that renal dysfunction is present and therefore requesting the appropriate test (e.g. serum creatinine/​urine analysis), and then identifying the underlying aetiology. A major clue to renal dysfunction in the hospitalized patient can be a reduction in urine output. Therefore, urine output should be carefully monitored in those patients who are at risk, which includes most significantly ill hospitalized patients.

Aetiology The likely causes of renal dysfunction arising de novo in the hospital and community settings are quite distinct. Renal dysfunction arising in hospital is often predictable and caused by a combination of underlying comorbidities, the current illness, and treatment or interventions, such as drugs. For example, septic or post-​operative patients are at high risk of hypotensive acute renal failure. In contrast, renal dysfunction arising in the community has a much wider differential diagnosis, which ranges from common causes such as diabetes and hypertension, to rarer primary renal diseases such as glomerulonephritis. Traditionally, renal dysfunction is arbitrarily divided into acute kidney injury (AKI) and chronic kidney disease (CKD). The key difference is that, in AKI, there is a rapid and potentially reversible fall in kidney function, characterized by a reduction in glomerular filtration rate (GFR). CKD is characterized by long-​standing (>3 months) loss of kidney function, which is often, but not always, progressive and is often irreversible due to the presence of fibrotic change within the kidneys. AKI in hospital is usually divided into: • prerenal causes, which account for about 60% of hospital-​acquired AKI; often, there are multiple contributory factors which may act synergistically, for example, sepsis; with some hypotension during surgery; volume depletion; older age; and diabetes • intrinsic renal causes, which account for about 20% of hospital AKI and can be further divided into interstitial nephritis, vasomotor nephropathy, toxic tubular injury, and glomerulonephritis • post-​renal causes, which account for about 10% of hospital AKI In the community setting, obstruction is surprisingly a more common cause of AKI, largely due to prostatic disease (see Figure 156.1.

Without alveolar haemorrhage

• acute or chronic kidney disease with pulmonary oedema, due to fluid overload • pneumonia with renal failure (e.g. legionella) • heart failure with pulmonary oedema and secondary renal impairment • poisoning (e.g. with organic solvents or paraquat)

With alveolar haemorrhage

• anti-​glomerular basement membrane disease (Goodpasture’s disease) • systemic vasculitis • microscopic polyangiitis • Wegener’s granulomatosis (granulomatosis with polyangiitis) • Churg–​Strauss syndrome

There are many different causes for CKD, as outlined in Chapter 163. Often kidney failure occurs in conjunction with failure of other organs. Various autoimmune conditions cause a pulmonary–​renal syndrome (see Box 156.1)

Symptoms Renal impairment per se is typically asymptomatic until very near to end-​stage renal disease. Presenting symptoms may relate to an underling predisposing condition (see Table 156.1). For example, shortness of breath in cardiac disease, and rashes in autoimmune diseases, such as SLE. Rarely, renal disease presents directly, as, for example, peripheral oedema in nephrotic syndrome, frank haematuria and loin masses in renal malignancy, or uraemic symptoms in end-​stage renal disease, such as fatigue, itching, poor appetite, malaise, and nausea. Importantly, in the hospitalized patient, it is often difficult to tell the non-​specific symptoms of kidney failure apart from the underlying illness. Often, kidney failure in this setting is picked up early with frequent blood tests, and managed effectively before the symptoms of advanced AKI can be manifest. However, this is not always the case, and such symptoms may be manifest (see Box 156.2). Table 156.1  Presentations of renal diseases

4

11 25

25 25 25

Prostatic obstruction Surgical causes Cardiac/vascular causes Medical causes Unknown Other obstructive causes

Figure 156.1  Causes of acute kidney injury in a community-​based survey. Reproduced with permission from Barratt, Harris & Topham, Oxford Desk Reference Nephrology, Oxford University Press, Oxford, UK, Copyright © 2008.

Prerenal

Renal

Post-​renal

Diarrhoea/​ vomiting Sepsis Hypotension Haemorrhage Severe heart failure Liver failure

Haematuria (GN) Rash (SLE/​vasculitis/​interstitial nephritis) Arthralgia (SLE/​vasculitis) Myalgia (rhabdomyolysis/​GN) Neuropathies (amyloid/​ cryoglobulinaemia) ENT symptoms (Wegener’s) Eye symptoms (vasculitis/​SLE/​ TINU/​others) Oedema (GN/​NS) Frothy urine (NS)

Anuria Obstructive lower urinary symptoms Dysuria Renal colic Frank haematuria Renal mass Palpable bladder

Abbreviations: ENT, ear, nose, and throat; GN, glomerulonephritis; NS, nephrotic syndrome; SLE, systemic lupus erythematosus; TINU, tubulointerstitial disease with uveitis.

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Box 156.2  Features of uraemia and an estimated glomerular filtration rate 28 kg/​m2 • type 2 diabetes, or insulin resistance • systemic hypertension • ALT > 2× normal upper limit • AST:ALT > 1 • hypertriglyceridaemia Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index.

Weight reduction by lifestyle modification with diet and exercise should be recommended to all, as this will: favourably improve the cardiovascular profile • • improve hepatic steatosis • ameliorate hepatic inflammation (only with >7%–​9% weight loss)

Pharmacological therapies for the management of NAFLD Multiple pharmacological therapies have been trialled in the management of NAFLD and NASH, although most are used off-​label.

Orlistat Orlistat has been shown to lower aminotransferase levels, total cholesterol, triglycerides, and low-​density lipoprotein, with an improvement in insulin resistance. Histologically, improvement is also seen with regard to fatty infiltration and inflammatory indices.

Antiglycaemics Glitazones improve transaminase levels and steatosis and reduce inflammation (but not fibrosis) in the liver, but only as long as therapy continues. Due to adverse publicity regarding the effect of glitazones on cardiovascular mortality, further trials regarding their safety as therapeutic drugs are underway. Some studies have shown short-​term radiological and biochemical improvement with metformin, although histological changes have yet to be proven. However, there is emerging evidence that metformin has inherent anticancer effects, with >60% reduction of HCC in diabetics. Glucagon-​like peptide-​1 analogues reduce serum transaminases and radiological evidence of steatosis, but not independently of weight loss and improvement in glycohemoglobin levels. Their therapeutic potential in non-​diabetic individuals with NAFLD is currently the subject of a large, multicentre clinical trial.

Lipid-​lowering agents Fibrates and statins should be considered where indicated in view of their cardiovascular protective effects and are safe in patients with liver disease. Statins may also have inherent chemoprotective effects with respect to HCC.

Antihypertensives Certain agents targeting the renin–​angiotensin system have been shown to improve hepatic steatosis and, through the induction of hepatic-​stellate-​cell apoptosis, may also possess inherent antifibrotic properties.

Vitamin E Vitamin E is associated with a reduction in serum transaminases and a significantly higher rate of improvement in steatosis, steatohepatitis, and lobular inflammation but not fibrosis.

Bariatric surgery for the treatment of NAFLD Bariatric surgery should be considered for severely obese persons (BMI >40, or >35 if comorbidity is present) and for those who clearly wish to lose weight. It induces long-​term weight loss and decreases morbidity, the incidence of cancer, and mortality. Compelling data show a sustained decrease in steatosis in >90% of patients, and an improvement of steatohepatitis and fibrosis in >80%.

Liver abscesses Definition of liver abscess There are two main types of liver abscess:  pyogenic and amoebic. Fungal abscesses are rare and usually caused by Candida spp. in immunocompromised individuals. Tubercular abscesses also represent a rare hepatic manifestation of Mycobacterium tuberculosis infection.

Aetiology of liver abscesses Pyogenic abscesses usually arise by portal vein seeding from the following intra-​abdominal infections: • diverticulitis • Crohn’s disease and ulcerative colitis

bowel perforation • • delayed diagnosis of appendicitis • subphrenic abscess or gall bladder empyema • haematogenous spread (e.g. endocarditis, pyelonephritis with bacteraemia) Gram-​negative infections are usually the cause, with Escherichia coli and Enterobacter spp. being the commonest cultured organisms. Anaerobic organisms are a close second. It is not uncommon for a patient with a liver abscess to also have a polymicrobial infection. Amoebic liver abscesses are usually caused by the organism Entamoeba histolytica. Predisposing factors include: living in endemic areas • • poor hygiene and overcrowding • immunosuppression Liver abscesses can also be caused by biliary tract disease (35%) related to cholangitis or cholecystitis. In addition, parasitic infections by roundworms or liver flukes can be causative. Pancreatobiliary malignancy can account for abscesses originating in the biliary tree.

Typical symptoms of liver abscesses, and less common symptoms Symptoms of pyogenic liver abscesses The features of pyogenic liver abscesses are relatively non-​specific, with fever, rigours, right upper quadrant pain, and, occasionally, weight loss. On examination, there may be right upper quadrant tenderness or features of an underlying condition such as appendicitis. Jaundice may indicate the presence of biliary disease.

Symptoms of amoebic liver abscesses Coupled with a travel history to an endemic area, there may be an antecedent history of diarrhoea, but 90% of infected people will be asymptomatic in the initial stages of amoebic infection before liver abscesses develop. Once hepatic involvement is present, the majority will present with symptoms that develop quickly over a couple of weeks. These include right upper quadrant pain, fever, and a variety of constitutional symptoms. Involvement of the diaphragm can lead to referred right shoulder pain or symptoms of pleurisy. Pain is more common with point tenderness on examination. Hiccups may herald impending rupture.

Demographics of liver abscesses The estimated annual incidence for pyogenic liver abscesses is around 2–​3 per 100 000 people per year in the UK. Worldwide, 40–​50 million people are affected with amoebic liver abscesses annually (with the majority found in the developing world). The right lobe is affected in isolation in 60% of cases.

CHAPTER 216  Miscellaneous liver diseases

Lifestyle changes for the management of NAFLD

Natural history of liver abscesses, and complications of the disease Natural history of pyogenic liver abscesses, and complications Untreated cases of pyogenic liver abscesses can lead to overwhelming, fulminant sepsis. The abscess may rupture into adjacent areas (e.g. pleural or peritoneal space with development of subphrenic, perihepatic, or subhepatic abscesses). Metastatic septic embolic may occur. One rare association is endophthalmitis (infection of intra-​ocular fluid), particularly in the presence of klebsiella infection. Larger abscesses may result in the compression of hepatic venous drainage, causing a Budd–​Chiari-​type picture. Even with appropriate treatment. this condition can yield mortality rates approaching 30%.

Natural history of amoebic liver abscesses, and complications Amoebic liver abscesses have a much better prognosis with treatment, with considerably lower mortality rates, compared to pyogenic liver abscesses. Impending rupture may be indicated by the presence of hiccups. Rupture into the lung parenchyma may result in a lung abscess or bronchopleural fistula. Haematogenous spread leading to infected emboli has been reported, but this is comparatively rare. Clinical improvement is usually noted within the first week of therapy, with a marked lag in radiological resolution.

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Approach to diagnosing liver abscesses Ultrasound of the liver is always indicated when a patient is febrile and has a derangement in liver biochemistry. Ultrasound enables distinction between solid and fluid-​filled structures, but patient body habitus may cause difficulty leading to diagnostic inaccuracy.

Other diagnoses that should be considered aside from liver abscess The differential for liver abscess includes the multitude of conditions giving rise to fever, right upper quadrant pain/​tenderness, and deranged liver biochemistry, such as:

CHAPTER 216  Miscellaneous liver diseases

cholecystitis • • right lower lobe pneumonia • pulmonary tuberculosis • hepatic malignancy • ascending cholangitis • acute alcoholic hepatitis • hepatic infarction • hepatic adenoma (radiological differential) • hepatic haemangioma (radiological differential) Another radiological differential is hydatid cystic disease (caused by Echinococcus spp.). Primary hosts are usually dogs, with sheep and cattle acting as secondary hosts. This disease usually causes asymptomatic hepatomegaly and normal liver function tests. Serology is often negative. On ultrasound, one may see multiple daughter cysts. If the patient is asymptomatic, leave them alone, as rupture may cause massive anaphylaxis. If the patient is symptomatic, a suitable alternative to surgery is albendazole. Surgery is indicated for increasing size or pressure symptoms.

Gold-​standard diagnostic test for liver abscesses Gold-​standard diagnostic test for pyogenic liver abscesses Ultrasound-​guided aspiration confirms the diagnosis of pyogenic liver abscess in 90% of cases.

Gold-​standard diagnostic test for amoebic liver abscesses Ultrasound, with positive antibodies to Entamoeba histolytica, is diagnostic for amoebic liver abscesses in over 90% of cases.

Acceptable diagnostic alternatives to the gold-​ standard diagnostic tests for liver abscesses Acceptable diagnostic alternatives to the gold-​standard diagnostic test for pyogenic liver abscess Blood cultures are positive in 50% of cases of pyogenic liver abscesses. Helical CT may aid in the diagnosis of smaller abscesses and perhaps give further clues to the underlying source for the abscess.

Acceptable diagnostic alternatives to the gold-​standard diagnostic test for amoebic liver abscess Aspiration of an amoebic liver abscess will reveal a thick, ‘anchovy sauce’-​like paste which is odourless (unlike that from a pyogenic abscess). Aspiration is indicated when pyogenic or secondary infection cannot be excluded, the abscess is very large, or the patient is not responding to treatment or is in severe pain. Unfortunately, aspiration does not usually yield diagnostic material in most cases. Serological tests (e.g. immunoelectrophoresis, complement fixation, haemagglutination assays) are positive in patients with invasive disease only (not asymptomatic carriers). These tests are extremely sensitive (except the complement fixation test). Depending on the test used, the titres may remain positive for some time after the infection (e.g. indirect haemagglutination may remain positive for many years). The biliary tree is not usually involved in amoebic liver abscesses, as bile is toxic to amoebae. Compression of the biliary system may give rise to jaundice but, in the presence of a cholangitis, suspect ascending secondary bacterial infection.

Other relevant investigations for liver abscesses Other relevant investigations for liver abscesses include: • full blood count (to look for neutrophil leucocytosis, or anaemia of sepsis or chronic disease)

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serum liver biochemistry • • blood cultures (essential in any febrile patient) • hot (fresh) stool (for trophozoites) • a plain chest film (may show a flat right hemidiaphragm) • cholangiography (if indicated; to demonstrate the site of biliary obstruction)

Prognosis for liver abscess, and how to estimate it Prognosis for pyogenic liver abscesses If untreated, pyogenic liver abscesses are associated with high mortality.

Prognosis for amoebic liver abscesses With good treatment, the mortality of amoebic liver abscesses falls to 1%–​3%.

Treatment of liver abscesses, and its effectiveness Treatment of pyogenic liver abscesses Treatment of pyogenic liver abscesses includes the following: • broad-​spectrum antibiotic cover (e.g. IV metronidazole and IV ceftriaxone) while awaiting microbial sensitivities • urgent percutaneous drainage of a single abscess or the larger abscess in the case of multiplicity • surgical drainage, if there is evidence of the causative disease process (e.g. peritonitis from viscus perforation), if the abscess is very large (>5 cm), if the location of the abscess makes percutaneous drainage difficult, or if previous treatment via percutaneous drainage and antibiotics has failed

Treatment of amoebic liver abscesses A 10-​day course of IV metronidazole is effective in the majority of cases. This should be followed by a further 10-​day course of diloxanide, to prevent recurrence. Consider aspiration with/​without drainage if abscesses are >5 cm or located on the left side of the liver (left-​sided liver abscesses have a higher mortality and an increased frequency of leaking into peritoneum and pericardium), or if a response is not detected in the first 5 days. Amphotericin or fluconazole can be used to treat fungal abscesses (seek specialist microbiology advice).

Nodular regenerative hyperplasia Definition of nodular regenerative hyperplasia Nodular regenerative hyperplasia (NRH) is the diffuse transformation of normal hepatic parenchyma into smaller regenerative nodules in the presence of little or no fibrosis. This leads to nodules pressing directly onto one another with small atrophic hepatocytes in between (cf. cirrhosis, which has nodules separated by fibrous tissue).

Aetiology of NRH NRH is hypothesized to be due to alterations in blood flow, with frequent observations of portal and central vein anomalies. This pathological entity has been explained by uneven microcirculatory perfusion, leading to atrophy of the poorly perfused areas, and compensatory (regenerative) hypertrophy of the areas of maintained perfusion. The nodular areas are thus hypothesized to be hypertrophied areas which develop in response to slightly increased blood flow. Etiological associations of NRH have been provided in Table 216.2.

Typical symptoms of NRH, and less common symptoms NRH can remain asymptomatic for many years before incidental deranged liver biochemistry is found in the absence of other identifiable causes. Tests of synthetic function may often be normal. Non-​ specific features may be malaise, abdominal pain, and fatigue. In other cases, the features that dominate are fundamentally those of (non-​ cirrhotic) portal hypertension and decompensated liver disease,

Table 216.2  Associations of nodular regenerative hyperplasia Rheumatological

Haematological

Hepatobiliary disease (without cirrhosis)

Cardiovascular

Other

Systemic sclerosis Polyarteritis nodosa Polymyalgia rheumatica Rheumatoid arthritis Felty’s syndrome SLE

Hodgkin’s and non-​Hodgkin’s lymphoma Chronic lymphocytic leukaemia Waldenström’s macroglobulinaemia Multiple myeloma

Primary biliary cholangitis Budd–​Chiari syndrome

Congestive cardiac failure Hypertension Severe coronary artery disease Hereditary haemorrhagic telangiectasia

Thiopurines and other drugs (probably the most important cause) Type 2 diabetes mellitus Renal transplantation Coeliac disease Certain anticonvulsants.

Demographics of NRH Older studies of autopsy figures have shown that NRH is present in 5.3% of those over 80, with most patients having systemic disease. Case series reviews point towards NRH being the cause for >25% of cases of non-​cirrhotic portal hypertension.

Natural history of NRH, and complications of the disease There is little documentation regarding the true course of NRH, given the large percentage of asymptomatic disease. The medical literature tends to focus on the symptomatic cases, thus giving a slightly skewed view on the condition. In the same breath, it is not fully known whether NRH is fully reversible following treatment of the underlying cause. Complications, when present, are essentially those of decompensated liver disease. Extra-​hepatic portal vein thrombosis has been reported to occur in >70% of cases.

Approach to diagnosing NRH Although NRH can be suspected based on abnormal liver function tests (usually a cholestatic picture) in the absence of other underlying causes, a significant proportion of patients will have normal biochemistry. Further suspicion is raised in the presence of unexplained portal hypertension in the absence of cirrhosis. Ultrasound may demonstrate nodularity in the liver.

Other diagnoses that should be considered aside from NRH NRH and cirrhotic liver disease can be difficult to distinguish, but differentiation is important, as treatment for the two and consequent prognoses are different. Other nodular disorders of the liver include: malignancy (see Chapter 218) • • liver cysts • hepatic adenoma • focal nodular hyperplasia

Gold-​standard diagnostic test for NRH The gold-​standard diagnostic test for NRH is liver histology with reticulin stain.

Acceptable diagnostic alternatives to the gold-​standard test for NRH Increasingly, advanced MRI and CT techniques are being employed to evaluate nodular liver disease. However, confirmation of NRH can only be reached through tissue diagnosis.

Other relevant investigations for NRH Other investigations in NRH are directed at excluding other causes of chronic liver disease, identifying possible underlying causes, and assessing portal hypertension (see Chapter 210).

Prognosis of NRH, and how to estimate it See ‘Natural history of NRH, and complications of the disease’.

Treatment of NRH, and its effectiveness Treatment is guided towards the underlying diagnosis and complications of portal hypertension and should be along standard lines. Antiplatelet and anticoagulant therapy should be managed in a specialist setting, given the risks of variceal bleeding with portal hypertension. The need for liver transplantation is rare.

Further Reading Dowman JK, Tomlinson JW, and Newsome PN. Systematic review: The diagnosis and staging of non-​ alcoholic fatty liver disease and non-​alcoholic steatohepatitis. Aliment Pharmacol Ther 2011; 33: 525–​40. Harleb M, Gutkowski K, and Milkiewics P. Nodular regenerative hyperplasia: Evolving concepts on underdiagnosed cause of portal hypertension. World J Gastroenterol 2011; 17: 1400–​9. Pang TCY, Fung T, Samra J, et  al. Pyogenic liver abscess:  An audit of 10 years’ experience. World J Gastroenterol 2011; 17: 1622–​30. Schwenger KJP and Allard JP. Clinical approaches to non-​alcoholic fatty liver disease. World J Gastroenterol 2014; 20: 1712–​23.

CHAPTER 216  Miscellaneous liver diseases

although ascites is less common than in cirrhosis. Examination findings may reveal the presence of hepatosplenomegaly.

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217 

The liver in systemic disease

Satish Keshav and Palak Trivedi

Introduction

Many conditions can predispose to hepatic ischaemia; some are provided in Table 217.1.

The liver may be involved in systemic diseases that primarily affect other organs. In most cases, the systemic disease should be treated effectively first.

Typical symptoms of cardiovascular-​disease-​related liver disease, and less common symptoms

The liver in cardiovascular disease Definition of cardiovascular-​disease-​related liver disease Circulatory disturbances can cause liver dysfunction by ischaemia (due to arterial hypoperfusion) and hepatic venous congestion. Liver congestion usually occurs in the setting of acute or chronic right-​sided cardiac failure causing hepatic venous congestion and sinusoidal stasis, and is also termed ‘passive congestion of the liver’ (cf. Budd–​Chiari syndrome). In ischaemic hepatitis, patients develop a dramatic transaminitis, raised bilirubin, and raised lactate dehydrogenase (LDH) after a very short time (e.g. 24–​48 hours) following a period of haemodynamic compromise leading to liver hypoperfusion. Hepatic infarction is relatively rare compared to ischaemic hepatitis (due to the fact that the liver has a dual blood supply, which is provided by the hepatic portal vein and the hepatic arteries) and represents focal liver injury, which is usually iatrogenic. In contrast, the bile ducts receive their blood supply solely from the hepatic artery and peribiliary plexus. Any interruption of blood flow to the latter damages the perihilar intra-​hepatic and extra-​ hepatic bile ducts, leading to ischaemic cholangiopathy.

Aetiology of cardiovascular-​disease-​related liver diseases Hepatic congestion mainly results from the causes of right-​sided heart failure, such as: congestive cardiac failure • • tricuspid regurgitation (pressure from the right ventricle is transmitted directly through to the hepatic veins so the degree of congestive hepatopathy can be severe) • right ventricular failure (and, hence, the causes of pulmonary hypertension (e.g. mitral stenosis, severe respiratory disease)) • pericardial constriction

In congestive hepatic disease, individuals may be asymptomatic but with deranged liver function tests (LFTs). There may be pain from stretching of the Glisson’s capsule. Look for ascites, peripheral oedema, and signs of hepatosplenomegaly on examination. In ischaemic hepatitis and hepatic infarction, a haemodynamic insult is usually apparent before the appearance of liver injury. Patients may show features of an acute hepatitis (e.g. fever, right upper quadrant pain, vomiting, and jaundice). Suspect ischaemic hepatitis and hepatic infarction in the post-​transplant patient. In ischaemic cholangiopathy, patients may present with the features of biliary obstruction (pale stools, dark urine, jaundice, and pruritus). There may also be features of a cholangitis with fever, vomiting, and rigours.

Demographics of cardiovascular-​disease-​ related liver disease No accurate data are available on the demographics of cardiovascular-​ disease-​related liver disease.

Natural history of cardiovascular-​disease-​ related liver disease, and complications of the disease The natural course of congestive liver disease depends on that of the underlying cardiac disorder. Liver function tends to return to normal within 1 week of improvement in cardiac failure. Long-​standing liver congestion and sinusoidal stasis may result in the accumulation of deoxygenated blood; parenchymal atrophy; necrosis; collagen deposition; and, ultimately, fibrosis. This rare eventuality is termed cardiac cirrhosis. In ischaemic hepatitis, typically, there will be elevation of liver enzymes (transaminitis peaks at 24–​72 hours post insult) following the hypoperfusion insult, coupled by a rise in LDH. The transaminase level will settle within a week or so following resolution of haemodynamic compromise. Following the decline in liver enzymes, the

Table 217.1  Causes of hepatic ischaemia

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Ischaemic hepatitis

Focal hepatic infarction

Ischaemic cholangiopathy

Any cause of left ventricular dysfunction: acute myocardial infarction • cardiac dysrhythmia • cardiac tamponade • restrictive cardiomyopathy • Causes of shock: dehydration • haemorrhage • burns • dehydration • Focal interruption of blood supply to liver: sickle cell crisis • portal venous thrombosis • post-​transplantation arterial thrombosis • any cause of left ventricular dysfunction •

Hepatic artery thrombosis: atherosclerosis • prothrombotic states • post liver transplant • Embolic phenomenon: therapeutic embolization • tumour embolization • infective endocarditis • Iatrogenic: hepatic artery ligation during transplantation • chemoembolization • Toxaemia of pregnancy Vasculitides (esp. polyarteritis nodosa) Amphetamine use Dissection of the aorta

Paroxysmal nocturnal haemoglobinuria (hypercoagulability) Iatrogenic: post liver transplantation • vascular injury post biliary surgery • chemoembolization • radiotherapy • AIDS related

Approach to diagnosing cardiovascular-​disease-​ related liver disease Congestive hepatic disease is more common with right-​sided heart failure and should be included in the differential workup of deranged liver function in the presence of underlying cardiopulmonary disease. A clue is provided by Doppler studies of liver vasculature, with loss of the normal triphasic flow in the hepatic veins. In contrast, suspect ischaemic hepatic injury in those with an acute hepatitis with predominant transaminitis in the presence of left ventricular dysfunction, systemic shock, or sickle cell crisis, or post liver transplant. A haemodynamic insult is usually apparent clinically before the appearance of liver injury, although transient minor reductions of hepatic perfusion may produce ischaemic injury and not be clinically apparent. The precipitating cause is usually evident before focal hepatic infarction ensues. Ischaemic cholangiopathy should be suspected post transplant in the presence of clinical cholangitis with obstructive LFTs.

Other diagnoses that should be considered aside from cardiovascular-​disease-​related liver disease Differential diagnoses of an ischaemic hepatic injury include an acute hepatitis, such as drug-​induced liver injury, viral hepatitis (not just from hepatotropic viruses, such as the hepatitis A and B viruses, but also EBV, rubella, CMV, and mumps), and alcohol. These should be screened for in any case of acute hepatitis. Three features distinguish ischaemic hepatitis from acute viral hepatitis: LDH elevation is more marked in ischaemia; serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations rapidly return to normal in ischaemic hepatitis upon correction of the underlying cause; and ischaemic hepatitis is more often complicated by renal dysfunction. It can be sometimes be difficult to differentiate between focal hepatic infarction and pyogenic liver abscess radiologically, in which case, attempt at aspiration may be helpful. Other entities which can mimic the presence of an ischaemic cholangiopathy include the various causes of biliary stricturing disease, biliary obstruction, and cholangitis (e.g. biliary, pancreatic, or duodenal malignancy; biliary stones). Another important diagnosis to consider is primary sclerosing cholangitis, although other coexisting features may also be present (e.g. history of inflammatory bowel disease or other autoimmune disease).

Gold-​standard diagnostic test for cardiovascular-​disease-​related liver disease Characteristic features of congestive liver disease are present on histological analysis, but biopsy is rarely needed, as other clues point towards the diagnosis. The gross histological appearance of congestive liver disease has earned it the name ‘nutmeg liver’. There will be a central red area (sinusoidal congestion, bleeding into atrophic areas surrounding an enlarged hepatic vein) intermixed with a yellow area (representing fatty liver). In the absence of cardiac cirrhosis, there will be no inflammatory change. Chronic cardiac failure will cause

the accumulation of collagen, with fibrous bands extending outwards from the central veins. This is the appearance of cardiac sclerosis; eventually, a micronodular cirrhosis will result. In contrast, no real gold-​standard diagnostic test for ischaemic hepatitis is available, so the diagnosis is made from the accumulation of clinical signs, biochemical tests, and, occasionally, histological tissue. Biopsy shows hepatocyte necrosis in Zone 3 (the region most poorly perfused by the hepatic artery), with architectural collapse around the central vein. With a prolonged insult, necrosis may reach the mid-​zone of hepatocytes. Concerning ischaemic cholangiopathy, following a history of the condition, definitive diagnosis can be made on cholangiography.

Other relevant investigations for cardiovascular-​ disease-​related liver disease In patients with congestive liver disease, echocardiography with right-​ sided and pulmonary pressures is essential. Doppler hepatic venous studies are also helpful. LFTs show that serum bilirubin is elevated mostly in the unconjugated form. Bilirubin concentrations rapidly (i.e. within days) return to normal following improvement of right-​sided heart failure. In those who show a transaminitis, the change in AST is more marked than that in ALT. Elevated serum alkaline phosphatase (ALP) is observed in 10%–​20% of patients with right-​sided heart failure, but ALP levels return to normal within 1 week after improvement of heart failure. Other investigations focus on diagnosing the cause of cardiac failure. A high LDH favours the diagnosis of ischaemic hepatitis over that of an acute viral hepatitis. In hepatic infarction, an abdominal CT scan may reveal a wedge-​shaped low-​attenuation area indicating the infarct.

Prognosis for cardiovascular-​disease-​related liver disease, and how to estimate it The prognosis for congestive liver disease depends on the aetiology of the underlying cardiac failure, as well as its severity and reversibility. Ischaemic hepatitis usually has a benign prognosis, once resolution of the underlying problem has taken place. However, if it is superimposed on underlying cirrhotic liver disease or cardiac failure, fulminant liver failure may occur. There is limited data on the management of ischaemic cholangiopathy and, thus, outcome after treatment. If it occurs in the first 4 weeks or so post liver transplant, retransplantation is indicated.

Treatment of cardiovascular-​disease-​related liver disease, and its effectiveness In congestive liver disease, right upper quadrant discomfort rapidly resolves with effective diuretic treatment; the remainder of management rests on cardiac failure therapy. In ischaemic liver disease, treatment rests on that of the underlying condition. Little data are available regarding the effectiveness of treatment of ischaemic cholangiopathy but there is some evidence for endoscopic dilatation and stenting of strictures. Disease occurring in the first month post transplantation warrants urgent retransplantation.

CHAPTER 217  The liver in systemic disease

bilirubin rises while synthetic function (clotting and albumin) usually remain unchanged. The liver recovers completely. Ischaemia-​related, non-​anastomotic biliary strictures and necrosis of bile ducts are well-​described complications of liver transplantation. The natural course and, consequently, prognosis of ischaemic cholangiopathy depends on the location of the blockage and underlying aetiology. In proximal hepatic artery blockade via hepatic artery ligation/​embolization (outside the transplant setting), limited consequences are seen due to rapid development of collateral ‘shunt’ vessels and a retrograde portal supply. In the transplanted liver, proximal blockade (thrombosis) is generally followed by severe morbidity from biliary damage. The transplanted liver differs from the non-​excised liver in that excision interrupts arterial blood supply from transcapsular peripheral arteries, and therefore compromises collateralization through this route. In contrast, distal occlusion of smaller hepatic arteries has been shown (in experimental data) to cause significant ischaemic biliary injury.

Sepsis-​induced liver dysfunction Definition of sepsis-​induced liver dysfunction The liver is a key organ in sepsis, both as source of inflammatory mediators and as a victim of the inflammatory response. The two main characteristics that illustrate this ‘dual’ role are: • the heterogeneous cellular makeup of the liver:  Kupffer cells, hepatocytes, and cells lining the sinusoidal endothelium are all involved in the immune response • the liver’s unique blood flow: the portal vein receives blood from the splanchnic circulation; in sepsis there can be marked vasoconstriction and translocation of harmful pathogens across this vascular bed As an active participant in the response to sepsis, the liver will scavenge, attempt to inactivate bacterial products, and modify its metabolic functions towards amino acid synthesis and increased

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gluconeogenesis. There will be increased production and release of coagulation factors, complement, and acute phase proteins. As a victim in sepsis, the liver can suffer primary dysfunction related to shock and hypoperfusion (see discussion of ischaemic hepatitis in ‘The liver in cardiovascular disease’), or secondary dysfunction, which is more related to microcirculatory changes in the hepatic circulation. Secondary dysfunction is insidious in its presentation and is characterized by functional and structural hepatic injury, as well as bacterial and endotoxin spillover, with the liver becoming the source of soluble mediators in the systemic inflammatory response syndrome. Cholestasis is also a common complication in patients with extra-​hepatic bacterial infections and sepsis and is increasingly recognized as a cause of jaundice in hospitalized patients, as part of the secondary dysfunction triggered by a burst of inflammatory mediators. As hypoxic liver injury has already been discussed (see ‘The liver in cardiovascular disease’), the bulk of the discussion in this section primarily focuses on sepsis-​induced jaundice and cholestasis.

CHAPTER 217  The liver in systemic disease

Aetiology of sepsis-​induced liver dysfunction Sepsis-​induced jaundice occurs most frequently with Gram-​negative bacteria. The primary site of infection is usually intra-​abdominal (e.g. peritonitis, diverticulitis) but can be from a pneumonia or endocarditis. Other specific extra-​hepatic infections known to cause jaundice are pneumococcus, clostridia, legionella, and typhoid infections. Jaundice can occur in isolation in patients with sepsis, but is frequently associated with other elements of cholestasis. As the principal clinical manifestation of cholestasis is also jaundice, literature to date has primarily focused on the sepsis syndrome of jaundice with cholestasis. Accurate epidemiological documentation regarding the incidence of isolated jaundice (without cholestasis) in sepsis remains unclear. Possible causes of jaundice in sepsis are: aberrant processing of bilirubin by hepatocytes • • increased bilirubin load from haemolysis • hepatocellular injury • cholestasis (decreased bile acid transport secondary to lipopolysaccharide and various cytokines) • antibiotics/​drugs

Typical symptoms of sepsis-​induced liver dysfunction, and less common symptoms Functional cholestasis with jaundice usually predominates as the liver manifestation in sepsis. Ischaemic hepatitis or progressive sclerosing cholangitis can be found in severe cases, with the presentation varying according to the severity of the infection. Primary hepatic dysfunction can lead to disseminated intravascular coagulation; reduced lactate and amino acid clearance; and reduced gluconeogenesis and glycogenolysis, thus leading to hypoglycaemia. A raised LDH with transaminase leakage can be seen, reflecting hepatocyte injury. Reduced perfusion appears to be the primary initiating event here (caused by reduced cardiac output with the vasoconstriction of hepatic artery and portal veins that is observed in sepsis). Secondary hepatic dysfunction may be silent and involve localized hepatic areas, which become inflamed as a consequence of bacterial detoxification by Kupffer cells. This induces activation of the coagulation, kallikrein, and complement cascades.

Demographics of sepsis-​induced liver dysfunction Sepsis and bacterial infection are responsible for up to 20% of cases of jaundice seen in all patient groups. Sepsis with jaundice is more likely to present in children than in adults.

Natural history of sepsis-​induced liver dysfunction, and complications of the disease Cholestasis usually resolves with the appropriate antibiotics. Persistent/​ worsening hyperbilirubinemia can indicate ongoing sepsis and is associated with a worse outcome. Persistently high ALP and gamma-​glutamyl transpeptidase (γGT) levels should raise suspicion of progressive sclerosing cholangitis due to sepsis. Ischaemic hepatitis usually resolves on correction of haemodynamic instability and hypoxia.

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Approach to diagnosing sepsis-​induced liver dysfunction Sepsis-​related cholestasis gives rise to a hyperbilirubinemia (mostly conjugated) with a modest rise in ALP and transaminases in the presence of a normal LDH. Resolution should occur with appropriate antibiotic therapy. Ischaemic hepatitis is discussed in ‘The liver in cardiovascular-​disease-​related liver disease’.

Other diagnoses that should be considered aside from sepsis-​induced liver dysfunction Other diagnoses that should be considered aside from sepsis-​induced liver dysfunction are: antibiotic-​induced liver dysfunction (see Chapter 215) • • progressive sclerosing cholangitis: this can occur following severe sepsis, burns, or severe trauma; patients with this disease have rising levels of ALP and γGT, and deep jaundice over several months; as this disease tends to involve the smaller bile ducts, diagnosis is usually confirmed on cholangiography (severe intra-​hepatic stenosis); prognosis is usually poor • cholecystitis • structural biliary tract obstruction • parenteral nutrition • liver abscess

Gold-​standard diagnostic test for sepsis-​induced liver dysfunction Biopsy is occasionally needed for diagnosis of sepsis-​induced liver dysfunction and demonstrates the following characteristic findings in cholestasis: Kupffer cell hyperplasia • • portal mononuclear cell infiltrates • an increased amount of smooth endoplasmic reticulum as a result of cholestasis; this may lead to hepatocytes having a ground-​glass appearance • focal hepatocyte dropout

Acceptable diagnostic alternatives to the gold-​standard test for sepsis-​induced liver dysfunction A thorough history, examination, and investigation of the septic illness, coupled with exclusion of other common causes of jaundice, usually suffice in achieving the diagnosis.

Other relevant investigations for sepsis-​ induced liver dysfunction Other relevant investigations for sepsis-​ induced liver dysfunction include: split bilirubin (to help evaluate the cause of jaundice in sepsis) • • hepatobiliary ultrasound • full septic screen, including • blood • urine • lines and drains • recent operation sites • lumbar puncture (if appropriate and safe) • chest X-​ray

Prognosis for sepsis-​induced liver dysfunction, and how to estimate it In the absence of systemic signs of sepsis, the cholestasis that can accompany an extra-​hepatic bacterial infection is usually mild and of no prognostic significance. Should sepsis develop (with systemic features), jaundice is associated with a poor prognosis, and most patients with sepsis-​associated cholestasis die from extra-​hepatic causes associated with sepsis-​related multiple organ failure. It is crucial that emphasis is placed on identifying the focus of infection and providing treatment by appropriate antibiotic therapy and other anti-​infective strategies (e.g. aspiration or drainage of collections).

The cornerstone of the treatment of sepsis-​induced liver dysfunction rests on appropriate antibiotic therapy and effective management of the complications of sepsis. Ursodeoxycholic acid has been shown to improve parameters in other cholestatic diseases, but its use in sepsis-​induced cholestasis is still under investigation.

The liver in malignancy Definition of malignancy-​related liver disease There are many ways in which an oncological process may affect hepatic function. For example, tumours in and around the liver can affect function by directly reducing the volume of healthy, functioning tissue or by causing biliary obstruction. In addition, portal venous infiltration or hypercoagulability may compromise vascular supply. Paraneoplastic phenomena have been well documented, and humoral and immunological factors related to the primary malignancy are known to contribute to further cholestasis and inflammatory hepatic changes. Underlying malignancy may also affect hepatic drug metabolism (tumour cells release a host of cytokines as part of an inflammatory response which reduce the activity of certain cytochrome enzymes). Other ways that malignancy can affect hepatic function include: chemotherapy-​induced hepatotoxicity • • graft-​versus-​host disease • metastases of cancer cells to the liver In-​depth discussion regarding the latter two points is beyond the scope of this section and will not be discussed further.

Aetiology of malignancy-​related liver disease The chronic myeloproliferative disorders (including polycythaemia rubra vera and essential thrombocythemia) tend to cause damage or blockage to the hepatic circulation and can lead to: Budd–​Chiari syndrome • • portal vein thrombosis (PVT) • nodular regenerative hyperplasia (see Chapter 216) These topics will form the bulk of the discussion in this section.

Other haematological malignancies that lead to liver disease Acute leukaemia in liver disease Hepatic involvement is mild in the initial stages of leukaemia, and so patients may initially be asymptomatic. Acute lymphocytic leukaemia (ALL) generally gives rise to portal tract infiltration only, whereas infiltration in acute myeloid leukaemia (AML) involves the sinusoids also.

Chronic leukaemia in liver disease Mild-​to-​moderate hepatomegaly, together with extensive infiltration by lymphocytes with consequent impairment of liver function, is observed in chronic lymphoid leukaemia (CLL). Half of all cases of chronic myeloid leukaemia at presentation will show hepatomegaly. During blast crises, infiltration of sinusoids can cause massive liver enlargement.

Myelofibrosis in liver disease Liver enlargement is present in most patients, in keeping with extra-​ medullary haemopoiesis and increased hepatic blood flow. Nodular regenerative hyperplasia (see Chapter  216:  Miscellaneous liver diseases) may accompany intra-​hepatic portal vein obstruction.

Lymphoma in liver disease In lymphoma, infiltration of the liver by malignant cells, leading to hepatomegaly, may be seen. A  mild transaminitis and a relatively greater increase in ALP can also occur due to tumour infiltration. These are more common in non-​Hodgkin’s than in Hodgkin’s lymphoma. Cholestasis not due to extra-​hepatic duct obstruction or infiltrative disease has also been described. Acute liver failure may also occur.

Myeloma in liver disease Sinusoidal and portal infiltration occurs in up to 50% of cases. There may also be nodular regenerative hyperplasia. Extra-​ medullary haemopoiesis may also contribute to hepatomegaly and deranged LFTs.

Specific solid tumours in the liver Stauffer syndrome is a constellation of signs and symptoms of liver dysfunction that arises due to the presence of renal cell carcinoma, but it is not due to tumour infiltration into the liver and/​ or intrinsic liver disease:  it is a true paraneoplastic syndrome. It leads to elevated LFTs, which result from cholestasis (i.e. a cessation of bile flow). The symptoms resolve if the renal cell cancer is successfully treated.

Typical symptoms of malignancy-​related liver disease, and less common symptoms Budd–​Chiari syndrome (hepatic venous outflow obstruction, of the hepatic vein, the inferior vena cava (IVC), or both) causes congestion, necrosis, and, eventually, fibrotic change and cirrhosis. Features include abdominal pain, hepatomegaly, jaundice, ascites, and hepatic failure with features of decompensation. PVT (in any part of the portal circulation, including the mesenteric system, the splenic vein, and the intra-​hepatic veins) can also present with features of portal hypertension and hepatic decompensation (e.g. variceal bleeding and ascites).

Demographics of malignancy-​related liver disease Hepatomegaly is found in the majority of individuals with ALL or AML, at the time of diagnosis. CLL is largely an incidental finding, with most patients being asymptomatic, so most of the demographics on hepatic involvement in CLL come from post-​mortem studies; one study revealed that 98% of patients with CLL had hepatic leukaemic infiltration at autopsy. In myeloma, sinusoidal and portal infiltration occurs in up to 50% of cases and, in 10% of cases, there will be immunoglobulin light chain deposition or amyloid in the space of Disse; there may also be non-​ specific changes, such as haemosiderosis, in a smaller percentage of patients. Budd–​Chiari syndrome is rare in Western countries. The exact frequency of PVT in malignancy is unknown; however, it occurs in approximately 5% of patients with cirrhosis and portal hypertension.

Natural history of malignancy-​related liver disease, and complications of the disease The natural history of malignancy-​related, veno-​occlusive liver disease is not well known and its manifestation can change from asymptomatic presentation to fulminant liver failure in a matter of days to weeks. A chronic form of Budd–​Chiari progresses over a matter of months, and rapid deterioration with encephalopathy, renal failure, coma, and death can occur in untreated disease. In extensive PVT, the patient may present with mesenteric ischaemia. The natural history of hepatic involvement in other haematological malignancies is dependent on the underlying disorder.

CHAPTER 217  The liver in systemic disease

Treatment of sepsis-​induced liver dysfunction, and its effectiveness

Approach to diagnosing malignancy-​related liver disease In Budd–​Chiari syndrome, obstruction of hepatic venous drainage leads to elevated sinusoidal pressure, dilatation, and congestion. This leads to portal hypertension. When all three hepatic veins are obstructed, drainage from the caudate lobe (through separate spigelian veins) directly into the IVC becomes the only route of drainage, and this leads to caudate hypertrophy. This can be observed on Doppler ultrasound, CT, or MRI angiography. Absence of flow in the hepatic veins, as well as other features of portal hypertension, may also be seen. In PVT, simple imaging may identify splenomegaly with or without hepatomegaly and an enlarged azygous vein. Ultrasound may demonstrate a lack of normal portal flow or the presence of a thrombus in the portal vein.

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Table 217.2  Predisposing factors for hepatic veno-​occlusive disease Myeloproliferative disorders

Prothrombotic disorders

Other malignancies

Vascular disorders

Infections

Other

Polycythaemia rubra vera Essential thrombocythemia Myeloid leukaemia

Factor V Leiden Protein C deficiency Lupus anticoagulant Paroxysmal nocturnal haemoglobinuria Homocystinuria

Hepatocellular carcinoma Adrenal cancer Renal cancer Leiomyosarcoma

Behçet’s syndrome Sjögren’s syndrome

Amoebic abscesses Pyogenic abscesses Echinococcus infections

Pregnancy Oral contraceptives Cirrhotic liver disease Splenectomy

Other diagnoses that should be considered aside from malignancy-​related liver disease

the absence of ascites, or easily controlled ascites • • a low serum creatinine level

Other diagnoses that should be considered aside from malignancy-​ related liver disease include:

The 5-​year survival rate for Budd–​Chiari syndrome is 38%–​87%, following portosystemic shunting. The 5-​year survival rate following liver transplantation is 70%. The prognosis is poor in patients who have Budd–​Chiari syndrome and remain untreated or have venous occlusion caused by malignancy. There is high mortality in untreated cases of Budd–​Chiari syndrome, with death resulting from progressive liver failure at 3 months to 3 years from the time of diagnosis. In contrast, PVT has a much better prognosis, with 75% of patients alive after 10  years and an overall mortality rate of less than 10%. In the presence of cirrhosis and malignancy, the prognosis is understandably worse and is dependent upon the underlying condition.

CHAPTER 217  The liver in systemic disease

• other predisposing factors for hepatic veno-​occlusive disease (see Table 217.2) • congestive cardiac failure • constrictive pericarditis • IVC web (a common cause of Budd–​Chiari syndrome in the East) The main cause of PVT in children is sepsis with dehydration and consequent haemoconcentration. In adults, cirrhosis, pancreatic cancer, and hepatomas are other major causes.

Gold-​standard diagnostic test for malignancy-​related liver disease Hepatic venography may show the characteristic ‘spider-​ web’ appearance of intra-​hepatic veins in Budd–​Chiari syndrome. This may also demonstrate non-​patency of the IVC. Contrast-​enhanced CT can identify portal vein patency and any thrombi within.

Acceptable diagnostic alternatives to the gold-​standard test for malignancy-​related liver disease A liver biopsy is also crucial in Budd–​Chiari syndrome. Pathological findings are a high-​grade venous congestion and centrilobular liver cell atrophy. There may be thrombi within the terminal hepatic venules. The presence of necrosis or end-​stage fibrosis indicates a need for urgent decompression.

Other relevant investigations for malignancy-​related liver disease Other relevant investigations for malignancy-​related liver disease include: ascitic fluid analysis (serum ascites: albumin gradient 160 times that of the control population. The remainder of this chapter will primarily focus on HCC.

Aetiology of the disease The great majority of HCC develops in cirrhotic liver, and all causes of cirrhosis are associated with an increased risk of HCC. Secondary metastases are said to be less frequent in cirrhotic liver. Chronic hepatitis C is associated with about one-​third of HCC cases worldwide. Chronic hepatitis B is associated with over half of all HCC cases worldwide. Viral integration into the hepatocyte DNA may confer a direct oncogenic effect and, in those infected early in life, HCC may develop in the absence of established cirrhosis. Other causes of HCC include alcoholic liver cirrhosis (alcohol also confers increased risk in patients with coexisting viral hepatitis), haemochromatosis, which is associated with a 45% lifetime risk in cirrhotic individuals, fatty liver disease, and alpha-​1-​antitrypsin deficiency. Cirrhosis from autoimmune hepatitis, primary biliary cholangitis (PBC), or PSC also increases the risk of HCC, although the incidence is clearly dwarfed by viral and metabolic liver diseases in particular. A rare, autosomally recessive glycogen storage disorder, von Gierke disease, may cause hepatic adenomas that can transform to HCC. In contrast, hepatic adenomas associated with the use of the oral contraceptive pill (OCP) rarely or never transform. Another important etiological factor for the development of HCC is exposure to aflatoxins, which are produced by many species of the fungal genus aspergillus. Aflatoxin-​producing aspergillus can colonize and contaminate foods such as cereals, groundnuts, and sunflower seeds during periods of prolonged storage.

Typical symptoms of the disease, and less common symptoms HCC should be considered in any patient who has established cirrhosis and develops features of hepatic decompensation, ascites, an increased liver size, or jaundice over a very short period of time. Rarely, a hepatic arterial bruit may be audible; however, this can also be heard in acute alcoholic hepatitis. HCC can have distinct patterns of growth: • nodular: multiple nodules of varying size throughout the liver (this is the most common form)

• solitary: larger, solitary masses (more common in younger patients; these can be massive) • diffuse: widespread infiltration of minute tumour foci

Demographics of the disease HCC accounts for ~80% of primary liver cancers. The incidence is increasing and, at present, is about 2–​3 per 100 000 in Europe and the US. Much higher rates of 90 per 100 000 are observed in the Far East. The incidence of HCC increases progressively with advancing age in all populations, reaching a peak at 70 years. The mean age of onset in Chinese and black patients is much earlier. The age differences and higher incidence of HCC in Asia and Africa (85% of all HCC cases worldwide) are largely related to viral hepatitis. In addition, the disease is more prevalent in men than in women (4:1).

Natural history, and complications of the disease The median survival for those diagnosed with HCC is poor. This is usually because of advanced disease being present at time of symptom presentation. This issue is discussed further in ‘Prognosis and how to estimate it’.

Approach to diagnosing the disease International guidelines advocate that individuals with established liver cirrhosis be surveyed for HCC via ultrasound scanning every 6  months (Table 218.1). Select individuals with chronic hepatitis B infection in the absence of cirrhosis are also at risk of HCC, although the evidence base for offering surveillance to non-​cirrhotic individuals with chronic liver disease is contentious. Finding the following features on initial assessment should always raise suspicion of HCC, particularly in the context of existing cirrhotic liver disease: hepatomegaly, with or without bruit • • haemorrhagic ascites • acute rise in alkaline phosphatase • secondary polycythaemia (a paraneoplastic phenomenon) • pyrexia of unknown origin

Table 218.1  Groups in whom surveillance for hepatocellular carcinoma is recommended by international guidelines Population group

Incidence of hepatocellular carcinoma (%/​year)

Non-​cirrhotic hepatitis B males >age 40

0.2

Non-​cirrhotic hepatitis B females >age 50

0.2

African/​North American blacks with hepatitis B

0.2

Cirrhotic hepatitis B carriers or non-​ cirrhotic carrier with family history of hepatocellular carcinoma

2.5–​8.0

Hepatitis C cirrhosis

2.0–​8.0

Stage 4 primary biliary cholangitis

3.0–​11.0

Genetic haemochromatosis and cirrhosis

3.0–​4.0

Alpha-​1-​antitrypsin deficiency and cirrhosis

Unknown, but probably >1.5

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CHAPTER 218 Liver cancer

Other diagnoses that should be considered

Gold-​standard diagnostic test

The differential diagnosis must distinguish between other causes of hepatic decompensation in a patient with previously stable chronic liver disease (see Chapter 210), other tumours of the hepatobiliary system (malignant and benign), and abscesses and anomalies on ultrasound scanning that may simulate a focal liver mass. It includes:

A single, universally acceptable diagnostic test for liver cancer does not exist. Ultrasound scanning (USS) has a sensitivity of 58%–​89% and a specificity of >90% and is the first imaging modality of choice when suspecting HCC. However, diagnosing HCC radiologically on a background of nodular cirrhosis can be challenging. Once concern of HCC has been raised with USS, additional radiological modalities should be employed in order to confirm the diagnosis (Figure 218.1). Current guidelines advocate that lesions 2 cm in diameter require confirmation by only one of the contrast-​enhanced investigations.

cholangiocarcinoma • • hepatic adenoma: • increased risk with oestrogen use (was rarely seen prior to the use of OCPs) • can spontaneously rupture during menstruation or pregnancy • can progress to HCC • although surgical resection is usually offered, hepatic ademonas have been known to remit once the etiological agent (usually OCP) has been removed • haemangioma: • this is a common benign hepatic tumour (develops in 20% of the normal population), occurring more commonly in women as a single, asymptomatic mass • usually located in the right lobe, existing as a blood-​filled vascular sinusoid • risks of tumour growth or bleeding are minimal • intervention is usually not needed • focal nodular hyperplasia: • a round, non-​encapsulated mass with a vascular scar and with fibrous septa radiating from the scar like ‘bicycle spokes from a central hub’, with hepatocytes in-​between • the second most common benign liver tumour • although not thought to cause the anomaly, OCPs have been shown to enhance its growth once the lesion is already present, and should be stopped • resection is not usually necessary • focal fatty infiltration: • often seen in alcoholism, obesity, diabetes, retroviral disease, and starvation • can look similar to focal liver lesions; once the underlying disease process is corrected, this appearance rapidly disappears • liver abscesses and cysts (discussed in further detail in Chapter 216).

Acceptable diagnostic alternatives to the gold standard Liver biopsy, even with expert histopathology, is not as reliable as might be expected because well-​differentiated HCC can resemble the surrounding cirrhotic liver parenchyma. Moreover, liver biopsy may lead to ‘tumour seeding’ along the biopsy tract. Nonetheless, this remains a useful tool in investigating indeterminate lesions or in situations which preclude more advanced imaging techniques (e.g. contrast allergy, pacemaker insertion).

Other relevant investigations Alpha-​fetoprotein (αFP) is the most widely used serum biomarker, although its use as a marker is no longer advocated for surveillance. When combined with USS, αFP provides additional detection of HCC in only 6%–​8% of cases. When used as a diagnostic test, αFP values of 20 ng/​ml show good sensitivity but poor specificity.

Suspicious liver nodule on USS >2 cm

0.44 x 109/​l) is seen in atopy, parasitic infestations, allergy to drugs, bullous disorders, eosinophilic fasciitis, and some cases of polyarteritis nodosa • immunological studies: • to diagnose connective tissue disease • IgE and radioallergoabsorbent tests in allergy/​atopic diseases • specific antibodies to diagnose autoimmune blistering disease • genetic studies

Wood’s lamp A Wood’s lamp is a UV lamp; in the light produced by it, visible rays are excluded via the use of a nickel oxide filter. Use of Wood’s lamp aids in making a diagnosis in the following conditions:

• fungal infections: tinea capitis caused by Microsporum spp. appears fluorescent green, while pityriasis versicolor appears yellow; however, most fungi do not fluoresce • bacterial infections:  erythrasma caused by Gram-​ positive corynebacteria glows coral pink, while that caused by Pseudomonas pyocyanea appears yellow-​green • pigmentary change (e.g. vitiligo; ash leaf macules in tuberous sclerosis; café-​au-​lait patches in neurofibromatosis) is made more visible • porphyrias: urine and faeces fluoresce in porphyria cutanea tarda; teeth fluoresce in erythropoietic porphyria; and blood fluoresces in protoporphyria

Identification of scabies mites Scabies mites may be visualized with a dermatoscope (illuminated magnification), but it is possible to extract a mite from a burrow with a needle, see it using a microscope, and then show it to the patient to prove the diagnosis. Potassium hydroxide (10%) added to the scrapings under a coverslip helps dissolve the cell membranes. Gentle scraping of a burrow (e.g. in an affected interdigital space) may reveal the mite, its eggs, and its faecal pellets.

Swabs, scrapings, and clippings Material from the skin, hair, or nails can be used for examination under the microscope or cultured to look for evidence of infection. This is especially useful in suspected fungal infections.

Skin biopsy Microscopic examination of tissue in a skin biopsy is an important technique often used to confirm or establish a diagnosis and also to

Figure 245.1 A punch biopsy. Reproduced with permission from the Hampshire Hospitals NHS Foundation Trust.

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remove malignant lesions. The procedure can be performed under local anaesthetic (1% or 2% lignocaine, with or without adrenaline to reduce bleeding, unless performed on the fingers or toes) in an outpatient setting with the patient’s consent. It is important to check that the patient is not being treated with an anticoagulant and to warn that scars on the upper trunk may heal with keloid formation and that scars on the lower legs of elderly patients may suffer from slow healing. A punch biopsy is a quick method used to obtain a small piece of skin. The biopsy is obtained by pushing a round, sharp-​ended metal cylinder blade into an area of anaesthetized skin, with a downward twisting movement (Figure 245.1). The small plug of tissue is removed from the cylinder, and the base of the wound is treated with pressure, electrocautery, or a small suture to achieve haemostasis (Figure 245.2). An elliptical biopsy provides larger samples for diagnosis or complete removal of even quite large lesions from an area of anaesthetized skin. An incisional diagnostic biopsy should be taken at right angles to the margin and include a margin of normal perilesional skin. Excisional biopsies require a wide-​enough ellipse around the (A)

whole lesion, with a margin of normal skin. The edge must be cut vertically and not slant in towards the tumour. The long axis of the wound should follow the natural creases of the skin. The edges are brought neatly together with sutures, some subcuticular absorbable ones if necessary, and the finest possible sutures in the skin itself give a good cosmetic result with a fine linear scar. Curettage is a useful device for removing hyperkeratotic lesions. A  sharp-​edged, spoonlike curette is used to remove the lesion from anaesthetized skin, and the wound is cauterized to achieve haemostasis. It may be difficult to assess the adequacy of removal. A shave biopsy is used for the removal of protuberant superficial lesions; in this procedure, the lesion is removed with a sharp blade flat to the skin. A snip biopsy is used for the removal of skin tags. Following the biopsy, the specimen is transported in a buffered formalin solution. It is processed, cut up, and stained, usually with haematoxylin and eosin, but there are numerous ‘special’ stains (e.g. Ziehl–​Neelson stain for acid-​fast bacilli; Congo Red stain for amyloid). In addition, there are many immunochemistry panels for specific cell markers (e.g. S-​100 1, for melanocytes; tryptase 1, for mast cells; IgG and IgM for immunofluorescence labelling; and numerous markers for lymphoma and leukaemia). It is important to give the histopathologist good clinical information so the correct stains can be employed to confirm or refute the diagnosis.

CHAPTER 245  Investigation in skin disease

Skin testing for suspected allergy

(B)

Substances introduced to the skin can give valuable information about immunological and pharmacological reactions. The significance of the results has to be interpreted according to each patient’s individual clinical details. Epicutaneous/​patch tests are used to find out if a suspected allergic contact dermatitis exists; this is a test for delayed hypersensitivity. Possible allergens, diluted in suitable vehicles, are placed in small discs in contact with the skin, most often on the back (Figure 245.3). There are several ‘batteries’ of allergens, for specific conditions; some (e.g. standard, facial, and hairdressing batteries) may be applied together with one or two allergens prepared from suspected substances brought by the patient. The patch testing may be extended to include testing for photoallergy, and often for possible sunscreen allergy. The discs are removed at 48 hours, and the results are read at 48 and 96 hours. A positive reaction with erythema and palpable swelling at 48 and/​or 96 hours confirms delayed hypersensitivity to the allergen in the disc at that site. Intradermal injection or prick tests are used to see if there is an immediate hypersensitivity to a particular allergen. In this test, a drop of the test solution is placed on the skin, and a sharp needle is used to make a small prick through the drop. The size of any resulting weal-​and-​flare reaction is measured at 15 minutes and is compared to positive (histamine) and negative controls. When testing patients with severe allergic reactions (e.g. to peanuts), it is important to be prepared for the severe reactions that occasionally occur with prick

(C)

Figure 245.2  A punch biopsy procedure. Reproduced with permission from the Hampshire Hospitals NHS Foundation Trust.

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Figure 245.3  Patch tests, applied to the back.

Radiology and imaging In most patients with a skin problem, the skin can be seen and felt and further imaging is not necessary. However, imaging via X-​rays, MRI, PET, and/​or high-​resolution ultrasound is useful for: detecting lymphadenopathy or metastatic skin cancer • • guiding biopsies • determining the extent of an infection • differentiating between cellulitis and necrotizing fasciitis • detecting an internal disease that is linked to a skin condition (e.g. nervous system involvement in neurofibromatosis; muscle involvement in dermatomyositis; chest involvement in sarcoidosis) • examining peripheral lower leg arteries (via Doppler assessment) before using high-​ compression bandaging in the treatment of venous leg ulcers

Photography and telemedicine Photography may be used to document the size, extent, and nature of skin changes. This aids the detection of ongoing change in the skin (e.g. looking for worrying changes in atypical naevi, documenting improvement of a rash with treatment, showing healing or extension of a leg ulcer). Photography is also helpful when the patient suffers an intermittent rash, as a photograph is better than the patient’s description in many cases. Telemedicine can be effective if it is difficult for the patient to reach the dermatologist (because the patient is from abroad, live in a remote area, or has a disability) but is not as efficient or diagnostically reliable as the patient attending the dermatologist’s clinic in person. Images may be sent electronically, and if the telemedicine consultation is set up well, with good photography and a primary care physician present (a ‘real-​time’ teleconsultation), the accuracy of the diagnosis, as well as satisfaction with the consultation, is improved.

Further Reading Ashton R, Leppard B, and Cooper H. Differential Diagnosis in Dermatology (4th edition), 2014. Radcliffe Publishing Ltd. Griffiths C, Barker J, Bleiker T, et  al. (eds). Rook’s Textbook of Dermatology (9th edition), 2016. Wiley-​Blackwell.

CHAPTER 245  Investigation in skin disease

testing. In addition, larger doses of allergen may be injected intradermally to test for delayed hypersensitivity to bacterial, fungal, and viral antigens indicating infection (e.g. the tuberculin test). Moderate to large doses of corticosteroids may inhibit the positive response to patch tests but have no effect on prick-​test reactions. Antihistamines, however, inhibit the weal-​and-​flare reaction of prick tests.

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246 

Skin infection and infestation

Christine Soon

Definition of the disease An infection of the skin means a breach of the skin barrier has resulted in an organism gaining an opportunity to infect the area and causing inflammation, pain, erythema, and swelling. There can be associated systemic unwellness such as pyrexia, tachycardia, and hypotension. An infestation occurs when creatures inhabit the skin, lay eggs, and multiply. These creatures are usually dependent on their host for food and transmission to others. They typically cause intense pruritus in the affected areas.

Aetiology of the disease Organisms causing infection of the skin include bacteria, viruses, fungi, and yeast. Bacterial infection can lead to cellulitis, impetigo, cutaneous tuberculosis, leprosy, and others. Viral infections include herpes simplex, varicella, herpes zoster, HHV8, and HPV. Fungi infections include trichophyton infections, microsporum infections, deep fungi infection, histoplasmosis, and so on. Yeast infections are caused by organisms such as candida, Malassezia furfur, and so on. Infestations of the skin include scabies and those caused by lice and fleas.

Typical symptoms of the disease, and less common symptoms Symptoms will depend on the aetiology. A bacterial infection such as cellulitis is typically caused by staphylococci or streptococci. The skin will become warm, erythematous, tender, and swollen. It may occur after a break in the skin barrier and can be associated with systemic symptoms such as malaise, pyrexia, nausea, tachycardia, and rigours. There may be associated lymphadenopathy. If the area affected becomes too swollen, blisters may occur. Impetigo is a common skin infection in children. The causative agents are usually staphylococci or streptococci. The lesion is erythematous and often has a golden crust. It is contagious. In severe cases, blistering is seen. Cutaneous tuberculosis has several different types of presentations: lupus vulgaris, scrofuloderma, tuberculid, military tuberculosis, and verrucosa cutis. It can be associated with lung tuberculosis or it can run a fairly indolent course. Other mycobacterium infections include Mycobacterium marinum infection. It usually spreads in a sporotrichoid fashion up one limb such as the arm. It often lives in tropical fish tanks, and owners of tropical fish are more at risk. Leprosy can present as hypopigmented patches of skin with loss of sensation and thickened nerves. It can also resemble a widespread erythematous rash with nodules, papules, and plaques. Infestations with scabies mites, fleas, and lice are usually intensely pruritic. Patients may scratch themselves constantly and present with excoriations, bleeding on skin, scratch marks, and general distress. In scabies, burrows may be present. They sometimes have urticated lesions as well. Infants with scabies can have pustules on their palms and soles. Flea bites often present as erythematous, itchy papules, especially on the lower limbs. Head lice cause intense itching on the scalp. The eggs of the head lice, known as nits, may be seen on affected hair shafts. Nits and even the lice themselves may be extracted through the use of a

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very fine-​toothed comb. Pubic lice cause itchy papules in the genital region. Bedbugs are experiencing resurgence. Their bites appear as itchy red papules, often grouped in a linear fashion and colloquially referred to as ‘breakfast, lunch, and dinner’. Viral infections of the skin may present as vesicles and erythema, as in varicella. Varicella affects the mucus membranes as well and may result in difficulty eating and drinking. It is also typically itchy. Shingles, or herpes zoster, is reactivation of the varicella virus. It tends to affect a single nerve root and, therefore, the appearance is of erythema, vesicles, and crusting affecting just one dermatome. It seems to be more common when a person’s immunity is compromised or when there is increased stress. It affects the elderly more often and can result in post-​herpetic neuralgia. This can persist despite the skin lesions settling. Herpes simplex is commonly seen as a crusted nodule around the mouth or nose. It can also present in the genital area as a crop of intensely tender vesicles. Genital herpes is considered a sexually transmitted disease. Fungus infection of the skin can appear as an itchy, erythematous, scaly, annular lesion with a well-​defined ring. It can appear as numerous lesions or as a solitary lesion. It can also present as a scaly area on the scalp, often associated with some hair loss. When it affects the nails, the nails often become thickened, brittle, and yellow. Less commonly, deep fungal infections of the skin occur, especially in the immunocompromised. This can present as erythematous nodules that may exude pus and ulcerate. The most common yeast infection seen is thrush, caused by candida. It can affect the moist skin-​fold areas and cause erythema and soreness. It is often associated with satellite lesions. Candida in the genital area is often accompanied by a white, cottage-​cheese-​like discharge. Oral candida appears as white patches on the tongue and oral mucosa. It can be very sore. Malassezia can cause pityriasis versicolor. This presents as flaky, pigmented patches typically on the upper back and chest in a Christmas tree distribution. When it settles, it can leave hyperpigmentation or hypopigmentation of the skin.

Demographics of the disease Cellulitis is more common in skin that has been damaged, creating an opportunity for the organism to invade the skin. It is also more common in patients with damaged lymphatic flow, such as patients with lymphoedema. Scabies commonly occur in institutions where individuals are in close proximity with each other. This can be in residential and nursing homes, hospitals, or hostels. Tinea capitis (fungal infection of the scalp), head lice, and impetigo are more common in children and are often passed on through close play and contact with others. Pubic lice, genital herpes simplex, and HPV genital warts are sexually transmitted and seen more often in the sexually active. Fleas tend to originate from animals, and flea bites are more common in pet owners, although fleas can survive in carpets and soft furnishing for many months after the pet has been removed. Other animals such as cats, dogs, and horses can transmit fungal infection. Leprosy and tuberculosis are more common in the developing world and are spread by droplet infection. Bedbugs live in mattresses and soft furnishings such as carpets and cushions, and can be transmitted via suitcases and clothing to other areas.

Natural history, and complications of the disease

Acceptable diagnostic alternatives to the gold standard

Most infections and infestations have a good prognosis. They are, however, contagious, and care should be taken to give adequate advice to patients and their close contacts. It is important to establish the diagnosis and treat appropriately. They can be more common in immunocompromised patients, the elderly, children, and patients with underlying conditions such as diabetes. Most viral infections are self-​limiting and will resolve on their own. Post-​herpetic neuralgia is a complication of herpes zoster. Cervical and anal cancer can be a complication of HPV genital warts. Bacterial infections can be more troublesome and often require a course of antimicrobials. It is helpful to establish the organism and treatments that it is sensitive to. Recurrent cellulitis can lead to damage of the lymphatic system and cause lymphoedema. Leprosy can have long-​term complicated sequelae, including mutilating disease such as deformation of digits. Both leprosy and tuberculosis may involve other systems of the body and, if inadequately treated, can result in significant morbidity. Scabies requires a host to survive. It can spread amongst individuals. Norwegian scabies is a crusted form that is particularly virulent and spreads easily. Norwegian scabies is more common in the very old, the very young, and immunocompromised individuals.

A good history and high clinical suspicion are very important. Blood tests are sometimes carried out to support the diagnosis. For example, a hot, red, swollen lower limb associated with a high white blood count and raised level of C-​reactive protein would be a good pointer towards cellulitis as a diagnosis.

A careful history should be sought. This includes time of onset; duration of symptoms; area affected; distribution of the lesions; history of contact with other affected people and animals; social history; and systemic symptoms. Examination is important for making the diagnosis. In infestations, the mites, fleas, or lice may be seen. Close contacts may need to be examined, too.

Other diagnoses that should be considered The differential diagnoses for cellulitis would include deep vein thrombosis. A history of recent long distance travel, major surgery, long periods of inactivity, oral contraceptives, or a family history of clotting disorders should help point towards this diagnosis. Dermatitis can be difficult to differentiate from scabies, as scabies sufferers often have a widespread rash that is easy to mistake as dermatitis. Granuloma annulare is often mistaken as ringworm. The clue is that granuloma annulare is usually asymptomatic and non-​scaly. Psoriasis can also cause discoloured, thickened nails. It is important here to examine other parts of the body, including the scalp, to look for signs of psoriasis plaques.

‘Gold-​standard’ diagnostic test The gold-​standard diagnostic test for skin infection and infestation is the isolation and identification of the organism. In infestations, the offender can often be caught. It is important to look in the correct area; for example, look for scabies mites in burrows; fleas in the carpet, pets, and soft furnishings; bedbugs in the mattress, where blood stains can often be seen; and head lice in the hair, using a fine-​toothed comb. Skin scrapings can be taken of superficial fungal and yeast infections of the skin, nails, and scalp. Hair pluckings and nail clippings can also be taken. Often, hyphae and spores can be seen when examined under the microscope. Skin swabs should be taken from bacterially infected skin and sent for microscopy, culture, and sensitivities. In deep fungal infections, tuberculosis, and leprosy, a skin biopsy could be sent for culture. PCR can also be carried out on the skin biopsies. In leprosy, split skin smears can be taken from the ear and sent for culture. Periodic acid–​Schiff staining of skin biopsies may also help to identify fungal spores. PCR can also be carried out on viral swabs for the identification of the virus.

In bacterial infections, blood tests with raised acute inflammatory markers and a white blood cell count will be helpful. In tuberculosis, a chest X-​ray, a T-​spot test, or a Mantoux test should be carried out. Bronchoscopy, if there is chest involvement, may be helpful for obtaining further evidence of the infection.

Prognosis and how to estimate it If treated appropriately, most infections and infestations will resolve. However, some such as tuberculosis and leprosy will require prolonged treatment for many months. Patient compliance can therefore be an issue. It is very easy to be reinfected in infestations, and education is important.

Treatment and its effectiveness Head lice are becoming more resistant to topical insecticides. Treatment can be applied to wet hair and washed off after the recommended time. Retreatment is recommended after a week. It is important to check the hair of close contacts and treat them if they are affected as well. It is very easy to get reinfection with head lice. Avoiding close head-​to-​head contact with affected individuals is a good way of preventing reinfection. Using a hair conditioner and a fine-​tooth comb to comb hair for a number of weeks may avoid the use of topical insecticides. Body lice are spread through clothing. Pubic lice are spread through close contact and sexual contact. Washing clothes at 60°C should kill the lice and eggs. Affected individuals can be treated with topical insecticides. Scabies causes intense itching. Symptoms appear 2–​6 weeks after exposure in people affected for the first time, and 1–​4  days after re-​exposure. Treatment with topical insecticide such as malathion 0.5% liquid or permethrin 5% cream is commonly used in UK. All skin surfaces, including the genital areas, the soles of the feet, and under the nails, should be treated. In children, the scalp should be treated too. With malathion 0.5% liquid, treatment is left for 24 hours and then washed off. With permethrin 5%, treatment is left on for 8–​12 hours. Retreatment a week later is recommended. All close contacts should be treated at the same time to prevent recurrence. Clothes should be washed at 60°C. It is common to have a post-​scabies itch, which can persist for a few weeks despite successful eradication. With fleas, pets in the family should be treated. The premises and soft furnishings should be treated as well. This is especially important for bedbugs. Suitcases have become a popular vector of transmission for bedbugs. Bacterial infections should be treated with the appropriate antibiotics. As most skin bacterial infections are caused by streptococci or staphylococci, penicillin and flucloxacillin are usually the first choice to try. If cultures and sensitivities have been taken, it will be helpful to ensure that the antibiotic is sensitive to the particular strain of bacteria. Impetigo can be treated with topical antiseptics and topical antibiotics such as fucidin. Fungal infections can be treated with terbinafine cream. Nail fungal infections will require a course of oral antifungals such as oral terbinafine or pulsed itraconazole. Tinea capitis may require oral terbinafine or griseofulvin. Topical azoles can help in the treatment of yeast infections.

CHAPTER 246  Skin infection and infestation

Approach to diagnosing the disease

Other relevant investigations

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CHAPTER 246  Skin infection and infestation

The treatment for tuberculosis and leprosy can involve a prolonged course with multiple agents. In the UK, these diseases are seen less commonly and it is important to seek the advice of experts who may be based in tertiary centres. Antiviral such as aciclovir can be used in varicella, herpes zoster, and herpes simplex. However, treatment should be given promptly, ideally within 24 hours of the first symptoms occurring.

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Further Reading Britton WJ and Lockwood DNJ. Leprosy. Lancet 2004; 363; 1209–​19. Chambers HF, Moellering RC, and Kamitsuka P. Management of skin and soft-​tissue infection. N Engl J Med 2008; 359: 1063–​7. Chosidow O. Scabies. N Engl J Med 2006; 354: 1718–​27. Heukelbach J and Feldmeier H. Scabies. Lancet 2006; 367: 1767–​74.

247 

Cutaneous vasculitis

Christine Soon

Definition of the disease

Approach to diagnosing the disease

Vasculitis is inflammation of the blood vessels. It can affect large vessels, medium-​sized vessels, or small vessels. Cutaneous vasculitis is inflammation of the blood vessels of the skin. This can include the capillaries, the venules, and the arterioles.

When diagnosing cutaneous vasculitis, a careful history is required. Systemic symptoms such as arthralgia, pyrexia, and general malaise are important. Dipstick of the urine should be carried out to detect any abnormalities. A  comprehensive drug history must be taken. Family history and racial origins are important. Shortness of breath, chest pain, headaches, abdominal pain, and polyarthritis are all important to elucidate. A  vasculitic screen is usually carried out to identify any underlying cause and to determine whether any internal organs are involved.

Aetiology of the disease There are many possible causes of cutaneous vasculitis. These include infection, medication, and underlying disease such as connective tissue disease, solid-​organ malignancies, haematological malignancies, inflammatory bowel disease, and other conditions. However, in many cases, an underlying cause is not found.

Typical symptoms of the disease, and less common symptoms Purpura and petechiae are the common signs of cutaneous vasculitis. Symptoms usually present on the lower limbs first. Purpura is an area of extravasation of red blood cells under the skin. Petechiae are small areas of purpura. In severe cases, the overlying skin may become necrotic. The patient may complain of pain, bleeding, or itching. Livedo reticularis may be seen in association with connective tissue disease and is a lacelike, reddish-​purple discoloration of the skin caused by capillary dilatation and the stagnation of blood within it. Occasionally, gangrene of the peripheries may be seen and necrotic ulcers may also be a feature. Oedema, nodules, vesicles, bullae, pustules, plaques, and urticated papules or plaques may also be noted. Systemic symptoms such as fever, malaise, gastrointestinal symptoms, or arthralgia may also occur.

Demographics of the disease Vasculitis can affect children or adults. A common childhood vasculitis is   IgA vasculitis (Henoch–​Schönlein Purpura). This is an IgA-​mediated immune-​complex vasculitis. It affects small blood vessels and may involve the gastrointestinal system, the skin, and the kidneys. It is usually self-​limiting, and supportive treatment is usually enough. The lower limbs and buttocks tend to be affected. Amongst adults, cutaneous small vessel vasculitis tends to be one of the most commonly seen forms of cutaneous vasculitis. It commonly affects women and tends to affect the lower limbs. It is a small vessel vasculitis. Urticarial vasculitis is a form of cutaneous vasculitis that presents as urticated papules and plaques which persist for more than 24 hours. Erythema elevatum diutinum is a form of leucocytoclastic vasculitis that can be seen in adults. It appears as reddish-​violaceous papules, plaques, or nodules that occur symmetrically over the dorsal surfaces of the knees, the hands, the Achilles tendons, and the buttocks. Granuloma faciale is a rare cutaneous vasculitis characterized histologically by a prominent eosinophilic infiltrate that appears as nodules on the face. It typically affects white males.

Natural history, and complications of the disease Cutaneous vasculitis without systemic involvement is usually a self-​ limiting condition.

Other diagnoses that should be considered Meningococcal septicaemia can present with a purpuric eruption. The speed of onset of the eruption and associated systemic symptoms such as headache, pyrexia, and photophobia are important clues to aid diagnosis. Platelet and coagulation disorders can lead to purpura occurring in the skin. A full blood count, coagulation screen, and liver function tests should help in aiding the diagnosis. Raised intravascular pressure can lead to petechiae or purpura appearing on lower legs, such as in gravitational or venous stasis, and on the face after prolonged coughing or vomiting. Petechiae can be a sign of embolism from endocarditis, atrial myxoma, fat embolism after trauma, or cholesterol embolism. In amyloidosis, pseudoxanthoma elasticum, and Ehlers–​ Danlos syndrome, the decreased vascular support can lead to purpura.

‘Gold-​standard’ diagnostic test Skin biopsies for histology and immunofluorescence would confirm the diagnosis.

Acceptable diagnostic alternatives to the gold standard Acceptable diagnostic alternatives to the gold-​standard diagnostic test are good history taking and examination, together with characteristic clinical appearances.

Other relevant investigations Other relevant investigations include: chest X-​ray • • ECG • full blood count • urea and electrolytes • erythrocyte sedimentation rate • C-​reactive protein level • antineutrophil cytoplasmic antibody assay • antinuclear antibody assay • extractable nuclear antigen antibody assay • complement level • immunoglobulin and serum electrophoresis • urine dipstick test • urine protein estimation • T-​spot test • anti-​streptococcal antibody test • serology for hepatitis B and C • cryoglobulins

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Prognosis and how to estimate it The prognosis will depend on the underlying cause. Leucocytoclastic vasculitis tends to be self-​limiting, and patients generally do well. Cutaneous vasculitis occurring as part of a systemic vasculitis tends to run a more chronic course. Vasculitis can occasionally recur.

Treatment and its effectiveness

CHAPTER 247  Cutaneous vasculitis

Supportive treatment to keep the patient symptom free is usually all that is required. This would include analgesia for pain, with rest and elevation of the lower limbs. In more severe cases, topical steroids

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or even systemic steroids might be required. Second-​line agents such as dapsone and methotrexate have been used in refractory cases. If an underlying cause such as infection has been identified as the trigger, it is important to treat this, as treatment of the trigger usually helps the rash.

Further Reading Burge S and Ogg GS. ‘Cutaneous vasculitis, connective tissue diseases, and urticaria’, in Warrell DA, Cox TM, and Firth JD, eds, Oxford Textbook of Medicine (5th edition), 2010. Oxford University Press.

248 Acne Ben Esdaile

Definition of the disease Acne vulgaris is a common, chronic inflammatory disorder of the pilosebaceous unit (the hair follicle and accompanying sebaceous gland). It can be classified as mild, moderate, or severe. Mild acne is characterized by comedones (non-​inflammatory lesions: ‘blackheads’ and ‘whiteheads’) being the predominant lesions. Papules and pustules may also be present but are few in number. Moderate acne is defined by more inflammatory lesions such as papules and pustules, with comedones also usually present. Severe acne is defined as widespread inflammatory lesions, nodules, cysts, and scarring. Moderate acne that has not settled within 6 months of treatment, or acne that is causing serious psychological effects, is also categorized as severe.

Aetiology of the disease The exact cause of acne vulgaris is not fully understood. The aetiology is complex with multifactorial influences on the pilosebaceous unit. There appears to be a genetic predisposition to acne, based on strong concordance in twin studies and family history. There appear to be four main contributors to the pathogenesis of the disease: blocking of the hair follicle with the formation of the comedone • • androgenic stimulation of the sebaceous gland, leading to increased sebum production • colonization of the hair follicle with the gram-​positive bacteria Propionibacterium acnes • inflammation of the hair follicle and its surroundings

Typical symptoms of the disease, and the less common symptoms The production of sebum form the sebaceous glands often results in ‘greasy’ skin. The skin lesions, namely comedones, papules, and pustules, are often asymptomatic but some of the large pustules, nodules, and cysts can become extremely tender. The prominent cosmetic distribution of acne can lead to a great psychological impact on the patient, and support groups can be extremely helpful. A severe form of nodulocystic acne, acne fulminans, can produce severe systemic symptoms, including fever, arthralgia, and myalgia and requires urgent intervention.

Demographics and natural history of the disease Acne vulgaris is the commonest skin condition to affect man. It is principally a disease of adolescence and it has been estimated to affect over 80% of those between 12 and 25. Although widely thought to be an adolescent disease, 3% of men and 12% of women will continue to have acne until their mid-​forties.

Approach to diagnosing the disease The diagnosis of acne vulgaris is a clinical one. Non-​inflammatory acne is characterized by the presence of open (blackheads) and closed (whiteheads) comedones. Closed comedones are skin-​coloured papules and are easily distinguished from the often black, discoloured, dilated follicular openings of the open comedone. When comedones become inflamed, they expand to develop pustules, inflammatory papules, nodules, and cysts. All of these lesions can result in scarring.

Acne fulminans is the most severe form of nodulocystic acne and is characterized by the abrupt onset of nodulocystic acne in association with systemic features, including fever, arthralgia, and myalgia. Severe eruptive nodulocystic acne without systemic features is known as acne conglobata.

Other diagnoses that should be considered Although the diagnosis of acne vulgaris in adolescents is usually not difficult, in other age groups or when atypical features are present, other diagnoses may be considered. Rosacea is the most common differential diagnosis to acne vulgaris. Patients with rosacea often complain of both redness and spots. Important clues from the history are that sufferers often notice an exacerbation of their symptoms with alcohol, exercise, spicy foods, and emotion. They often also report easy flushing in their youth. Clinically, patients with rosacea have evidence of erythema, telangiectasia, and inflammatory papules and pustules. There may also be evidence of sebaceous hyperplasia, which can result in enlargement of the nose. A significant proportion of suffers have ocular involvement, with blepharitis and conjunctivitis. Another cause of a red face is seborrhoeic dermatitis, which presents as a red, often scaly face, especially in the distribution of the nose and eyebrows, the so-​called T-​zone of the face. They usually also report scaling of the scalp; however, inflammatory pustules and papules are not usually present. Table 248.1 summarizes possible differential diagnoses.

‘Gold-​standard’ diagnostic test There is no ‘gold-​standard’ diagnostic test for acne vulgaris. It is a clinical diagnosis and it is therefore essential to perform a thorough history and examination of the patient. From the history, it is important to ascertain the use of all over-​the counter preparations as well as comedogenic cosmetics, including pomades as well as topical steroids. In females, a menstrual and oral contraceptive history is important to evaluate the hormonal influence on the acne. It is important to establish the severity (using validated scoring system), the type of lesions (inflammatory or comedonal), and the presence of scarring.

Other relevant investigations Usually no investigations are required; however, a skin swab from a pustule can provide sensitivities of P. acnes and hence can help tailor therapy. Skin and nasal swabs can also help to exclude a gram-​negative folliculitis. In certain patients where a hormone abnormality is suspected (i.e. very irregular menstrual cycle, significant hirsutism), a sex hormone profile including testosterone, sex hormone-​binding Table 248.1  Differential diagnoses of acne vulgaris Comedonal acne

Inflammatory acne

Milia Sebaceous hyperplasia Miliaria rubra Syringomas Trichoepitheliomas

Rosacea Perioral dermatitis Contact dermatitis Folliculitis Keratosis pilaris SLE Steroid-​induced acne

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globulin, prolactin, follicular-​stimulating hormone, and luteinizing hormone can be measured. In rare circumstances when a diagnosis of late-​ onset congenital adrenal hyperplasia is suspected, the 17-​α-​h ydroxyprogesterone levels can be measured.

Treatment and its effectiveness The treatment of acne is directed towards the four main areas in the pathogenesis of the disease. A summary of the treatments for acne vulgaris is shown in Table 248.2.

Oral antibiotics (e.g. oxytetracycline, tetracycline, doxycycline, lymecycline, minocycline, erythromycin, and trimethoprim) are prescribed for moderate-​to-​severe inflammatory acne. Their primary mechanism of action is the suppression of growth of P. acnes but they also possess intrinsic anti-​inflammatory properties. There are increasing reports of resistance to erythromycin and some of the tetracyclines.

Hormonal manipulation

Topical treatments Topical retinoids Retinoids (e.g. adapalene, tazarotene, tretinoin) work by normalizing follicular keratinization and hence have anticomedonal properties. They also have significant anti-​inflammatory affects and hence can be used as first-​line treatments for both mild inflammatory and comedonal acne. Topical retinoids can be used as monotherapy or in combination with benzoyl peroxide or antibiotics. They can cause local drying, irritation of the skin, and thinning of the outer layer of the epidermis (stratum corneum). Some are also unstable in the sun; therefore, patients should be advised to apply them in the evening. Female patients should be advised not to become pregnant while using topical retinoids, as there is a theoretical risk of systemic absorption of this known teratogen.

Benzoyl peroxide

CHAPTER 248 Acne

Oral treatments Oral antibiotics

Benzoyl peroxide is a bactericidal agent and acts on the P. acnes within the hair follicle. It is available in multiple strengths, from 2.5% to 10%, as washes, soaps, gels, and lotions and in combinations with topical antibiotics. Patients should be warned that benzoyl peroxide can be an irritant as well as bleach clothes and bedding.

Topical antibiotics Topical antibiotics (e.g. clindamycin, erythromycin, sodium sulfacetamide) should not be used in the long term due to the possibility of the development of bacterial resistance. They are available in combination with benzoyl peroxide or topical retinoids.

Salicylic acid Salicylic acid has comedolytic and mild anti-​inflammatory properties. It is available in strengths up to 2% in gels, creams, and lotions.

Azelaic acid Azelaic acid is a naturally occurring dicarboxylic acid found in cereal grains. It has both anti-​inflammatory effects and comedolytic activity. It also has the added benefit of helping post-​inflammatory hyperpigmentation. It also has fewer side effects, compared to topical retinoids.

Hormone therapy is an established second-​line therapy for female patients suffering from moderate-​to-​severe acne vulgaris. The oral contraceptive pill works by decreasing the production of both adrenal and ovarian androgens. A number of formulations that combine oestradiol with the anti-​androgenic cyproterone acetate are widely used. Other formulations combine oestradiol with a low-​androgenic progestin such as drospirenone.

Isotretinoin Isotretinoin is a retinoid and an isomer of tretinoin. It is used for severe nodulocystic acne, significant acne that has not responded to adequate courses of antibiotic treatment or acne that is causing physical or psychological scarring. Its mechanism of action is not fully understood but it is known to inhibit maturation of the basal cells of the sebaceous gland, resulting in decreased sebum production. It also acts to normalize follicular keratinization as well as having anti-​ inflammatory and antimicrobial activity. It is the only treatment to target all four of the pathogenic contributors to acne. Isotretinoin has a number of common side effects, including severe dryness of the skin and mucous membranes, causing nosebleeds, cracking of the lips, and intolerance of contact lenses. As it is teratogenic, it should not be prescribed in women of childbearing years unless they are registered with a pregnancy prevention programme. Therapy can also result in an elevation in serum triglyceride and cholesterol levels as well as abnormalities in liver enzymes. A causal link between oral isotretinoin and psychological disturbance is not fully proven but it is prudent to get a specialist psychiatric opinion prior to initiating therapy if there are any mood concerns. Therapy should be stopped if there is any significant alteration in mood during therapy.

Surgical treatments Comedones can be treated with a number of surgical techniques such as electrocautery, or the comedone can simply be expressed with a needle or scalpel blade. Deep, inflamed cystic lesions can be improved with steroid injections with triamcinolone acetonide. Low-​ concentration chemical peels have also been successful in the treatment of comedones.

Table 248.2  Acne vulgaris treatment algorithm Acne Treatment Algorithm Mild

Moderate

Severe

Comedonal (blackheads/​ whiteheads

Papular/​ Pustular

Papular/​ Pustular

Nodular

Nodular/​ Conglobate

1st Choice

Topical Retinoid

Topical retinoid + topical antimicrobial

Oral antibiotic +/​− topical retinoid +/​− benzoyl peroxide

Oral antibiotic +/​− topical retinoid +/​− benzoyl peroxide

Oral Isotretinoin

Alternatives

Alternative topical retinoid or azelaic acid or salicylic acid.

Alternative topical antimicrobial + alternative topical retinoid or azelaic acid.

Alternative oral antibiotic + alternative topical retinoid +/​− benzoyl peroxide

Oral Isotretinoin or alternative oral antibiotic + alternative topical retinoid +/​− benzoyl peroxide/​azelaic acid.

High dose oral antibiotic + topical retinoid + benzoyl peroxide

Options for Females Maintenance

Oral contraceptive/​anti-​androgen Topical retinoid

Topical retinoid +/​− benzoyl peroxide

Reprinted from Journal of the American Academy of Dermatology, Volume 49, issue 1, Harald Gollnick, William Cunliffe, Diane Berson, Brigitte Dreno, Andrew Finlay, James J. Leyden, Alan R. Shalita, Diane Thiboutot, Management of Acne A Report From a Global Alliance to Improve Outcomes in Acne, pp. S1-​S37, Copyright (2003), with permission from Elsevier.

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Acne scarring is difficult to treat satisfactorily. Chemical peels may be used to treat scars resulting from acne. Other techniques include dermabrasion and laser resurfacing, which aim to alter the contours of the scars.

Further Reading

Nast A, Dreno B, Bettoli V, et al. European evidence-​based guidelines for the treatment of acne. J Eur Acad Dermatol 2012; 26(S1): 1–​29. NHS Clinical Knowledge Summaries: Acne Vulgaris (http://​cks.nice. org.uk/​acne-​vulgaris). Zaenglein AL and Thiboutot DM. ‘Acne vulgaris’, in Bolognia JL, Jorizzo JL, and Rapini PR, eds, Dermatology, 2008. Mosby (Elsevier).

CHAPTER 248 Acne

Goodfield MJD, Cox NH, Bowser A., et al. Advice on the safe introduction and continued use of isotretinoin in acne in the UK 2010. Brit J Dermatol 2010; 162: 1172–​9.

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249 Psoriasis Ben Esdaile

Definition of the disease Psoriasis is a common, chronic inflammatory skin disease that is associated with joint disease in approximately 25% of patients. The most common variant of psoriasis is chronic plaque psoriasis (psoriasis vulgaris), which has the hallmark of well-​demarcated erythematous plaques covered by silvery scale. There are a number of other variants of psoriasis, including guttate, inverse, palmoplantar, flexural, pustular, and erythrodermic.

Aetiology of the disease Psoriasis is a polygenic disease. Twin studies have shown a 67% concordance for monozygotic twins versus 18% for dizygotic twins. Several susceptibility loci have so far been identified and the PSOR1 gene (C6p21.3), situated within the major histocompatibility complex (MHC) region of Chromosome 6, has been shown to be involved in around 50% of patients with psoriasis. The association of psoriasis with MHC alleles suggests an important role of T-​lymphocytes in the pathogenesis. This has been confirmed as, once the disease is triggered, there appears to be a large recruitment of T-​lymphocytes to the dermis and epidermis, resulting in the characteristic plaques. There is a resultant large production of pro-​inflammatory mediators, including tumour necrosis factor alpha and interferon gamma, as well as numerous cytokines which have become targets for novel therapies. Psoriasis can be triggered by external factors such as infection, physical trauma, or sunburn. The development of psoriasis in sites of trauma to the skin is known as the Koebner phenomenon. Other external factors include infections, especially streptococcal upper respiratory tract infections. Several drugs are known to trigger psoriasis, including beta blockers, lithium, and antimalarials.

Typical symptoms of the disease, and less common symptoms Chronic plaque psoriasis is often asymptomatic but may itch or sting and can bleed easily when scratched (Auspitz sign). Psoriasis can have an enormous psychological impact and can limit normal social and leisure activities. This can be measured using the Dermatology Life Quality Index, which provides a score between 0 and 30. A  score of greater than 10 is regarded as a severe impact on a patient’s quality of life.

Demographics of the disease In most reviews, the prevalence of psoriasis worldwide varies between 0.1% and 3%. In the UK, the prevalence is estimated at between 1% and 2%. There are certain parts of the world, such as Canada and the US, where the prevalence has been reported up to 4.7%. In contrast to this, there are some parts of Africa where the prevalence is estimated as low as 0.4%. Psoriasis affects both sexes equally.

Natural history, and complications of the disease Psoriasis can first appear at any age but there appears to be two main peaks in a person’s twenties and fifties; 75% of disease occurs before the age of 40. It tends to run a chronic relapsing and remitting

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course. Psoriasis can be complicated by its pustular and erythrodermic variants. Psoriasis is associated with metabolic syndrome and its components, including diabetes, hypertension, and obesity. The increased risk of myocardial infarction in patient with psoriasis highlights the importance of addressing reversible risk factors.

Approach to diagnosing the disease The diagnosis of psoriasis is usually made clinically and does not require histological confirmation. A full history is important and can reveal a family history of psoriasis, as well as details of all medications and recent illnesses which may be important triggers for the disease. The most common variant of psoriasis is chronic plaque psoriasis (psoriasis vulgaris). Clinically, the patient presents with well-​demarcated ‘salmon-​pink’ symmetrical scaly plaques with an overlying silvery scale. The plaques classically present on extensor surfaces and can vary in size (from tiny papules to extremely large plaques). There are certain sites of predilection that can give clues to the diagnosis, such as the sacrum, the umbilicus, the nape of neck, the hairline of the scalp, and extensor surfaces. Approximately 50% will have nail changes such as pitting, onycholysis, and subungual hyperkeratosis. Plaques can occur in the flexures, in which case the condition is termed flexural psoriasis. When this is the only site of involvement, the term ‘inverse’ psoriasis is often used. The severity of chronic plaque psoriasis can be quantified using a scoring system known as the Psoriasis Area and Severity Index score. Other variants of psoriasis include guttate psoriasis, which is common in children and young adults, with often an antecedent history of an upper respiratory tract infection. Clinically, patients present with a scattered ‘rain-​drop’ appearance of small papules/​plaques over the body. Psoriasis can present with a pustular variant that is either localized (palmoplantar pustulosis/​acrodermatitis of Hallopeau) or generalized. The generalized variant presents as multiple sterile pustules on an erythematous background. Importantly, this can be induced by the rapid cessation of oral steroids or the inappropriate use of topical steroids. Psoriasis is one of the causes of erythroderma, and patients can present with generalized erythema and desquamation from their psoriasis.

Other diagnoses that should be considered The diagnosis of psoriasis is classical but differentials that may be considered are outlined in Table 249.1.

‘Gold-​standard’ diagnostic test The gold-​standard diagnostic test for the diagnosis of psoriasis is a skin biopsy. In chronic plaque psoriasis, there is epidermal hyperplasia

Table 249.1  Differential diagnoses for chronic plaque psoriasis Single plaque

Multiple plaques

Lichen simplex chronicus Bowen’s disease (squamous cell carcinoma in situ) Lichen planus Tinea corporis/​capitis

Eczema Cutaneous T-​cell lymphoma Lichen planus Tinea corporis

Acceptable diagnostic alternatives to the gold standard The diagnosis of psoriasis is usually made clinically without the need for histological confirmation or further investigations.

Other relevant investigations Skins swabs can provide clues for potential triggers of flares of psoriasis. Patients who are commenced on systemic therapies need regular blood test monitoring that will be outlined in ‘Systemic treatments’. The association of psoriasis and metabolic syndrome means that it is worth measuring lipids and other cardiovascular risk factors.

Prognosis, and how to estimate it Chronic plaque psoriasis is a chronic disease that usually runs a relapsing and remitting course.

Treatment and its effectiveness There are many factors that influence the choice of therapy in the management of psoriasis including patient choice, disease extent, lifestyle, and comorbidities. The different therapy choices available are detailed in this chapter.

Topical treatments Vitamin D analogues Vitamin D3 analogues (e.g. calcipotriol, calcitriol, tacalcitol) act by inhibiting the proliferation of keratinocytes and inducing normal differentiation. They can have an effect on calcium homeostasis and so a maximum weekly dose of 100 g is recommended. They can also be combined with topical corticosteroids. They are used as monotherapy or in combination as a first-​line agent for mild-​to-​moderate chronic plaque psoriasis.

Coal tar The mechanism of action of coal tar is not understood but it has a range of anti-​inflammatory properties. There are a number of preparations of tar used in creams, lotions, shampoos, gels, and ointments. It is also used in its crude form for special inpatient topical regimens. It is often combined with other products including salicylic acid, coconut oil, and corticosteroids. It is also occasionally used in combination with UV light.

Glucocorticoids Topical corticosteroids have become one of the major first-​ line therapies for chronic plaque psoriasis. This is mainly due to their cosmetic acceptance and relative ease of use. Inappropriate use of topical steroids can not only lead to relapses and flares but can also induce pustular psoriasis. The topical corticosteroids are important in flexural disease due to their lack of irritancy.

Phototherapy It is well described that a number of patients note an improvement in their psoriasis after exposure to the sun. Phototherapy with UVA and UVB radiation is one of the mainstays of treatment of moderate-​to-​ severe psoriasis. Phototherapy with broadband UVB has largely been replaced with narrow band UVB produced by TLO1 bulbs. UVA radiation is used in combination with photosensitizers 8-​methoxypsoralen and 5-​methoxypsoralen either orally or topically. Phototherapy does have side effects, with dose-​dependent burning, photoageing, and the increased risk of skin carcinogenesis with cumulative doses.

Systemic treatments When disease control fails with topical or light therapy, patients are often offered a systemic therapy. These drugs all have side effects and so the choice of agent is made after a balanced discussion between doctor and patient. Patients require careful monitoring.

Methotrexate Methotrexate is the most commonly used systemic therapy for psoriasis in the UK. It is a derivative of folic acid and acts as an antimetabolite by inhibiting the enzyme dihydrofolate reductase and hence cell division. The drug also has anti-​inflammatory properties on lymphocytes and neutrophils. Methotrexate is usually started at a dose of 5 mg weekly and a full blood count is recorded after 7 days to check for an idiosyncratic reaction of myelosuppression. The dose can then be increased, usually to a maximum of 15–​25 mg weekly. Monitoring of liver tests, renal tests, and full blood counts takes place weekly for 2 weeks after any dose change and then 2–​3 monthly once the dose is stable. Specific markers for liver fibrosis are the serum pro-​collagen III N-​terminal peptides levels, which are measured on a 3-​monthly basis where available. This test has now superseded the previous invasive liver biopsies that were routinely performed before and after a cumulative 1.5 g dose. The co-​administration of 5 mg of folic acid is said to help reduce the main side effect of nausea.

Ciclosporin Ciclosporin acts as a calcineurin inhibitor and prevents T-​lymphocyte activation. It was originally used to prevent organ rejection in transplant patients. Ciclosporin is a highly effective drug in the treatment of psoriasis but its use is limited by its inevitable side effects. The major side effect is that of nephrotoxicity, which usually limits the therapy to short courses of 3–​4 months. The usual starting dose is 2.5 mg/​kg per day and can be increased up to a maximum of 4 mg/​ kg per day. Close monitoring of blood pressure and renal function is required during therapy.

Acitretin Vitamin A (retinol) is an essential epithelial growth factor whose precise mode of action is not fully understood. A deficiency in vitamin A leads to reversible dry skin and squamous metaplasia. Acitretin is given in doses usually ranging from 10 mg to 50 mg daily. It is often combined with UVB therapy. Acitretin is useful in all forms of psoriasis but is especially in erythrodermic and pustular variants. The most important side effect is that of teratogenicity and it is therefore not usually used in women of childbearing age. It is important to monitor liver function and lipid metabolism during therapy.

Other systemic therapies

Topical retinoids

Other systemic therapies include the fumaric acid esters and hydroxyurea.

Tazarotene is an acetylic retinoid which has an antiproliferative effect on the keratinocytes. Its use is limited by both efficacy and irritation.

Biological therapy

Dithranol Dithranol (anthralin) is derived from the bark of the araroba tree, which is indigenous to South America. It has a marked antiproliferative effect on the epidermis. It can cause burning and erythema to normal skin as well as stain clothes and bath enamel. It is rarely used on the flexures or face due to irritation. It is often used as part of an inpatient regimen but there are now some more ‘short-​contact’ non-​staining preparations that can be used in the day setting or even at home.

CHAPTER 249 Psoriasis

(acanthosis), with flattening of the rete ridges and loss of the granular cell layer with cells in the stratum corneum still possessing flattened nuclei (parakeratosis). There are often neutrophils found in the epidermis in so-​called Munro microabscesses.

Biologic therapies for psoriasis target specific molecules involved in the inflammatory cascade of psoriasis. There are now a number of licensed drugs which have transformed the lives of patients with psoriasis. Many of the biologics specifically target tumour necrosis factor and include infliximab, etanercept, and adalimumab. There are some newer monoclonal antibodies against other interleukins in the inflammatory cascade, such as ustekinumab, which targets interleukins 12 and 23. The long-​term safety of these drugs is not proven, with potential long-​term side effects including malignancy (e.g. lymphomas and skin cancers) and opportunistic infections (e.g. tuberculosis).

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Further Reading

CHAPTER 249 Psoriasis

Cohen SN, Baron SE, and Archer CB. Guidance on the diagnosis and clinical management of psoriasis. Clin Exp Dermatol 2012; 37 (Suppl 1): 13–​18. Menter A and Griffiths CE. Current and future management of psoriasis. Lancet 2007; 370: 272–​84. National Institute for Health and Clinical Excellence. Psoriasis: Assessment and Management. 2012. Available at http://​guidance. nice.org.uk/​CG153 (accessed 15 Jul 2017).

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Smith CG, Anstey AV, Barker JN, et  al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Brit J Derm 2009; 161: 987–​1019. Van de Kerkhof PCM and Schalkwijk J. ‘Psoriasis’, in Bolognia JL, Jorizzo JL, and Rapini PR, eds, Dermatology, 2008. Mosby (Elsevier).

250 Eczema Ben Esdaile

Definition of the disease

Approach to diagnosing the disease

Eczema is a descriptive term for a set of symptoms and signs which usually involve itchy inflammation of the skin, and is subcategorized into many different forms. Atopic eczema (atopic dermatitis) is the most common chronic inflammatory disease amongst children. Other types of eczema include seborrhoeic eczema, discoid eczema, asteatotic eczema, contact allergic eczema, contact irritant eczema, pompholyx eczema, venous eczema, juvenile plantar dermatosis, and lichen simplex. In this chapter, we will cover atopic eczema, which is called ‘atopic’ due to its association with other atopic disorders such as asthma and allergic rhinitis.

A diagnosis of atopic eczema is usually readily made from a history and clinical examination. The rash of atopic eczema is usually symmetrical, with ill-​defined patches of erythema and scale and with serous exudate and vesiculation seen in acute states (the eczema usually starts on the face and then extends to involve the trunk and limbs). In infants, the face and extensor surfaces are mostly affected but, as children mature, it tends to involve the flexural areas, especially the antecubital fossae, the popliteal fossae, the wrists, and the neck. Chronic eczema leads to thickening of areas of scratching (lichenification) and post-​ inflammatory hyper-​or hypopigmentation. The decrease in epithelial/​skin barrier function can result in secondary infection, with the classical yellow overlying crust of impetiginized eczema. Patients with eczema also appear to be more susceptible to viral infections, with higher incidences of molluscum contagiosum, warts, and herpes simplex viral infections (eczema herpeticum).

Aetiology of the disease The aetiology of atopic eczema has yet to be fully understood but it is known to have both genetic and environmental factors. A gene encoding a protein called filaggrin, which is involved in keratin aggregation, has been shown to be mutated in 20%–​50% of children with the disease. The rising prevalence over the last few decades, with the simultaneous increasing levels of hygiene, led to the ‘hygiene theory’ that children who were exposed to more antigens were less likely to develop atopy. Factors that are known to exacerbate eczema include sweating, irritants such as detergents and solvents, infection, stress, and, in some cases, contact allergens, including aeroallergens.

Typical symptoms of the disease, and less common symptoms The main symptom of atopic eczema is pruritus. Patients develop further symptoms from the sequelae of scratching (e.g. infection). Virtually all patients with atopic eczema have constitutional dry skin known as xerosis.

Demographics of the disease Atopic eczema has an estimated prevalence of between 10% and 20% in Northern Europe and the US, with lower rates in Africa. It is slightly more common in girls. In the UK, it is associated with an estimated cost of over £500 million per year.

Natural history, and complications of the disease The majority of patients with atopic eczema first develop their disease in early infancy, usually after 2  months. Many children with atopic eczema improve by the age of 3. Over 50% are disease-​free by the age of 6, and up to 80% by the age of 14. Some may relapse in early adult life but most recover by their thirties. A small proportion will go on to suffer from lifelong disease. Eczema can be complicated by infection, with bacteria being the most common offending agents. Secondary infection with herpes simplex virus can lead to eczema herpeticum with a characteristic (bullet-​ spray) appearance of punched-​ out erosions and vesicles. Patients can become systemically unwell, as well as have ophthalmic involvement. Eczema herpeticum can be life-​threatening. Patients with severe eczema can develop a generalized exfoliative erythroderma. This is a dermatological emergency, as patients can develop problems with temperature regulation, sepsis, and even cardiac failure.

Other diagnoses that should be considered In infancy, the main differential is seborrhoeic dermatitis. Seborrhoeic dermatitis is not usually pruritic and there is usually no associated family history of atopy. The main clue is the distribution, with seborrhoeic eczema being more prominent on the scalp (cradle cap), face, and nappy areas. In older children and adults, a diagnosis of scabies should always be considered in any itchy rash. When a patient presents with no family or personal history of eczema, one should always consider the possibility of an allergic contact dermatitis. Cutaneous T-​cell lymphoma can mimic chronic eczema. It is sometimes difficult to differentiate eczema and psoriasis, especially when a patient presents with a hand/​foot dermatitis.

‘Gold-​standard’ diagnostic test The diagnosis of atopic eczema is a clinical one and there is no ‘gold-​ standard’ diagnostic test. A skin biopsy is, therefore, rarely needed but the histological features of eczema will depend on the stage of the eczema. In acute eczema, there is oedema between the epidermal cells, known as spongiosis. In more chronic eczema, there is thickening of the epidermis with epidermal hyperplasia.

Acceptable diagnostic alternatives to the gold standard As mentioned previously, the diagnosis of atopic eczema is a clinical one and rarely needs a skin biopsy. Patch testing is used to investigate any extrinsic allergens exacerbating the atopic eczema.

Other relevant investigations Elevation of serum IgE levels and eosinophilia are often found in atopics, but approximately 25% will have normal levels. Total IgE levels are often elevated in atopic eczema patients but the usefulness of the detection of specific IgE-​directed antibodies against certain allergens (radioallergosorbent testing (RAST)) in finding triggers of disease is controversial. RAST and skin prick testing can potentially provide some useful information about allergen avoidance but careful patient selection, based on their history, is advised (e.g. flares in exposed sites and associations with house dust mite allergy).

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Prognosis, and how to estimate it Prognosis is difficult to predict in atopic eczema but severe disease in infancy and disease on the extensor surfaces of the elbows and knees are poor prognostic markers.

Treatment and its effectiveness Education plays a vital role in the management of eczema. A reduction of trigger factors such as harsh chemicals, the use of soaps, and avoidance of house dust mite are all beneficial. Cotton clothing appears to be less irritating to the skin than clothing made of other material. The importance of treating the xerosis of the skin and breaking the itch–​scratch cycle is vital.

Topical treatments Emollients Emollients are an essential aspect of the treatment of atopic eczema. The xerosis and impaired barrier function are vital targets for therapy. There are numerous commercially available different emollients with varying ingredients, usually containing paraffin. The greasier the emollient, the more effective it will be but, usually, the less acceptable it will be to the patient. Emollients should be generously applied as many times a day as practical. They should also be applied after bathing, to damp skin.

CHAPTER 250 Eczema

Soap substitutes and bath additives Soaps are irritating to the skin and so it is important to avoid them and use a soap substitute for washing. There are, again, a number of soap substitutes available, including *ones with emulsifying ointment and aqueous cream. In fact, many emollients can be used as a soap substitute. There are now a number of bath additives and shower gels designed for patients with eczema. Some are now combined with an antiseptic agent that can be useful in patients with recurrent infective exacerbations.

Topical corticosteroids Topical glucocorticosteroids are the mainstay of treatment for atopic eczema. The choice of steroid is dependent on the age of the patient and the site and stage of the eczema. In general, low-​potency steroids such as hydrocortisone and clobetasone butyrate are used on the face. Moderately potent steroids are used in the flexures. It is advised that a potent steroid is used at first to gain control, prior to reducing its strength. The vehicle of the active ingredient is important, as ointments lead to better absorption, compared to creams. Inappropriate chronic daily use of topical corticosteroids can lead to complications of skin atrophy, telangiectasias, and striae. There is also a risk of cataract development if potent steroids are used near the eye for a prolonged duration. A table summarizing the potency of some of the commonly used steroids is shown in Table 250.1.

Topical pimecrolimus and tacrolimus Pimecrolimus and tacrolimus are licensed for mild-​to-​moderate and moderate-​to-​severe atopic eczema, respectively. They are steroid-​ sparing immunosuppressants that act via inhibition of the T-​ cell activator calcineurin. They have an important role in the long-​term management of eczema (especially on the face) to reduce the use Table 250.1  The potency of some of the commonly used steroids

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Generic name (brand names)

Potency

Hydrocortisone 0.5%–​2.5%

Mild

Clobetasone butyrate 0.05%

Moderate

Betamethasone valerate 0.1%

Potent

Mometasone furoate 0.1%

Potent

Clobetasol propionate 0.05%

Very potent

of topical steroids. They can cause stinging when first used but this effect fades after a number of applications.

Occlusive bandaging Occlusive bandaging of the limbs can be extremely useful in the treatment of atopic eczema affecting the limbs. Steroids can be applied underneath the bandages, which can contain antipruritic substances such as zinc and ichthammol. The process of ‘wet wrapping’, a two-​ layer bandaging technique where the inner layer is soaked in warm water, is also useful in the paediatric setting.

Antihistamines The sedating antihistamines do have a role in the treatment of atopic eczema. Their sedative properties can help break the itch–​scratch cycle, especially at night. (It is the sedative properties that are useful.)

UV phototherapy UVB TLO1 There are a number of different phototherapy regimens that have been used with success in treating eczema but narrow-​band UVB seems to be the safest and appears effective in some, but not, all patients.

Oral treatments Systemic treatments are reserved for patients in whom optimal topical therapy does not result in disease control.

Oral corticosteroids Systemic corticosteroids are used for acute severe flares of atopic eczema that fails to respond to topical therapy. Their use in protracted courses can result in systemic side effects.

Azathioprine Azathioprine is an immunosuppressive corticosteroid-​sparing agent that is an antimetabolite thought to inhibit the proliferation of lymphocytes. Note, however, that there is a genetic polymorphism for an enzyme called thiopurine methyltransferase (TPMT), which is important in the metabolism of azathioprine; although >1% of the population is homozygous for an allele of low activity of TPMT, they are at risk of profound myelosuppression at standard doses. For this reason, patients should have their TPMT levels checked prior to starting therapy.

Ciclosporin Ciclosporin acts as a calcineurin inhibitor and prevents T-​lymphocyte activation. It was originally used to prevent organ rejection in transplant patients. The major side effect is that of nephrotoxicity which usually limits the therapy to short courses. The usual starting dose is 2.5 mg/​kg per day but can be increased up to a maximum of 4 mg/​kg per day. Close monitoring of blood pressure and renal function is required during therapy.

Other systemics There are many other agents that have been used with variable success in the long-​term control of atopic eczema, including methotrexate and mycophenolate mofitil.

Further Reading Kang K, Polster AM, Nedorost ST, et  al. ‘Atopic dermatitis’, in Bolognia JL, Jorizzo JL, and Rapini PR, eds, Dermatology, 2008. Mosby (Elsevier). Primary Care Dermatology Society and British Association of Dermatologists:  Guidelines for the Management of Atopic Eczema (http://​www.bad.org.uk) Shams K, Grindlay DJC, and Williams HC. What’s new in atopic eczema? An analysis of systematic reviews published in 2009–​ 2010. Clin Exp Dermatol 201; 36: 573–​7. Williams, HC. Atopic dermatitis. N Engl J Med 2005; 352: 2314–​24.

251 Urticaria Sarah Wakelin

Definition of the disease Urticaria is an inflammatory complaint characterized by short-​lived skin swellings termed ‘weals’ or ‘hives’. It can be divided into acute urticaria, where the disease is short-lived and chronic urticaria, where weals occur on a regular basis for more than 6 weeks. Inducible or physical urticaria is a subgroup of chronic urticaria where an underlying external/​physical trigger can be identified. Contact urticaria is a localized weal or swelling of the skin or mucosa following contact with a chemical substance. Angioedema represents a similar process affecting the deeper dermal tissue and has a predilection for the skin around the eyes and mouth. It may occur in association with urticaria or as an isolated complaint.

Aetiology of the disease The primary event is degranulation of activated  dermal mast cells and release of pro-​ inflammatory mediators including histamine. These cause vasodilation and increased vascular permeability leading to leakage of plasma proteins and leukocytes into the perivascular tissue. Mast cell degranulation may occur in response to cross-​linking of surface high-​affinity IgE receptors by allergens or IgG autoantibodies or it can be directly triggered by non-​immunological agents such as opiates, neuropeptides, and C5a anaphylaxotoxin. An underlying cause may be identified in approximately 50% of patients with acute urticaria. In most cases, this is infective. Food allergy may need investigating if there is a temporal relationship. A detailed drug history is also mandatory. In chronic spontaneous urticaria, (CSU) some patients have evidence of underlaying autoimmunity especially autoimmune thyroid disease. It is seldom related to food allergy which can be excluded by taking a careful history. Parasite infection such as strongyloidiasis rarely causes urticaria in developed countries, but may be more significant in tropical regions. Causes of inducible urticaria include friction (symptomatic dermographism), heat and sweating (cholinergic), stress (adrenergic), UV radiation (solar), pressure, and cold. Contact urticaria is usually mild and localized and may be caused by a range of environmental chemicals and proteins. Immunological contact urticaria (e.g. natural rubber latex allergy) is a manifestation of IgE-​mediated, immediate-​type hypersensitivity, and atopic individuals are predisposed to develop this complaint  the aetiology of non-immunologic contact urticaria is not clear, but prostaglandins and other inflammatory mediators have been implicated.

Typical symptoms of the disease, and less common symptoms Weals vary in size from a few millimetres to many centimetres (giant urticaria) and are raised, smooth red areas of skin, sometimes surrounded by pallor (see Figure 251.1). They are usually itchy and uncomfortable, and symptoms are aggravated by heat, sweating, and tight clothing. Weals of CSU are often round or annular, while those of symptomatic dermographism are typically linear and occur at sites of friction. Weal duration may be short-​lived, as in contact urticaria and most forms of physical urticaria, where resolution usually occurs within an hour. However, in delayed pressure urticaria and delayed dermographism, the onset of weals is delayed for several hours and they can persist for over

Figure 251.1  Widespread ordinary urticaria; the smooth erythematous papules and plaques may expand into annular shapes. Please see colour plate section. Reproduced from Burge, S., Wallis, D. Oxford Handbook of Medical Dermatology (Copyright Oxford University Press 2010).

24 hours. Persistent, painful weals lasting for over 24 hours with residual bruising are a feature of urticarial vasculitis. Exercise-​induced (cholinergic) urticaria and immunological contact urticaria may, on rare occasions, progress to anaphylaxis with symptoms of hypotension and collapse.

Demographics of the disease Statistics on the incidence of urticaria vary widely, depending on the age group studied and subtypes. The lifetime prevalence for all types of urticaria is around 10%, making this one of the commoner inflammatory dermatoses. Urticaria may affect all ages and races. Allergic urticaria is associated with atopy in childhood. CSU is commoner in women than men (2:1), while some forms of inducible urticaria such as delayed pressure urticaria are commoner in men.

Natural history, and complications of the disease If acute urticaria and angioedema are caused by an underlying immediate-​type hypersensitivity reaction, there may be associated systemic features, including bronchospasm and hypotension. CSU often coexists with a inducible urticaria, and both complaints are associated with a significant impairment in quality of life. NSAIDs and dietary pseudoallergens may exacerbate chronic urticaria.

Approach to diagnosing the disease A careful history should be taken in patients with acute urticaria to identify any possible infective, dietary, or drug trigger. This may include over-​the-​counter medication. In chronic urticaria, enquiry about physical triggers and the duration of individual wheals is

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Table 251.1  Typical duration of individual wheals in urticaria Type of urticaria

Typical duration of individual wheals

Physical urticaria

From minutes up to 2 hours

Delayed pressure urticaria (delay of 30 min to 12 hours)

From >24 hours to several days

Chronic spontaneous (idiopathic) urticaria

From 2 hours to 12 hours

Urticarial vasculitis

From 24 hours to several days

essential, as this will help distinguish the different types of urticaria (see Table 251.1). Dermographism can be easily demonstrated as an exaggerated and pruritic wheal-​and-​flare response by firmly stroking the skin with a blunt, fine-​tipped object such as an orange stick.

CHAPTER 251 Urticaria

Other diagnoses that should be considered Other intensely pruritic skin complaints include eczema, scabies, and insect bites. In these conditions, individual lesions persist for days to weeks and are usually excoriated. Bullous pemphigoid should be considered in elderly patients who present with fixed urticarialike plaques and in pregnant women with an urticarial rash over the abdomen. Drug rashes may resemble urticaria, but lesions are typically polymorphic and persistent. A  characteristic feature of acute eczema/​dermatitis is that inflamed skin takes days to settle and resolves with surface changes of dryness and flaking. Urticarial vasculitis is characterized by tender, long-lasting weals that leave bruising.  Recurrent non-​ pruritic weals with arthralgia, fever, and a raised erythrocyte sedimentation rate are features of auto-inflammatory disease such as  Schnitzler’s syndrome, which is associated with an underlying IgM gammopathy. Angioedema without urticaria may be a feature of hereditary or acquired C1-​esterase inhibitor deficiency. It may also be induced by angiotensin-​converting-​enzyme inhibitors and can present many months after commencing the drug.

‘Gold-​standard’ diagnostic test Diagnostic tests are not usually required for urticaria, as the appearance is characteristic. In atypical cases, a skin biopsy can be helpful, especially to exclude urticarial vasculitis. Provocative testing can be carried out for inducible urticaria, for example the ice cube test for cold urticaria, and solar simulator exposure for solar urticaria.

Other relevant investigations For inducible urticaria, no specific tests are required, with the exception of cold-​urticaria, where underlying viral infections and coagulopathy should be excluded. The routine investigations for CSU are full blood count, erythrocyte sedimentation rate, thyroid function tests, and thyroid autoantibodies.

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In patients with a suspected underlying immediate-​type allergy, further investigation with serological tests to measure antigen-​specific IgE levels or with skin prick testing is indicated.

Prognosis, and how to estimate it The prognosis depends on the underlying cause. Acute urticaria is usually an isolated and short-​lived event, unless there is an unidentified allergen which is not avoided, in which case recurrent exposure can lead to further intermittent attacks. The prognosis for CSU is variable. Studies have shown complete resolution in about a third of patients within 1–​5 years, and partial improvement in another third. Patients who are under the age of 30 and have more severe symptoms and physical triggers fare less well. Associated angioedema is also a marker of chronicity.

Treatment and its effectiveness Patients with acute urticaria and anaphylaxis require emergency management of this condition (see Chapter  75). Acute urticaria without systemic symptoms should be treated with oral antihistamines. Second-generation oral H1 antihistamines are the treatment of choice for CSU and inducible urticaria, as they are generally non-​sedating at standard dosages, due to improved receptor selectivity and poor permeability across the blood–​brain barrier. They are usually effective at reducing weal duration and pruritus. The aim is symptom control and they can be prescribed at increased doses in refractory cases. Simple advice includes wearing loose soft clothing, keeping cool, and avoiding alcohol because of its vasodilatory effects. Disease severity should be quantified for example with the UAS7 score and the dermatology life quality index. In patients with uncontrolled disease, addition of oral H2 antihistamines or leukotriene-​receptor antagonists have been advocated but evidence for their effectiveness is limited. In a minority of patients, chronic urticaria runs a severe, recalcitrant course and may justify additional  treatment with immunosuppressive drugs such as ciclosporin or methotrexate or the anti-IgE biological drug omalizumab which is licensed for severe CSU in patients aged 12 years and older. Corticosteroids, while effective for acute disease control, should be avoided for long-​term treatment because of their adverse effects. Low-​salicylate or additive(pseudoallergen)-​free diets have been advocated for chronic ordinary urticaria and may help a minority of individuals.

Further Reading Powell RJ, Leech SC, Till S, et al. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy 2015; 45: 547–​65. Zuberbier T, Aberer W, Asero R, et  al. The EAACI/GA(2) LEN/ EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014; 69: 868–​87.

252 

Bullous disorders

Emily Davies

Introduction

a slight female predominance. They typically present in old age and in preschool children, respectively.

This chapter focuses on immunobullous diseases. Please refer to Chapter 69 for all other causes of bullous disorders.

Dermatitis herpetiformis

Definition of the disease The immunobullous disorders are a group of diseases in which pathogenic autoantibodies bind to target antigens either in intra-​ epidermal desmosomes (intercellular adhesion junctions) or in part of the basement membrane zone, resulting in loss of adhesion, and blister formation. The immunobullous disorders can be categorized by the level of blister formation (see Table 252.1). This chapter will mainly focus on the following disorders:  pemphigus vulgaris and pemphigus foliaceus; bullous pemphigoid; linear IgA disease and chronic bullous disease of childhood (CBCD); and dermatitis herpetiformis; it will also make mention of mucous membrane pemphigoid, pemphigoid gestationis, and epidermolysis bullosa acquisita.

Demographics of the disease Pemphigus vulgaris and pemphigus foliaceus Pemphigus is a chronic, blistering disorder affecting people of middle age (40–​60 years). It has an equal sex distribution and affects all races, but pemphigus vulgaris is commonest in those of Jewish ancestry. Pemphigus folicaeus is very rare in the UK. Endemic pemphigus foliaceus (Fogo Selvagem) is common in parts of Brazil. It can be induced by some drugs.

Bullous pemphigoid Bullous pemphigoid is a chronic, blistering disease affecting elderly people, usually with onset after the age of 60. Children can occasionally be affected. It is slightly commoner in men. Studies have found a higher frequency of neurological conditions such as multiple sclerosis in patients with bullous pemphigoid. It is the commonest immunobullous disease in Western Europe (2 per 100,000). Occasionally, it can be drug induced.

Linear IgA disease and CBCD Linear IgA disease and CBCD are chronic, blistering diseases of adults and children, respectively. They are rare (1 per 2 million), with

Table 252.1  Classification of immunobullous disorders by the level at which blisters form Level of blister

Disease

Intra-​epidermal

Pemphigus vulgaris (and foliaceus) IgA pemphigus Drug-​induced pemphigus

Sub-​epidermal

Bullous pemphigoid Linear IgA disease, and chronic bullous disease of childhood Dermatitis herpetiformis Mucous membrane pemphigoid Pemphigoid gestationis Epidermolysis bullosa acquisita Drug induced

Dermatitis herpetiformis is a rare, chronic, recurrent blistering disorder (1 per 15 000 in the UK). It affects all ages and has an equal sex distribution. Ireland has the highest incidence, with 600 per million people affected. It may be associated with coeliac disease.

Aetiology of the disease The autoantibodies in patients with these disorders play a pathogenic role in inducing blister formation. The target antigens for many of these conditions have now been identified (see Table 252.2).

Typical symptoms of the disease, and less common symptoms Pemphigus vulgaris and pemphigus foliaceus Pemphigus vulgaris usually presents with painful erosions of the oral mucosa. Over 50% of patients also have cutaneous involvement with widespread flaccid blisters and erosions. The nasal and genital mucosae, the conjunctivae, and the oesophagus may also be involved. Pemphigus foliaceus tends to be less severe than pemphigus vulgaris with a more insidious onset. Patients present with crusted, scaly lesions affecting the face, scalp, and upper trunk. Blisters are not usually seen as they are small and flaccid and easily rupture. There is no mucous membrane involvement, and the lesions heal without scarring.

Bullous pemphigoid Bullous pemphigoid often presents with a prodrome of pruritus (may last for months), followed by development of urticated papules and plaques, and then tense bullae, on either erythematous or normal skin. Blisters most frequently appear on the central abdomen and limbs, often favouring the flexures. There may be mucosal involvement (usually the mouth), with blisters and erosions. The patient is systemically well.

Linear IgA disease and CBDC In children, there is often an abrupt onset of CBDC. The rash affects the perineum, vulva, face, trunk, and limbs. The rash consists of annular polycyclic lesions with blistering around the edge, termed the ‘string of pearls’ sign. The onset of linear IgA disease in adults may be insidious, but is usually abrupt. The trunk is always involved, but the limbs, face, and scalp are also commonly affected. The characteristic ‘string of pearls’ appearance is less common. Pruritus in both age groups varies considerably. Blisters may arise from normal skin, and mucosal involvement is frequently seen.

Dermatitis herpetiformis Dermatitis herpetiformis is an intensely pruritic, recurrent disease with a symmetrical distribution, and predilection for the extensor surfaces of knees, elbows, shoulders, and buttocks. Upon examination, only erosions may be seen. All patients have an underlying gluten-​sensitive enteropathy, but this may be asymptomatic.

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Table 252.2  The target antigens in immunobullous disorders Disease

Blister

Target antigen

Direct immunofluorescence

Indirect immunofluorescence

Pemphigus vulgaris

Intra-​epidermal

Desmoglein 3 +/​− 1

Intercellular deposition of IgG +/​− C3

Positive

Pemphigus foliaceus

Subcorneal

Desmoglein 1

Intercellular deposition of IgG +/​− C3

Positive

Bullous pemphigoid

Sub-​epidermal

BP180 BP230

Linear deposition of IgG +/​− C3

Positive

Linear IgA disease, and chronic bullous disease of childhood

Sub-​epidermal

LAD285 BP180 BP230 Collagen VII

Linear deposition of IgA

Positive

Dermatitis herpetiformis

Sub-​epidermal

Tissue transglutaminase

Granular deposition of IgA

Negative

CHAPTER 252  Bullous disorders

Natural history, complications of the disease, and prognosis The severity and disease duration of pemphigus vulgaris is variable. Disease activity usually decreases with time. The mortality is between 5% and 15%. This is related to disease severity, dose of prednisolone used for treatment, and comorbidities. The mortality rate was much higher before the use of corticosteroids. Pemphigus foliaceus is a much more benign, chronic disease. It responds well to treatment and may remit. Bullous pemphigoid is a chronic, self-​limiting disease with exacerbations and remissions. It is associated with significant morbidity and has a marked impact on a patient’s quality of life. There is also an increased mortality rate in elderly patients, probably related to side effects from steroids and immunosuppressive agents. Most cases of linear IgA disease and CBDC spontaneously remit after 3–​6  years. The vast majority of childhood cases resolve by puberty. In contrast, dermatitis herpetiformis is usually a lifelong condition and spontaneous remissions are rare (up to 10%). In all these disorders, possible complications of cutaneous blistering may occur, such as secondary bacterial infections and scarring. Oral involvement can lead to severe pain and subsequent restriction of dietary intake and poor oral hygiene. The mouth and genital mucosa may become secondarily infected with candida.

Approach to diagnosing the disease The clinician should take a history, including a detailed enquiry about the blisters, time course, any preceding itch or rash, previous episodes, and areas affected. A  past medical history, a detailed drug history, a family history, and a systems enquiry including any gastrointestinal symptoms should be recorded (dermatitis herpetiformis). This should be followed by a thorough examination of the skin, hair, nails, and mucous membranes; look for blisters, excoriations, erosions, and evidence of scarring and/​or secondary infection.

Other diagnoses that should be considered The differential diagnosis for these conditions includes all causes of immunobullous disorders as well as other causes of blistering such as bullous impetigo and bullous erythema multiforme. Patients who have pemphigus but who only have oral involvement should have aphthous ulcers, herpes, mucous membrane pemphigoid, lichen planus, and erythema multiforme excluded. In the non-​bullous phase of bullous pemphigoid, conditions such as eczema, scabies, and drug reactions should be considered. CBDC has sometimes been misdiagnosed as sexual abuse in cases with vulval involvement. Bullous drug reactions, as well as drug-​induced pemphigus/​bullous pemphigoid should be considered.

‘Gold-​standard’ diagnostic test All patients should have a skin biopsy performed. An incisional skin biopsy should be taken through an intact blister for histopathology. The level of the split (subcorneal, intra-​epidermal or suprabasal) will help indicate possible diagnoses. The inflammatory infiltrate should

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also be recorded. A  sample of perilesional, uninvolved skin should also be taken for direct immunofluorescence to look for deposition of immunoglobulins/​complement.

Acceptable diagnostic alternatives to the gold standard Indirect immunofluorescence is performed on serum or blister fluid and detects circulating immunoglobulins/​complement. If a skin biopsy is not appropriate in a particular patient, this test will aid with diagnosis, depending on the pattern and type of immunoglobulin/​complement deposition. This test is negative in dermatitis herpetiformis.

Other relevant investigations All patients should have baseline blood tests performed, including a full blood count to assess for anaemia and evidence of any infection (elevated white-​cell count). A  swab should be taken if infection is suspected.

Treatment and its effectiveness The general principle of treating immunobullous disease is to make the patient comfortable with the lowest dose of immunosuppression required. Most morbidity and mortality is from treatment rather than the disease and this has to be weighed up when making management decisions. In some patients, disease can be managed with superpotent topical steroids in combination with anti-​inflammatory agents, such as a tetracycline, erythromycin, or nicotinamide. Many cases require oral steroids. In most cases of bullous pemphigoid, oral prednisolone (0.5–​1 mg/​kg) will control the disease within a couple of weeks. When control is established, steroids should be tapered very slowly to avoid relapse. In those patients with more resistant disease and who are unable to come off steroids, an additional immunosuppressive agent, such as azathioprine or mycophenolate mofetil, is added. Pemphigus is often more challenging to treat and therefore more frequently requires the addition of azathioprine or mycophenolate mofetil. Oral disease should be managed with good oral hygiene, topical antiseptics, and topical steroids (sprays/​gels/​mouthwashes). Any superimposed candida infection should be treated with oral fluconazole. Treatment of dermatitis herpetiformis is usually with a combination of dapsone and a gluten-​free diet. Pruritus is relieved within a couple of days of commencing dapsone, but the lesions will rapidly return if it is stopped. Dapsone has no effect on the enteropathy. Haemolysis and methaemoglobinaemia are present in virtually all patients on dapsone, although these are usually tolerable. Patients on a strict gluten-​free diet may be able to reduce their dapsone dose or stop it completely. Sulfapyridine is used as an alternative in those patients who are unable to tolerate dapsone. All patients should be referred to gastroenterology. Erythromycin is now used as the first-​line treatment for CBDC. Those who do not respond require dapsone therapy. Dapsone or sulphapyridine are used to treat linear IgA disease.

Any patient with a suspected immunobullous disorder should be referred to dermatology for specialist investigation and treatment, although long-​term management is often with a multidisciplinary team.

recur with subsequent pregnancies. Treatment is with topical or oral corticosteroids.

Other bullous disorders

Epidermolysis bullosa acquisita is an extremely rare chronic blistering disorder with trauma-​induced blistering. Scarring and deformities can result and treatment is difficult.

Mucous membrane pemphigoid is a rare, chronic blistering disease which usually affects middle-​aged or elderly people. It is predominantly a mucosal disease, most frequently affecting oral and conjunctival mucosa. Scarring can result in blindness. It runs a varied course and is often very treatment resistant. Patients should be managed by a multidisciplinary team, including ophthalmologists and oral surgeons. Oral and topical corticosteroids in combination with azathioprine or mycophenolate mofetil are used.

Pemphigoid gestationis Pemphigoid gestationis is a rare blistering disorder, which occurs in association with pregnancy. The average onset is around 21 weeks gestation. The rash initially affects the periumbilicus and then spreads to involve the trunk, palms, and soles. The rash consists of urticated papules, plaques, and blisters. It usually remits after delivery, but can

Further Reading Roujeau JC, Lok C, Bastuji-​Garin S, et al. High risk of death in elderly patients with extensive bullous pemphigoid. Arch Dermatol 1998; 134: 465–​9. Schmidt E and Zillikens D. The diagnosis and treatment of autoimmune blistering skin diseases. Dtsch Arztebl Int 2011; 108: 399–​405. Stanley JR and Amagai M. Pemphigus, bullous impetigo, and the staph­ ylococcal scalded-​skin syndrome. N Engl J Med 2006; 355: 1800–​10. Venning VA, Taghipour K, Mohd Mustapa MF, et al. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol 2012; 167: 1200–​14. Wojnarowska F, Kirtschig G, Highet AS, et  al. Guidelines for management of bullous pemphigoid. Br J Dermatol 2002; 147: 214–​21.

CHAPTER 252  Bullous disorders

Mucous membrane pemphigoid

Epidermolysis bullosa acquisita

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253 

Hair disorders

David de Berker

Inflammatory scalp diseases Definition of inflammatory scalp diseases Inflammatory diseases of the scalp can affect all epidermal surfaces or focus upon the follicle, with relative sparing of the interfollicular skin. Eczema and psoriasis are examples of the former; they affect the scalp in the manner of affecting skin elsewhere. The process is non-​scarring in most instances, unless associated by bacterial infection. Other diseases, such as lichen planopilaris (LPP) or discoid lupus erythematosus (DLE) have a greater propensity to inflame the follicle than to cause inflammation in the surrounding skin. They can cause scarring. Some other follicular diseases, such as the family of diseases based on alopecia areata (alopecia areata (small areas of hair loss), alopecia totalis (whole scalp), and alopecia universalis (whole body)), cause barely visible follicular inflammation which results in hair loss but no scarring.

Aetiology of inflammatory scalp diseases Eczema and psoriasis are lymphocyte-​mediated diseases with significant inherited components. Atopic eczema is closely allied to mutations in the gene for filaggrin, an intermediate filament that contributes to the barrier structure of skin. In addition, there is a link with increased concentration and activity of IgE. DLE and lichen planus are also lymphocyte mediated, characterized by a histological picture of lymphocytes interacting with the basal layer of the epidermis and causing keratinocyte death. Where this is associated with substantial damage to the basement membrane zone, there may be scarring. In some with DLE, sunlight plays an exacerbating factor. Alopecia areata and related conditions are characterized by lymphocyte attack on the hair bulb—​the deepest component of the hair follicle. Hair follicle function is halted by the attack, and the hair is lost. However, once the attack subsides, hair growth may recommence.

Typical symptoms of inflammatory scalp diseases, and less common symptoms Eczema and psoriasis may present with itch, where scaling is particularly prominent in the latter. In some psoriatics, scale may build up to large, aggregated clumps of keratin matting the hair. In those with eczema, it is more likely to be exudative, especially if there is substantial itch which attracts scratching and secondary infection. In such instances, there may be regional lymphadenopathy. Scale and itch are less prominent with DLE and LPP, although new areas or disease activity may initially be indicated by slight itch. Symptoms are typically absent from those with alopecia areata, although, when there is rapid onset of severe disease, patients will often describe a preliminary tingling or slight discomfort of the scalp. All of these diseases may present at other body sites with associated features characteristic of the diagnosis.

Demographics of inflammatory scalp diseases Atopic eczema is most common in childhood, dropping to about 10% prevalence in adults, with a slight preponderance in women. Psoriasis is slightly more common in women than men, with a peak presentation age in the twenties. It is more common in Caucasians, with a prevalence in Western societies of about 2%. LPP is most common in women between the ages of 40 and 65. DLE is most common between the ages of 20 and 40 and seen twice as often in women as men. There is a slight excess in those

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of African origin over other races, with an overall prevalence of approximately 0.02%. Alopecia areata can occur at any age or race and has no clear gender preference, with a prevalence of 0.1%–​0.2%.

Natural history of inflammatory scalp diseases, and complications of these diseases Eczema wanes with emerging adulthood, but then deteriorates again with senescence and the loss of skin barrier function. Psoriasis is less common with age, but may still present in the elderly. Neither cause scarring and so, with disease fluctuation, the scalp can return to normal during remission. With DLE and LPP, areas of more intense inflammation are associated with scarring, which means that remission leaves areas of permanent alopecia. Treatment aims to abbreviate and diminish the intensity of episodes of inflammation so that follicles are not lost. A single area of alopecia areata is said to have an 80% chance of remission. This is not the same as saying that the disease itself will fully remit, and patients often suffer intermittent periods of variable hair loss. The prognosis of recovery is inversely proportional to the amount of hair lost and the duration of its loss.

Approach to diagnosing inflammatory scalp diseases Diagnosis is performed by assessing for local signs in the context of the history, and for signs elsewhere on the skin (see Table 253.1).

Other diagnoses that should be considered aside from inflammatory scalp diseases Fungal scalp infection is the main differential for scalp disease where there is scaling and hair loss. This is most common in children, but can also present in adulthood. Folliculitis decalvans is an alternative scarring alopecia and usually presents with pustules mixed in with foci of hair loss and tufts of residual hair clumped into aggregated follicular opening.

‘Gold-​standard’ diagnostic test for inflammatory scalp diseases The gold-​standard diagnostic test for inflammatory scalp disease is a scalp biopsy; ideally, this should be done using a ‘double-​punch’ technique, where two 4 mm punch biopsies are taken and prepared for sections in the horizontal and vertical axes. Where DLE is suspected, half of a vertically bisected punch should be sent fresh for immunofluorescence.

Acceptable diagnostic alternatives to the gold-​standard test for inflammatory scalp diseases Often, the history and clinical examination provides a fully adequate basis for diagnosis with no histology. In any condition where there is scaling and uncertainty, scalp scale and hair should be sent for mycology. A biopsy of an affected body site may be a substitute in some instances.

Other relevant investigations for inflammatory scalp diseases DLE can merge with SLE, either at presentation or with time. It is useful to test for autoantibodies (e.g. antinuclear antibodies, anti-​ double-​stranded DNA antibodies, extractable nuclear antigen antibodies) to establish the antibody status at the outset. Where hair shedding accompanies any disease, it is advisable to check the full blood count, ferritin level, and thyroid function. The latter may be

Table 253.1  Diagnosis of inflammatory diseases Disease

History

Local signs

Signs at other sites

Eczema

Family history common Atopy: asthma, hay fever, contact allergy

Redness Light scale Sometimes crust

Eczema at other sites, particularly the flexures if atopic Skin may be dry if the patient is elderly

Psoriasis

Family history common May have joint problems

Silvery scale that can build up and become matted Rash in patches and within and behind ears

Nail changes and rash on extensor surfaces

Discoid lupus erythematosus

50% have deterioration in bright sunlight Scalp irritation

Discoid red or purplish areas in scalp with prominent follicles as well as some rash between follicles Central zones may have scarring

Similar less follicular discoid patches may be seen at other sites and, in particular, on the head and neck

Lichen planopilaris

Scalp itch Progressive hair loss

Small cuff of redness and slight scale around the follicular openings in a zone of scalp which may be discoid or at a hair margin Pale scarred areas in zones of previous disease

Rarely have lichen planus at other sites, such as mucosae of mouth and genitals, or skin lichen planus on the wrists or other sites

Alopecia areata

History of previous episodes which have spontaneously remitted Family history in 20% of cases

Hair shed from circumscribed area with normal follicular openings May leave white hairs behind in early stages, or demonstrate regrowth of white hairs first with recovery Exclamation mark hairs seen at margins

Other patches of alopecia areata can be found at other body sites, such as the beard area, eyebrows, eyelashes, or limbs Nails can be involved, with pitting or a roughened surface and discoloration Alopecia totalis is the loss of all scalp hair Alopecia universalis is the loss of all body hair

Prognosis for inflammatory scalp diseases, and how to estimate it Scalp eczema and psoriasis are chronic relapsing and partially remitting conditions. They are unlikely to go away completely unless there is systemic treatment. However, they can become well controlled. DLE and LPP both demonstrate the tendency to ‘burn out’ after an unpredictable period of activity, causing irreversible hair loss. It is rare to see either disease progress to the extent that it creates substantial baldness, and wigs are rarely needed. Alopecia areata is thought to be worse if there is an onset in childhood and possibly worse if there is associated atopy. Overall prognosis is dependant on how much hair is lost—​such severe disease means a poor prognosis.

Treatment of inflammatory scalp diseases, and its effectiveness Scalp eczema and psoriasis can be treated with the same products used on the skin elsewhere—​typically, a range of steroids and, with psoriasis, calcipotriol. Tar and emollient can be used with both diseases, especially psoriasis, where the emollient can help lift scale. Treatments applied in the evening and retained overnight with a shower cap can be very effective. For cosmetic ease, people may choose a vehicle such as a gel, alcohol liquid, or thin emollient base. These do not mess up the hair as much as the heavier cream or ointment bases. Systemic therapy with immunosuppression can be indicated for very severe disease. DLE and LPP both respond to some extent to potent topical steroid, usually applied as a cream or gel as, focally, there is no hair to make greasy. Injected triamcinolone acetonide can be useful, and systemic treatment with hydroxychloroquine can help DLE. Systemic prednisolone or ciclosporin are short-​term options for LPP. Topical and injected steroids are the mainstay of treatment for alopecia areata. Systemic steroid is rarely used due to the high relapse rate and the risks of the treatment if used long term.

Hair shedding: Telogen effluvium and pattern hair loss Definition of hair shedding Some patients present with hair shedding or change of hair pattern as their primary complaint, with no scalp disease. Patterned loss, when manifest, is characteristic of ageing.

Aetiology of hair shedding Shedding is continuous and normal in humans and, in most instances, occurs at a rate of 150 hairs a day. When a significant event increases the proportion of hair follicles entering the resting phase (telogen), then more hairs will be shed. This event can be physiological, for example occurring 1–​3  months after a fever or haemorrhage, and is termed telogen effluvium. Alternatively, it can be toxicological, as with the ingestion of a poison such as a chemotherapy agent. In some instances, it is where a normal medication may have an adverse effect of impairing follicular function, as occurs with some forms of synthetic vitamin A (retinoids). Other patients, without conspicuous shedding, present with an altered pattern of scalp hair. This is usually following a period during which the normal rate of shedding has exceeded the rate of regrowth such that there is an overall decline in scalp coverage. This is the basis for patterned hair loss, which is seen in both men and women. Women are more likely than men to seek medical advice to determine whether there is a cause or treatment for the hair loss.

CHAPTER 253  Hair disorders

particularly relevant to alopecia areata, as they are both thought to share an autoimmune basis.

Typical symptoms of hair shedding, and less common symptoms Hair shedding is noted in the shower and sink and also commented on by social partners. There are rarely any physical associations unless there is a clear recollection of a preceding event or causal medication. Change of hair pattern is usually based on gradual realization.

Demographics of hair shedding All people and ages appear susceptible to telogen effluvium. Men and women suffer patterned hair loss with age, starting as early as mid-​ adolescence. There is a strong but ill-​defined genetic basis. Those of Chinese origin are thought to have less marked patterned balding than those of other origins.

Natural history of hair shedding, and complications of the disease Telogen effluvium evolves 1–​3 months after the event and may take a further 2–​3 months to peak. Return towards normal takes a further 3 months, such that it is common for people to be affected to some extent for a year. Patterned hair loss in men and women may be highlighted by a period of shedding that does not fully reverse. By the age of 70, 70% of men will have significant balding. By menopause, 30% of women will have a degree of male pattern balding with frontal recession. Most of the rest of the women will have some thinning on the crown, but will retain their frontal margin.

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Approach to diagnosing hair shedding A history of shedding is normally clear and substantiated by gently pulling strands of hair on the scalp as part of the examination. If these easily pluck, then it confirms the account. If it does not, it does contradict the account, but may mean that the period of active shedding is passed and regrowth can be anticipated. Diagnosing patterned hair loss is one of recognizing the pattern and ensuring that there are no other features in the history or examination.

Acceptable diagnostic alternatives to the gold-​standard test for hair shedding Biopsy is rarely needed, and clinical assessment usually provides all that is needed.

Further Reading

Other relevant investigations for hair shedding

Harries MJ, Sinclair RD, Macdonald-​Hull S, et  al. Management of primary cicatricial alopecias: Options for treatment. Br J Dermatol 2008; 159: 1–​22. Macbeth A and Harries M. Hair loss in hospital medicine: A practical guide. Br J Hosp Med (Lond) 2012; 73: 372–​9. Miteva M and Tosti A. Treatment options for alopecia: An update, looking to the future. Expert Opin Pharmacother 2012; 13: 1271–​81. Sinclair R, Patel M, Dawson TL Jr, et al. Hair loss in women: Medical and cosmetic approaches to increase scalp hair fullness. Br J Dermatol 2011; 165 (Suppl 3): 12–​8.

Fungal scalp infection can be considered if there is hair breakage or scalp scaling, but is not common in the age group presenting with these problems. Endocrine problems with masculinization can be relevant with androgen-​secreting tumours and will usually present with features such as amenorrhoea, evolution of hirsutism, and altered body habitus. A milder version of this pathology is represented by polycystic ovary syndrome.

‘Gold-​standard’ diagnostic test for hair shedding

CHAPTER 253  Hair disorders

Treatment of hair shedding, and its effectiveness Any medical abnormalities detected should be addressed. Telogen effluvium is self-​ limiting. If medication is thought to play a part (e.g. atenolol, oral retinoids, some anticonvulsants, progesterone-​ containing medication), then alternatives might be sought. Many argue that ferritin should be maintained significantly above the lower range of normal described by most laboratories, such that it is 70 ng/​ml. This may require iron supplementation. Anti-​androgens, such as the oral contraceptive pill with a synthetic progestogen (not norethisterone), cyproterone acetate, or spironolactone, are advocated by some. The potential for iatrogenic disease related to treatment for a normal variant should be considered with these options. Also, the end point of treatment and hence its duration is difficult to determine. In men, finasteride is licensed for use in male pattern balding and can result in some regrowth for 60% of men within 2  years. Over the subsequent 5 years, this improvement tails off, but probably the person will have some additional retained hair for as long as they take the medication. Data on improvement for women with other anti-​ androgens (finasteride is not licensed in women) is not so definite. Topical minoxidil 2% and 5% is available over the counter as a liquid applied twice daily to affected areas for a minimum of 6 months, to be continued as long as any benefit accrued is desired to be maintained. There is technical evidence of increased hair growth in men and women, although the change in front of the mirror is seldom marked.

Other diagnoses that should be considered aside from hair shedding

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there has been a stepped reduction in the bulk and extent of their hair. Prognosis for those with either male or female pattern hair loss is that it will gradually progress with time. Women do not go bald, although, with advanced age, there can be considerable loss of coverage.

In the presence of normal periods and no change in body habitus, the main test for telogen effluvium is the hair pull test. Where multiple hairs come out with the lightest pull, the diagnosis is confirmed. Patterned hair loss is characterized by miniaturization of the hair follicles and their hairs and can be confirmed by scalp biopsy. This needs to be done with horizontal sections of 4 mm punch biopsies in order that the number, hair cycle status, and bore of the hairs can be determined.

Iron deficiency and thyroid disease can be contributory and would normally be checked. Any other investigation would be done on the basis of some relevant part of the history or examination such as a testosterone if there were a degree of hirsutism or altered periods.

Prognosis for hair shedding, and how to estimate it Telogen effluvium has a good prognosis over a 12-​month period. As people age, they may find that the reversal is not complete and

254 

Nail disorders

David de Berker

Definition of the disease Nail diseases present as alteration of the nail plate, alteration of the periungual tissues, or as a combination of the two. Most commonly, external agents, such as fungus or trauma, affect the nail alone, whereas all inflammatory and neoplastic processes affect the surrounding tissues as a primary process giving rise to secondary nail plate alteration.

Aetiology of the disease The most common inflammatory diseases of nail are psoriasis, eczema, and lichen planus, which, in turn, are amongst the most common inflammatory disease of the rest of the skin. The most common infections arise through fungal invasion of the nail plate and the nail bed, which is the skin underlying the nail. Fungi are of two main families, dermatophytes and non-​dermatophytes. For dermatophytes, skin is a natural medium for existence, whereas non-​dermatophytes are more typically found in the soil, but may rarely become pathological to skin, nail, and hair. Trauma represents the third most common cause of nail abnormalities, with an increasing prevalence of traumatic disease affecting toenails as people age. Some trauma is directly upon the nail, made vulnerable through its location on the dorsal distal tip of the toe. Other trauma may be related to foot mechanics, which alter with time. Trauma to fingernails is less commonly a cause of significant dystrophy, outside the specific area of self-​inflicted damage arising from nail biting or a form of self-​mutilation known as onychophagia. Both benign and malignant neoplasia can present with nail changes. The former cause a space-​occupying effect, distorting the position of the nail. If the mass is proximal and pressing on the nail matrix, then it will alter the nail during its creation. More distal or lateral tumours will impinge on the nail following generation and will usually just alter its position. Glomus tumours, subungual exostoses, or periungual fibromas of the type seen in tuberous sclerosis can be found in either location. Malignancy of the nail unit presents as squamous cell carcinoma or malignant melanoma. The former is typically in situ in the first instance and has a very long prodrome before invasion. HPV 16 and 18, seen in genital squamous cell carcinoma, can be present. Malignant melanoma of the nail unit is rare and represents about 2% of all melanoma, with an incidence in the UK of 1 per million population per year. It is diagnosed later than melanoma on other skin sites and, consequently, is usually deeper and has a worse prognosis.

Typical symptoms of the disease, and less common symptoms All nail disease evolves from minor changes in appearance to more major alterations of nail integrity. Depending on the focus and inflammatory basis of the disease, there may be associated pain and loss of function. Onychomycosis is mainly associated with asymptomatic thickening and white-​to-​yellow nail discoloration extending from the distal edge. Less common diseases present with features such as sterile pustulation in psoriasis or chronic ooze from beneath the nail for a squamous cell carcinoma of the nail bed. Malignant melanoma most commonly presents initially as a dark longitudinal streak in the nail in a pale-​skinned person. When someone has a single such streak, it warrants close and expert assessment.

An important factor in any presentation of nail disease identifying a pattern. Disease that affects multiple digits is more likely to yield significant clues at other body sites. For psoriasis, the presence of pits in the nail, lifting of the nail (onycholysis), and nail thickening may be corroborated by scaling on the elbow, on the scalp, and in the ears. For eczema, the presence of itching and a typical rash at other body sites may illustrate the disposition. Conversely, if the pathology is limited to a single digit, then neoplasia or infection is more likely and, given that some neoplasias can be malignant, it is important to obtain a clear diagnosis.

Demographics of the disease Different nail diseases have their own demographic. Eighty percent of patients with psoriasis of the skin will develop nail psoriasis at some point in their lives, but only 30%–​40% will have it at any one time. It is not common in childhood and becomes particularly prevalent amongst those patients who have psoriatic arthritis of the distal interphalangeal joints. The demographic for eczema of the nail is only partly related to the peak of atopic manifestation. Whereas the latter occurs mainly in childhood, it is common for irritant and occupational factors to become major factors once people enter the workforce and are subject to repetitive activities, like wet work or building, that disturb periungual skin. Fungal nail infection (onychomycosis) is mainly a disease of middle age and beyond. It is more common in subgroups where there is a predisposing factor, such as psoriatics, the immunosuppressed, or those with damage to the nail. The accumulation of damage to the nail is a feature of time, so onychomycosis increases in prevalence in the elderly. Malignancy of the nail primarily is seen in those 40 and older. However, immunosuppression predisposes to squamous cell carcinoma, in which case people may present with malignancy of the nail at an earlier age.

Natural history, and complications of the disease All the inflammatory diseases are fluctuating, except for those with scarring potential, such as lichen planus, where the nail matrix and, consequently, the nail plate may be permanently lost. Onychomycosis is gradually progressive such that it will usually destroy a nail plate over 20 or more years, or immunity may hold it in check. Malignancy of the nail is slow to progress in most instances, save for where nodular variants present at the outset or evolve on the background of indolent disease. In such instances, the outcome can be fatal, especially for melanoma, where 5-​year survival rates are reported at around 50%–​70%.

Approach to diagnosing the disease Diagnosis is by assessment for characteristic signs within the digit, all other digits, and the rest of the skin. Some diseases may give clues through other systems, such as the joints for psoriasis, or asthma for atopic eczema. Where onychomycosis is a potential diagnosis, generous clippings of nail and subungual debris should be obtained for mycological examination and culture. It is only with the results of this that the clinician is equipped to prescribe oral antifungal medication. The presence of fungus does not rule out coexisting disease. Where pathology presents with a single digit, the author would advocate close attention to detail in order to not miss malignancy or some treatable structural abnormality. This objective may entail imaging

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with all soft tissue and bone modalities and taking an incisional diagnostic biopsy under local anaesthetic.

Other diagnoses that should be considered Some nail changes are manifestations of systemic disease. Examples include clubbing, splinter haemorrhages, and paraneoplastic changes within the nail unit. The latter may mimic psoriasis, but come about through internal malignancy. Hence, anyone presenting with a marked inflammatory change in their nails, usually in later life, in the absence of an obvious cause, should be assessed for internal malignancy.

‘Gold-​standard’ diagnostic test

CHAPTER 254  Nail disorders

If there were one test that the clinician could do, and no other, then it would be the incisional biopsy. However, usually there is enough information from the clinical examination and history, supplemented by a generous mycology sample, to conclude the diagnosis. In widespread nail disease, when a diagnosis cannot be made, it may be warranted to take a diagnostic biopsy in order to ensure that any proposed systemic therapy is appropriate. Such therapies are usually immunosuppressant and may be intermittently long term with side effects. To give such treatment without a clear diagnosis would be questionable. For diagnosis of the single digit, it is possibly more understandable to resort to biopsy, given the risk of malignancy. Who does the biopsy, what pattern of biopsy is done, and who interprets the histology make a difference. It is best that such tests are undertaken by those who do them frequently.

Acceptable diagnostic alternatives to the gold standard Clinical acumen with only marginal confidence may be adequate when balanced against complete confidence. This holds as long as the sequelae of the proposed treatment are not problematic, or as long as the significance of the diagnosis being missed because of a failure to obtain histological certainty is not a grave one. Mycology should be undertaken several times to ensure that fungus is not missed, as laboratory standards acknowledge a false-​negative rate for mycology of the nail at around 40%.

Other relevant investigations Skin biopsy or mycology of abnormal non-​nail tissue can sometimes provide enough information to give confidence to the interpretation of the nail problems.

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Prognosis and how to estimate it The prognosis of non-​scarring nail disease is that it will progress at approximately the same rate as that of the skin disease at other sites. It will fluctuate and respond well but variably to treatment. Compliance with treatment plans will make a difference and, typically, people tire of prolonged regimens of hand care and topical therapies. The prognosis of scarring nail disease will depend upon the natural aggressiveness of the disease and the intensity of immunosuppression. At times, the consequences of treatment will not be acceptable. Dermatophyte onychomycosis is cured in about 60% of people after systemic treatment but in more like 20% of those who have milder disease eligible for topical therapy. However, topical therapy may hold the disease back and render it manageable. Relapse after systemic therapy is about 20% over 5 years.

Treatment and its effectiveness Hand and foot care is important in all nail diseases, save possibly malignancy. It entails keeping nails short, using copious amounts of emollient, and wearing gloves during wet work. Where toenails are involved, this may be achieved for the elderly with the help of a podiatrist and carefully fitted footwear. Topical treatments for psoriasis are calcipotriol ointment with or without betamethasone valerate or dipropionate. This is applied to the affected periungual area; at times, in order to do this, the nail plate may have to be clipped back to expose the nail bed. For eczema, the steroid alone may be sufficient. In resistant cases, it is possible to inject steroid into the nail matrix. Systemic therapy is as for the disease in general, and the most successful for psoriasis has been ciclosporin or biologics such as infliximab and etanercept. Onychomycosis is usually treated with oral terbinafine, although there is a significant side-​effect profile that includes liver failure. Death has been reported. Malignancy is treated with surgery and, in more advanced cases, this may require distal or ray amputation to ensure adequate clearance.

Further Reading Braun RP, Baran R, Le Gal FA, et al. Diagnosis and management of nail pigmentations. J Am Acad Dermatol 2007; 56: 835–​47. de Berker D. Clinical practice. Fungal nail disease. N Engl J Med 2009; 360: 2108–​16. de Berker D. Management of psoriatic nail disease. Semin Cutan Med Surg 2009; 28: 39–​43.

255 

Mucosal disease

Kathy Taghipour

Pemphigus vulgaris Definition of pemphigus vulgaris Pemphigus vulgaris is an autoimmune disease that affects the skin and the mucosal membranes with blisters and erosions.

Aetiology of pemphigus vulgaris In pemphigus vulgaris, autoantibodies target components of desmosomes, the structures that provide cell-​to-​cell adhesion in the skin. An intra-​epidermal cleavage results from this immune reaction, leading to blister formation.

Typical symptoms of pemphigus vulgaris, and less common symptoms In pemphigus vulgaris, flaccid and thin-​walled blisters and/​or erosions are present on the skin and mucosal membranes, including in the oropharynx and the genital area. The oral lesions often present on buccal and palatal mucosa and are painful.

Demographics of pemphigus vulgaris Pemphigus vulgaris commonly affects individuals in their middle age. The incidence in the UK is 7 per million per year and both sexes are equally affected. It is more common in Eastern Europe, Middle East, India, and amongst Ashkenazi Jews, and certain HLA associations have been described.

Natural history of pemphigus vulgaris, and complications of the disease The clinical course of pemphigus vulgaris varies between individuals but, in most cases, immunosuppressive treatment is required for years to control the disease. Painful mouth lesions may lead to malnutrition. Most complications are, however, related to long-​term treatment with systemic steroids.

Approach to diagnosing pemphigus vulgaris A diagnosis of pemphigus should be considered when patients present with painful, non-​healing oral or genital erosions. A full skin examination is important in confirming the clinical diagnosis. Pemphigus has a predilection for scalp, face, and flexures, although mucosal erosion may be the only presenting sign. A full history of drug intake should be taken to exclude drug-​induced pemphigus.

Other diagnoses that should be considered aside from pemphigus vulgaris Other diagnoses that should be considered aside from pemphigus vulgaris include erosive lichen planus and mucous membrane pemphigoid. Erosive lichen planus presents with erosions of the oral and/​or genital mucosa. It may be associated with a skin rash and white, lacy streaks on buccal mucosa, namely Wickham striae. Mucous membrane pemphigoid is a rare sub-​epidermal bullous disease that leads to erosions and gingivitis in the mouth and may affect the genital mucosa, skin, conjunctivae, and gastrointestinal tract, leaving scars on the affected areas. Drug-​induced reactions such as Stevens–​ Johnson syndrome (see ‘Stevens–​ Johnson syndrome’) should also be considered when the history is suggestive of a recent relevant drug intake, in particular if conjunctivae are involved. Other differential diagnoses include infections and systemic disease (Box 255.1).

Box 255.1  Common disorders that affect mucosal membranes

Infections Viral

herpes simplex • • herpes zoster virus • Coxsackie virus (e.g. hand, foot, and mouth disease) • HIV

Bacterial

gram-​negative bacteria • • anaerobes

Fungal

• candida

Treponemal • syphilis

Skin diseases

erosive/​oral lichen planus • • autoimmune bullous diseases (e.g. pemphigus vulgaris, linear IgA disease, mucous membrane pemphigoid) • erythema multiforme • Stevens–​Johnson syndrome • Sweet’s syndrome • lichen sclerosus et atrophicus of vulva

Systemic diseases Gastrointestinal tract • inflammatory bowel disease • coeliac disease

Rheumatology

SLE • • Behçet’s syndrome • Reiter’s syndrome

Drug induced

chemotherapy • • other drugs (e.g. nicorandil, NSAIDs, angiotensin-​converting-​ enzyme inhibitors)

Malignancy

leukaemia • • squamous cell carcinoma • other malignancies

Iatrogenic

• radiotherapy

‘Gold-​standard’ diagnostic test for pemphigus vulgaris The gold-​standard diagnostic tests for pemphigus vulgaris are immunofluorescence studies on a perilesional skin biopsy (direct immunofluorescence) and on serum (indirect immunofluorescence), to confirm the presence of IgG antibodies in the intercellular space.

Acceptable diagnostic alternatives to the gold-​standard test for pemphigus vulgaris An acceptable diagnostic alternative to the gold-​standard test for pemphigus vulgaris is light microscopy of the lesional biopsy, showing

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rounding and separation of the keratinocytes (acantholysis) and intra-​epidermal cleavage. In addition, circulating antibodies to desmogleins 1 and 3 can be detected with ELISA.

Other relevant investigations for pemphigus vulgaris In pemphigus vulgaris, it is important to have a haematology and biochemistry workup and a relevant infection and malignancy screen before patients are commenced on immunosuppressive treatment. A  baseline bone densitometry scan is useful when long-​term oral steroids are considered.

Prognosis for pemphigus vulgaris, and how to estimate it Prognosis varies amongst individuals but, in general, older patients, patients with extensive disease, and those who require high doses of systemic steroids have poorer prognosis. Relapse and mortality is more common within the first 2–​5  years of diagnosis than at other times.

CHAPTER 255  Mucosal disease

Treatment of pemphigus vulgaris, and its effectiveness In pemphigus vulgaris, topical treatment with steroids and good oral care is important in providing comfort for patients. Systemic steroids provide the mainstay of treatment and are often required to reach disease control. Adjuvant immunosuppressants are usually used while steroids are tapered, and the most common agents include azathioprine, mycophenolate mofetile, and cyclophosphamide. More recently, an anti-​B-​cell monoclonal antibody (rituximab) has been used successfully in refractory disease.

Lichen planus Definition of lichen planus Lichen planus is a cell-​mediated immunological mucocutaneous disease. Oral lichen planus may present with erosions, white streaks, or plaques in the oral cavity.

Aetiology of lichen planus The exact aetiology of lichen planus is unknown. An association with hepatitis C virus has been documented in patients from Italy and is likely to be related to immunogenetics. Mercury in dental amalgam fillings has been suggested as an immunogenic or irritant factor that may trigger oral lichen planus.

Typical symptoms of lichen planus, and less common symptoms Oral lichen planus may be asymptomatic, and the onset may be insidious. It may present with rough plaques, sensitivity to acidic or hot food, soreness of the oral cavity and gums, and erosions and ulceration. A pruritic skin rash consisting of violaceous, flat-​topped papules may be present, and genitals may be affected. Associated frontal alopecia and nail involvement is less common.

Demographics of lichen planus There is no significant racial or geographical preponderance of lichen planus. Oral lichen planus is rare in childhood.

Natural history of lichen planus, and complications of the disease The disease course of lichen planus is chronic, with waxing and waning over years. Stress and anxiety may trigger exacerbation. Squamous cell carcinoma may rarely complicate oral lichen planus.

Approach to diagnosing lichen planus Asymptomatic oral lichen planus is usually detected by dental practitioners. A detailed drug history is important in differentiating lichen planus from lichenoid drug reactions. Examination of skin, scalp, genital mucosa, and nails should be performed to look for other manifestations of lichen planus.

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Other diagnoses that should be considered aside from lichen planus When considering a diagnosis of lichen planus, important differential diagnoses include oral manifestations of autoimmune bullous diseases, contact dermatitis, oral candidiasis, viral infection, and drug reaction.

‘Gold-​standard’ diagnostic test for lichen planus The diagnosis of lichen planus is clinical and can be confirmed with a biopsy from the affected area. The hallmark of the histology is a lichenoid (band-​like) lymphocytic infiltrate at the dermoepidermal junction, and basal cell layer degeneration. Immunofluorescence studies may help differentiate lichen planus from lupus or autoimmune bullous disease.

Acceptable diagnostic alternatives to the gold-​standard test for lichen planus There are no acceptable diagnostic alternatives to the gold-​standard test for lichen planus.

Other relevant investigations for lichen planus There are no other relevant investigations for lichen planus, aside from the gold-​standard test.

Prognosis of lichen planus, and how to estimate it Oral lesions in lichen planus are slow to heal, and complete remission is rare.

Treatment of lichen planus, and its effectiveness The treatment of lichen planus aims at symptomatic relief. Good oral hygiene and well-​fitting dentures to reduce trauma are important aspects of the treatment. Potent topical steroids and steroid oral rinses accelerate the healing, and anaesthetic mouthwash provides pain relief. Extensive ulceration requires systemic treatment with steroids or other agents such as retinoids and ciclosporin.

Stevens–​Johnson syndrome Definition of Stevens–​Johnson syndrome Stevens–​Johnson syndrome is an emergency dermatological condition in which an immunological hypersensitivity causes erosions and inflammation of mucosal membranes and the skin.

Aetiology of Stevens–​Johnson syndrome The main trigger factor for Stevens–​Johnson syndrome is drug intake. Antibiotics (e.g. sulpha-​ group antibiotics and penicillin), NSAIDs, allopurinol, antiepileptics, and some antiretrovirals may cause Stevens–​ Johnson syndrome. Certain HLA classes are associated with increased risk of developing drug-​induced Stevens–​Johnson syndrome. Idiopathic and infection-​related forms of Stevens–​Johnson syndrome are less common.

Typical symptoms of Stevens–​Johnson syndrome, and less common symptoms In Stevens–​Johnson syndrome, non-​specific symptoms such as flu-​like symptoms, fever, and soreness of eyes and throat may precede erosions and blistering of the skin and mucosa. Trunk and face as well as acral skin are most commonly affected, and oral, genital, and conjunctival mucosa are involved. In severe cases, the mucosal lining of the respiratory and gastrointestinal tract are also affected. Detachment of epidermis may be present in 30% of the skin is denuded in addition to oral, genital, or respiratory mucosal involvement. It is important to note that Stevens–​Johnson syndrome may evolve into toxic epidermal necrolysis. Staphylococcal scalded skin syndrome and some autoimmune bullous diseases such as paraneoplastic pemphigus and linear IgA disease may mimic Stevens–​Johnson syndrome.

Mortality in Stevens–​Johnson syndrome is estimated at 1%–​5% and is mainly due to sepsis. Prognosis worsens when erosions and denuded skin involve larger body surface area, and with transition of Stevens–​ Johnson syndrome to toxic epidermal necrolysis. When epidermal detachment occurs over more than 10% of skin surface area, the prognosis and severity of the condition should be estimated with a validated scoring system (SCORTEN) that evaluates age, malignancy, tachycardia, body surface area involved, serum urea, bicarbonate, and glucose. A patient with a SCORTEN score of 3 or above should be managed in intensive care. The outcome improves with early withdrawal of the culprit drug, although drugs with long half-​life are associated with a higher risk of death. The commonest sequelae in survivors of Stevens–​Johnson syndrome are ophthalmological complications.

‘Gold-​standard’ diagnostic test for Stevens–​Johnson syndrome

Treatment of Stevens–​Johnson syndrome, and its effectiveness

In Stevens–​Johnson syndrome, a skin biopsy complements the clinical diagnosis.

Following discontinuation of the causative drug, patients with Stevens–​ Johnson syndrome often require admission and symptomatic treatment. There is no specific treatment for Stevens–​Johnson syndrome, and supportive treatment should address haemodynamic, respiratory, and infectious complications. Topical care of skin, conjunctivae, and oral mucosa provides further symptom relief.

Other diagnoses that should be considered aside from Stevens–​Johnson syndrome

Acceptable diagnostic alternatives to the gold-​standard test for Stevens–​Johnson syndrome There are no acceptable diagnostic alternatives to the gold-​standard test for Stevens–​Johnson syndrome.

Other relevant investigations for Stevens–​Johnson syndrome In Stevens–​Johnson syndrome, in addition to routine haematology and biochemistry tests, skin swabs and blood cultures are useful in

Further Reading Thong BY. Stevens-​Johnson syndrome/​toxic epidermal necrolysis: An Asia-​Pacific perspective. Asia Pac Allergy 2013; 3: 215–​23. Wolff K and Johnson R. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology (6th edition), 2009. McGraw-​Hill Professional.

CHAPTER 255  Mucosal disease

retention, and renal failure are other complications; however, the most common sequelae is damage to the eyes, including symblepharon, corneal ulcerations, and opacities.

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256 

Genital disease

Susan Cooper and Tess McPherson

Definition of the disease The term ‘genital disease’ refers to a spectrum of diseases. Certain systemic diseases preferentially affect mucous membranes. Local factors including warmth, occlusion, irritants, and friction are important and contribute to skin disease in this region and increase risk of certain infections. Skin conditions may be difficult to diagnose as they may have atypical appearances. Therefore, the diagnosis of disease in the anogenital region may be complex. This chapter will focus on the most common genital diseases seen in the dermatology clinic:  lichen sclerosus, lichen planus, eczema, genital pain syndromes, and pre-​malignant and malignant disease. Other less common dermatological conditions seen in this area will be briefly covered.

Definition and aetiology of the most common diseases Lichen sclerosus is a chronic inflammatory disease of unknown aetiology, preferentially affecting the anogenital region. There appears to be a genetic component, with a positive family history in some patients and a relationship with certain HLA types. Lichen sclerosus appears to be related to other autoimmune conditions such as vitiligo and thyroid disease. Lichen planus is a chronic inflammatory disease which affects skin, nails, and mucous membranes. The aetiology is unknown but probably represents T-​cell-​mediated damage to epidermal cells. In patients with genital eczema, a mixed picture of both endogenous (e.g. atopic) and exogenous eczema is frequently seen. Atopic eczema may be associated with history of eczema in other sites or other atopic disease (asthma and hay fever). Contact dermatitis can be due to irritants or allergens and is an important contributor to genital eczema. Allergens seen on patch testing include rubber and fragrance. Haemorrhoid creams and medicated toilet paper are also frequent culprits. Lichen simplex chronicus is chronic dermatitis with skin changes caused by itching/​rubbing. Vulvodynia and scrotodynia may be localized (vestibulodynia) or generalized. These both probably represent a regional pain syndrome.

Typical symptoms of the disease, and less common symptoms There are only a limited number of symptoms in the anogenital area. Therefore, pruritus or itch and pain may be the presenting feature of a wide variety of diseases. Itch and soreness are presenting features of lichen planus, lichen sclerosus, and vulval eczema. The patient may report an abnormal clinical appearance, and this can be primary or secondary to scratching. A normal clinical appearance with localized pain or persistent burning is a presenting feature of vulvodynia and scrotodynia. Depression may be a feature of any chronic pain syndrome.

Demographics of the diseases Lichen sclerosus is more common in females; the female:male ratio is reported to be 6–​10:1. It may occur at any age, but two peaks of onset are during childhood and after menopause. In men, it most frequently occurs in the fourth or fifth decades, with an estimated prevalence of 1 in 660.

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Like lichen sclerosus, lichen planus is more common in females. It can present any time but is more common in the sixth decade. In the UK, lichen planus accounts for around 1% of referrals to dermatologists. Dermatitis is an extremely common condition, with a lifetime risk of over 30%.

Natural history, and complications of the disease Lichen sclerosus, lichen planus, and vulval eczema can be chronic or resolve after a period of time with or without treatment. An important complication of lichen sclerosus and lichen planus is an increased risk of malignancy.

Approach to diagnosing the disease In diagnosing genital disease, a full history of symptoms and their time course is required. Examination of all skin, as well as the mouth and nails, can lead to a clinical diagnosis and help differentiate between conditions that may present similarly in the genital area. Full examination of the mouth is essential and can show typical features of lichen planus (white lacy streaks on buccal mucosa) or evidence of other conditions, such as autoimmune bullous disorders. The nails and the scalp should be examined for evidence of lichen planus or psoriasis. Additionally, the presence of other autoimmune conditions, such as vitiligo, may be associated with lichen sclerosus. Other areas affected by dermatitis would be relevant. Lichen sclerosus preferentially affects the genitals and only rarely affects other cutaneous sites. On examination of the anogenital area, clinical findings for lichen sclerosus include pallor, atrophy, fissures, and foci of hyperkeratosis. Scarring may cause loss of architecture. Genital lichen planus can be seen with or without cutaneous disease; 50% of women with cutaneous lichen planus, and 25% of men with cutaneous lichen planus, have genital involvement. The most frequent finding is the classical violaceous papules and plaques on the labia minora and majora in woman, and on the glans or the shaft of the penis in men. Erosive lichen planus is a distinct subtype characterized by severe, scarring, erosive disease of the vestibule, the introitus, the vagina, and the oral cavity. Lacy white streaks, as seen orally, may be seen in these areas as well. Hypertrophic and lichen planopilaris are the least frequent forms of this disease. Genital eczema appearances range from mild erythema to extreme thickening and lichenification. Typical sites affected are the labia majora and the mons pubis in women, and the crura and the scrotum in men. Pain on examination may be feature of vulvodynia. This typically has normal clinical findings but there is overlap of some syndromes, and patients with lichen sclerosus may have vulvodynia. A skin biopsy of lesional (abnormal) tissue can be very useful in clarifying the clinical diagnosis. In particular, it is useful for distinguishing between an interface dermatosis, such as lichen planus and lichen sclerosus, and a spongiotic dermatitis, such as dermatitis. Histological analysis is also vital to distinguish malignant from inflammatory conditions. Perilesional skin can be biopsied for immunofluorescence if an autoimmune blistering disorder is suspected. Swabs may be important for diagnosing candida infection, which can complicate all anogenital pathology.

Other diagnoses that should be considered

Fixed drug eruption

If there is any clinical doubt when diagnosing genital disease, a biopsy will help differentiate between diagnoses.

A fixed drug eruption presents as recurrent, erythematous, blistered or eroded plaques that, upon exposure to the drug, recur at exactly same site.

Other causes of pale patches/​plaques in genital disease include morphoea and vitiligo. Morphoea presents with hypopigmented atrophic plaques. Vitiligo presents with asymptomatic hypopigmented patches. There may be cutaneous lesions elsewhere.

Other causes of erythematous patches/​plaques Pre-​malignant and malignant causes Vulval intra-​epithelial neoplasia and penile intra-​epithelial neoplasia The majority of intra-​epithelial neoplasias in genital disease are HPV related or occur in association with lichen sclerosus or lichen planus. The natural history of these conditions is unclear but an increased risk of malignancy would be expected.

Squamous cell carcinoma Squamous cell carcinoma is the most common vulval tumour and is most frequently seen in elderly patients. It is very rare in circumcised men.

Extra-​mammary Paget’s disease Extra-​mammary Paget’s disease is a rare intra-​epithelial adenocarcinoma of apocrine gland-​bearing sites. It may be primary or secondary to underlying malignancy. It is seen most commonly in the vulva (in women) or in the perianal region (in men). There may be pruritus/​ burning, or it may be asymptomatic. A slowly expanding erythematous plaque is typical. Erosions and scale cause a ‘strawberries and cream’ appearance. Because of the association of this disease with malignancy, if Paget’s disease is diagnosed, a systemic evaluation is required.

Inflammatory causes Psoriasis Psoriasis presents with erythematous, well-​ defined plaques with slight scale. It may look different from psoriatic areas on the rest of the body, with the typical silver scale being not present (as in other flexural sites). It is usually confined to hair-​bearing areas, so the labia minora are unaffected. Painful fissuring of the perianal and intergluteal clefts is a problem in both sexes. The presence of typical lesions elsewhere can help in the diagnosis of this disease.

Reiter’s disease Reiter’s disease may present on the penis with psoriasiform lesions.

Zoon’s (plasma cell) balanitis/​vulvitis Zoon’s (plasma cell) disorders predominantly affect males. Clinically, the disorders present with erythematous, moist, speckled, discrete plaques. Involvement of adjacent surfaces produces ‘kissing lesions’ in men. Circumcision is curative.

Causes of blistering Acquired autoimmune blistering disorders Bullous pemphigoid Bullous pemphigoid has a propensity for flexural sites. It presents with tense blisters on urticated plaques. There is mucosal involvement in 50% of patients.

Mucous membrane pemphigoid

‘Gold-​standard’ diagnostic test The gold-​standard diagnostic tests for genital disease include clinical findings and skin biopsy.

Acceptable diagnostic alternatives to the gold standard An acceptable diagnostic alternative to the gold-​standard tests for genital disease is a response to an appropriate treatment (e.g. strong topical steroids in lichen planus and lichen sclerosus).

Other relevant investigations In genital disease, if pruritus is a predominant symptom, a screen for any other underlying causes of pruritus (e.g. systemic disease, such as liver or renal disease) would be relevant. If a diagnosis of lichen sclerosus or lichen planus is suspected, investigations should screen for other autoimmune diseases.

Prognosis, and how to estimate it The risk of vulval squamous cell carcinoma is increased in both lichen sclerosus and lichen planus. It is estimated at approximately 2%–​5% in lichen sclerosus, although the risk has not been quantified in men. There is also thought to be an increased risk of squamous cell carcinoma in lichen planus. The natural history of intra-​epithelial neoplasia is not fully understood but an increased risk of squamous cell carcinoma is expected. Therefore, longitudinal evaluation is recommended for lichen sclerosus, lichen planus, and vulval intra-​epithelial neoplasia. Self-​examination should be taught. Any non-​healing ulcers, fissures, or nodules should be biopsied for histological evaluation.

Treatment and its effectiveness In genital disease amongst women, general care of the vulva can help all conditions. This includes avoidance of irritants and appropriate emollients. Lichen sclerosus responds well to strong topical steroids. Lichen planus tends to be a self-​limiting condition and responds to strong topical steroids, although genital disease can be more resistant to treatment than cutaneous disease is. Hypertrophic lichen planus may benefit from interlesional corticosteroids. Erosive lichen planus is more challenging to treat and may need longer maintenance with topical steroids. Eczema improves with soap/​irritant avoidance, and use of emollients and topical steroids for flares. It can be a chronic condition and challenging to manage. Allergic contact dermatitis is investigated by patch testing and managed by avoidance of proven allergens. Vulval pain improvement can be seen with the use of bland emollients and the avoidance of irritants and fragrance. Topical local anaesthetic agents and tricyclic antidepressants are the mainstays of treatment. Pre-​malignant and malignant conditions require an appropriate biopsy for diagnosis, together with education of the patient, and longitudinal observation for any risk of malignancy.

Mucous membrane pemphigoid is a scarring, blistering disorder.

Further Reading

Erythema multiforme and Stevens–​Johnson syndrome

Wojnarowska F and Cooper SM. ‘Anogenital (non-​venereal) diseases’, in Bolognia JL, Jorizzo JL, and Rapini RP, eds, Dermatology, 2012. Elsevier Wolff K and Johnson R. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology (6th edition), 2009. McGraw-​Hill Professional.

Both erythema multiforme and Stevens–​Johnson syndrome may present as a bullous eruption, particularly in the genital region. An association with herpes simplex virus is important in recurrent disease.

CHAPTER 256  Genital disease

Other causes of pale patches/​plaques

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257 

Polymorphic light eruption and actinic prurigo Jane McGregor

Definition of polymorphic light eruption and actinic prurigo Polymorphic light eruption (PLE) is an acute photodermatosis affecting approximately 10% of the population, predominantly women. It is almost always itchy and comprises erythema (redness) and papules which appear within a few hours of sufficient sun exposure to trigger the eruption. It usually lasts a few days to a few weeks, when it resolves spontaneously without scarring, unless re-​exposure occurs. It is a seasonal eruption in temperate climates between the months of March and September. Actinic prurigo is a much less common photodermatosis, but is probably related to PLE. It is a more long-​lasting, excoriated eruption that can leave scarring.

Aetiology of PLE and actinic prurigo

Approach to diagnosing of PLE and actinic prurigo The diagnosis of PLE is clinical, but lupus serology should be undertaken to exclude cutaneous forms of lupus, especially before phototherapy desensitization. The diagnosis of actinic prurigo is more challenging and must be distinguished from PLE. HLA typing can be helpful in supporting a diagnosis of actinic prurigo, since HLA-​DRB1 0407 is prevalent in this population, but rare in those with PLE and in the general population.

The aetiology of PLE and actinic prurigo are unknown, but there appears to be a genetic element. A  high proportion of patients with systemic and cutaneous lupus present with symptoms of PLE, but transformation of PLE into lupus is uncommon. About 10% of patients with PLE will have mildly elevated antinuclear antibodies, nonetheless.

Other diagnoses that should be considered aside from PLE and actinic prurigo

Typical symptoms of PLE and actinic prurigo, and less common symptoms

‘Gold-​standard’ diagnostic test for PLE and actinic prurigo

PLE typically presents as an acute itchy papular eruption confined to sun-​exposed sites, some hours after sufficient exposure. It resolves within a few days, to weeks without sequelae. Rarely, PLE can present as facial swelling and erythema (redness) or with blistering on sun-​exposed sites. Such cases should be investigated thoroughly for systemic lupus. Actinic prurigo may at first resemble PLE, but then patients develop more widespread itching and excoriation. The eruption may resemble eczema in its more chronic form. It resolves to leave small scars on exposed sites. It more frequently involves the face than PLE does.

The gold standard for the diagnosis of PLE and actinic prurigo is clinical; it therefore relies on an experienced clinician.

Demographics of PLE and actinic prurigo PLE is the most common of the photodermatoses and accounts for approximately 90% of all cases of photosensitivity (excluding sunburn). It is most common in temperate climates, but can affect all races, irrespective of skin type. Actinic prurigo is very rare and usually requires a specialist to confirm the diagnosis as it can be difficult to distinguish from PLE in some cases. It can affect all races.

Natural history of PLE and actinic prurigo, and complications of the diseases PLE and actinic prurigo typically present in young adulthood, but can be seen as early as at a few months of age or present for the first time in elderly patients. Both conditions appear to last several years and then remit, although more persistent forms do occur.

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A very small percentage of patients presenting with PLE will go on to develop systemic or cutaneous forms of lupus, and lupus serology should be undertaken at first and then periodically thereafter, particularly if symptoms worsen or change.

Subacute lupus erythematosus, discoid lupus erythematosus, and SLE can all mimic PLE. Occasionally, it is difficult to distinguish PLE from actinic prurigo.

Prognosis of PLE and actinic prurigo, and how to estimate it Both PLE and actinic prurigo have a good prognosis if managed well. A tiny percentage (6 mm diameter, atypical mole syndrome (particularly with a family history of melanoma), large congenital melanocytic naevi (>15 cm in diameter), and the nucleotide excision repair genodermatosis, xeroderma pigmentosum. Mutations in several high-​penetrance genes have been identified as influencing melanoma risk:  in particular, CDKN2A (chromosomal location:  9p21), which encodes a p16 tumour suppressor protein, and CDK4 (chromosomal location: 12q13). Polymorphisms in low-​penetrance genes have also been identified, including the melanoma susceptibility gene, MC1R (chromosome location: 16q24.7).

Aetiology of SCC

Symptoms of non-​melanoma skin cancer Symptoms of BCC

SCC is a malignant tumour arising from epidermal keratinocytes. Its occurrence is usually related to chronic UV-​radiation exposure and is therefore especially common in people with fair, sun-​damaged skin, and in UV-​sensitive genodermatoses such as oculocutaneous albinism and xeroderma pigmentosum. It may also develop as a result of previous exposure to ionizing radiation or to arsenic, or at sites of chronic inflammation (chronic wounds, scars, burns, ulcers, or sinus tracts). It may arise de novo or against a background of clinically apparent intra-​epidermal keratinocyte dysplasia (full thickness intra-​ epidermal SCC or Bowen’s disease; partial thickness intra-​epidermal dysplasia or actinic keratosis). Individuals with impaired immune function, for example those receiving immunosuppressive drugs following allogeneic organ transplantation or for autoimmune or inflammatory diseases, are at significantly increased risk of SCC. In organ transplant recipients, the

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risk of SCC increases 65–​250-​fold and the risk of BCC 10 to 16-​fold, compared to that in the non-​transplanted population, with consequent reversal of the usual BCC:SCC ratio of 3–​4:1. Age, duration of immunosuppression, skin phototype, and a history of high UV exposure are key risk factors in the pathogenesis of post-​transplant non-​melanoma skin cancer. However, complex genetic factors can determine individual risk. The risk of SCC with the new wave of ‘biological’ therapies (for inflammatory and haematological disease) has yet to be quantified. Patients with HIV/​AIDS or non-​Hodgkin lymphoma, specifically chronic lymphocytic leukaemia, may also develop aggressive SCC. Increased cutaneous HPV infection in these immunosuppressed groups, together with the occurrence of SCC in up to 60% patients with the rare genodermatosis epidermodysplasia verruciformis (which is associated with widespread cutaneous HPV infection) indicates a possible association between HPV and SCC.

Typical symptoms of the disease, and less common symptoms

BCCs usually arise on chronically and intermittently sun-​exposed skin of individuals over age 40, but can occur in younger people. Clinicopathological subtypes include nodular, superficial, infiltrating, and morphoeic. Nodular BCC accounts for 60%–​70% of cases. It is most common on the head and neck and presents as a pearly or translucent papule or plaque with rolled edges and overlying telangiectasia. It may ulcerate centrally and there may be a history of recurrent bleeding or crusting. Some lesions have cystic centres. In darker skin types, BCCs may be pigmented and simulate melanoma. Superficial BCC accounts for 15% of all BCCs and commonly affect the trunk of younger patients. They present as scaly papules or plaques with a pink to red-​brown colour and often have a characteristic thread-​like, pearly border. They are often misdiagnosed as patches of eczema, psoriasis, or tinea.

Table 259.1  Typical appearance of common primary skin cancers BCC

SCC

KS

MM

Nodular: skin-​coloured nodule with prominent overlying telangiectasia Soft in consistency Easily damaged by trauma Superficial BCC are scaly erythematous patches/​papules with a thin pearly border; they can be mistaken for patches of eczema, psoriasis, or tinea Infiltrative/​morphoeic subtypes may present with a scar-​like appearance

Indurated, crusted, nodular, or ulcerated lesion arising on sun-​damaged skin On lip or genitalia, presents as fissure or non-​healing ulcer

Classic KS: affects those of Jewish Ashkenazi/​ Mediterranean descent African endemic KS: adult male predominance, 1.3%–​10% of black Africans affected; lymphadenopathic variant seen KS in immunosuppression: observed in all iatrogenically immunosuppressed individuals, including post-​transplantation individuals AIDS-​related epidemic KS: high incidence in certain regions of Africa and the Caribbean

Changing or new mole (defined by ABCDE criteria*)

Abbreviations: BCC, basal cell carcinoma; KS, Kaposi’s sarcoma; MM, malignant melanoma; SCC, squamous cell carcinoma. *ABCDE criteria are used to identify early melanomas: Asymmetry, Border irregularity, Colour variation, Diameter > 6 mm, Elevation.

Infiltrative/​morphoeic subtypes are perhaps the most difficult to diagnose clinically as they may present with a scar-​like appearance. Because of their histological characteristics, with cords of tumour cells infiltrating beyond the apparent clinical margins of the BCC, they are the type most likely to recur after surgery.

papillomatosis and hyperkeratosis, may then complicate the clinical picture. Mucocutaneous lesions are usually asymptomatic.

Symptoms of cutaneous melanoma

SCC commonly arises on chronically sun-​exposed skin of elderly Caucasians over the age of 60. The usual sites for SCC are the dorsa of the hands; the forearms; the upper face; the lower lip; and the ears. SCCs most commonly present as indurated, keratotic nodules or plaques, which may ulcerate and are often tender on palpation. They may also present as a fissure or a non-​healing indurated ulcer on the lip or genitalia. Regional lymph nodes may be enlarged due to infection/​ inflammation of the tumour (dermatopathic lymphadenopathy) or as a result of metastases (with harder, irregular, matted nodes).

Symptoms of KS KS usually begins as macules, which evolve into papules, plaques, nodules, and tumours which may range in colour from violaceous, pink, red, or tan and become purplish-​brown. Lesions are usually palpable and firm to hard in consistency. Lesions may originate at a site of trauma and ulcerate or form an overlying crust. Skin lesions may be associated with deeper involvement of the lymphatic system or lymph nodes, resulting in lymphoedema, which common affects the lower limbs. Skin changes secondary to lymphoedema, including

All lesions suspected of being a melanoma should be urgently referred to a clinician trained in their diagnosis and management, usually a dermatologist. There are a number of presenting signs and symptoms for which urgent referral to the local skin cancer multidisciplinary team is indicated: • a new mole which appears after the onset of puberty and which is changing in shape, colour, or size • a long-​standing mole which is changing in shape, colour, or size • any mole which has three or more colours or has lost its symmetry • a mole which is itching or bleeding • any new persistent skin lesion, especially if growing, pigmented, or vascular in appearance, and if the diagnosis is not clear • a new pigmented line in a nail, especially where there is associated damage to the nail • a suspicious lesion growing under a nail

Symptoms of cutaneous metastases Most skin metastasis occurs in a body region near the primary tumour. The first sign of skin metastasis can be a firm, round or oval, mobile, non-​painful nodule. The nodules are rubbery, firm, or hard in texture and can vary in size. These may be skin-​coloured,

CHAPTER 259 Skin cancer

Symptoms of SCC

Table 259.2  Risk factors for the common skin cancers Risk factor

RR for developing BCC*

RR for developing SCC*

RR for developing melanoma*

UV exposure: history of blistering sunburn

+

1.9

2.5

Fitzpatrick skin type I (burns without tanning)†

+

2

1.7

Keratotic lesions >50

4

12.1

Multiple benign naevi

NA

NA

11

Multiple atypical naevi

NA

NA

11

Strong family history of melanoma§

NA

NA

35–​70

Previous history of melanoma

NA

NA

8.5

Previous history of non-​melanoma skin cancer (BCC and/​or SCC)

10

10

2.9

Immunosuppression: •  HIV • Transplant recipients

10-​fold

+ 50–​100-​fold

1.5 2–​17

Ionizing radiation

3.6

2.94

?+

Tanning beds

1.5

2.5

2.86–​4.44

Arsenic exposure

+

+

Tobacco smoking Photosensitizing drugs, e.g. fluoroquinolones, voriconazole

+ +

+

Abbreviations: BCC, basal cell carcinoma; RR, relative risk; SCC, squamous cell carcinoma. *Where quantifiable relative risk is not available, + confirms evidence of increased relative risk. † Fitzpatrick skin types: I: always burns/​never tans; II: usually burns/​sometimes tans; III: usually tans/​sometimes burns; IV: always tans/​rarely burns; V: Asian; VI: Black African and Afro-​Caribbean. § Defined as ≥3 family members affected.

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Table 259.3  Commonest primary tumours giving rise to skin metastases Primary tumour

Demographics

Common sites affected

Features

Breast

Commonest primary cancer in females of all ages

Trunk/​scalp

Firm, scar-​like area May appear as inflammatory plaques with well-​demarcated elevated margin

Colon/​stomach

Males > females

Abdomen/​pelvis

Nodule at umbilicus (Sister Mary Joseph nodule) is a sign of extensive colorectal carcinoma

Melanoma

Males ( Females (>40 years)

Trunk and extremities (males) Lower limbs (females)

Pigmented papules and dermal nodules

Lung

Commonest primary cancer in males (>40 years)

Trunk

Firm, erythematous nodules which tend to follow intercostal vessels when on the chest

Squamous cell carcinoma oral cavity/​larynx

Males > 40 years

Head and neck

CHAPTER 259 Skin cancer

red, or, in the case of melanoma, blue or black. Sometimes, multiple nodules appear rapidly. The skin metastases may break down and ulcerate through the skin. Depending on the location of the primary tumour, skin metastasis display certain characteristic features (see Table 259.3). More unusual patterns of cutaneous involvement by metastases include: • carcinoma erysipeloides:  sharply demarcated red patches that occur when the local spread of a primary cancer blocks lymphatic blood vessels in the adjacent skin • en cuirasse or sclerodermoid carcinoma: indurated, fibrous, scar-​ like plaques due to cancer cells infiltrating collagen in the skin • carcinoma telangiectoides: red patches with telangiectasia or lymphatic vessels (lymphangioma-​like)

Demographics of the disease Demographics of non-​melanoma skin cancer In 2007 more than 84 000 cases of non-​melanoma skin cancer were registered, but it is estimated that the actual number of new cases each year is at least 100 000, a figure which is steadily increasing. By 2030, the number of cases presenting to dermatologists could increase by an estimated 50%. The incidence of non-​melanoma skin cancer increases with age, and 80% of cases occur in people over the age of 60 years. In addition, the incidence is higher in men than in women.

Demographics of BCC BCC is the most common cancer in Europe, Australia, and the US and is showing a worldwide increase in incidence. Poor BCC data collection by many tumour registries means that accurate figures for the incidence of BCC in the UK are difficult to obtain.

Demographics of SCC SCC is the second most common skin cancer and, in many countries, its incidence is rising. It accounts for the majority of non-​melanoma skin cancer-​related deaths. The BCC:SCC ratio is approximately 3-​4:1 in most countries, but is often reversed in immunosuppressed populations.

Demographics of KS Classic KS was first described as a slow-​ growing endothelial cell tumour in elderly men of Mediterranean or Eastern European descent; subsequently, a slightly more aggressive form of the disease (so-​called endemic KS) was recognized at higher rates in African populations. With the onset of the AIDS epidemic, the worldwide incidence of this cancer has increased dramatically in the past 25 years, and a much more aggressive form of KS is now the commonest tumour amongst HIV-​infected people in Africa (>10/​100 000 males). KS became common amongst a subset of HIV patients in the West, but the incidence is now falling with the introduction of effective anti-​HIV drug therapy. An increased incidence of KS is also observed in organ transplant recipients and other iatrogenically immuonosuppressed individuals.

Demographics of cutaneous melanoma The incidence of cutaneous melanoma is rising faster than for any other major cancer, and rates are set to treble over the next 30 years.

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More than 10 400 cases of melanoma are diagnosed annually in the UK, with over 2000 deaths attributable to melanoma. In 2006, melanoma was more common in females than males, with a male:female ratio of 4:5. Although the incidence of melanoma rises with age, a disproportionately high incidence of melanoma is observed amongst young people; almost a third of cases (31%) occur in people aged 2 cm), the depth of invasion (>6 mm confers a 16% risk of metastasis), differentiation state (poor differentiated tumours fare worse), the rate of growth, and the anatomical location:  tumours on the ear and lip have a worse prognosis than tumours elsewhere. Mucosal SCCs have a greater tendency to recur and metastasize than SCCs located on the glabrous sun-​exposed skin. Tumours arising in actinic keratoses on the dorsa of hands are indolent and late in metastasizing. Lesions in sun-​exposed areas have a better prognosis than those arising from non-​sun-​exposed areas. There is an increased risk of a second primary SCC within 5 years after therapy for the first malignancy; this risk is approximately 30% for the general population, but up to 75% in immunosuppressed individuals.

Natural history of KS, and complications of the disease Although the skin is the most frequent organ of involvement, internal lesions of KS are commonly seen (e.g. affecting the lungs, abdominal viscera, or lymph nodes). Overall mean survival is 10–​15 years.

Natural history of cutaneous melanoma, and complications of the disease Cutaneous melanoma arises from epidermal melanocytes. It is one of the most aggressive skin cancers, occurring in all ages but predominantly affecting adults. Prognosis is closely related to the depth of the tumour (Breslow thickness), as well as tumour ulceration, mitotic rate, and nodal status (see Table 259.4). It accounts for 75% of all skin cancer-​related deaths. It is assumed that most melanomas increase in size with time and that early recognition and excision provides the greatest opportunity for cure. Moreover, melanoma is notoriously chemoresistant and often proves to be radiotherapy resistant. Over the last 30  years, there have been no new therapeutic approaches that have improved overall survival rates in metastatic disease but there are recent indications that new targeted and immunotherapybased  therapeutic interventions (e.g. BRAF-​ targeted therapy and PDL-1 inhibition) may improve this dismal situation.

Approach to diagnosing the disease Take a thorough history The following features must be established and can help with diagnosis: • duration of the lesion: BCCs are usually slow-​growing; SCCs often have a more rapid growth pattern • change in size: a pigmented lesion which is growing or changing in shape or colour is likely to be evolving and could be an early sign of malignant change • change in colour • change in shape • symptoms: itchiness or bleeding in long-​standing melanocytic naevi may be suggestive of malignant change, particularly if associated with changes in size, colour, or shape

Assess risk factors Skin phototype and a UV-​exposure history should be established. Individuals deemed to have had high UV exposure would be those with an outdoor occupation for >5  years, those who have lived in a sunny climate for >6  months, or ‘sun worshippers’ who have actively sought a suntan for >2 weeks per year for >10 years and/​or have ever used sunbeds. Conversely, a low-​UV-​exposure category would include individuals with indoor occupations, those who have

not lived in sunny climates, and those who avoid the sun or do not actively sunbathe. Intermediate UV exposure falls between these two categories. Patients with a history of long-​standing ulcers or wounds (e.g. burns), previous radiotherapy, UV therapy (e.g. psoralen and UVA therapy, for psoriasis), chronic immunosuppressive therapy, or arsenic ingestion are also more likely to develop skin cancers.

Physical examination Examination of the individual lesion should be undertaken, detailing the following: site: this can influence treatment options and prognosis • • size (maximum diameter): this is important to determine further treatment based on surgical margins • colour (flesh-​coloured, erythematous, pigmented); variability of colour should also be noted • elevation (palpable, nodular) • margins/​border (regular, irregular) • surface (smooth, scaling, roughened, crusted, ulcerated, bleeding) When skin cancer is suspected, regional lymph nodes should also be examined to determine any nodal spread. A complete examination of the entire skin should also be undertaken to identify any other pre-​malignant or malignant lesions.

Other diagnoses that should be considered Common differential diagnoses for skin cancers according to type are detailed in Table 259.5.

‘Gold-​standard’ diagnostic test ‘Gold-​standard’ diagnostic test for BCC and SCC The gold-​standard diagnostic test for all skin cancers is histological assessment. There are now well-​defined criteria for reporting of histological features to confirm the diagnosis and to determine the prognosis. For smaller tumours, primary excision may be both diagnostic and therapeutic. For larger lesions and for those in cosmetically sensitive sites, an initial diagnostic biopsy (incision or punch biopsy) may be required to confirm the diagnosis and histological subtype (e.g. superficial vs infiltrative BCC; well-​differentiated vs poorly differentiated SCC) before planning definitive treatment.

CHAPTER 259 Skin cancer

Classic or European KS is typically slowly progressive. African endemic KS has been described in two age groups:  young adults (mean age 35) with generally benign cutaneous nodular disease, and young children (mean age 3)  with fulminant lymphadenopathic disease, which is fatal within 3 years.

‘Gold-​standard’ diagnostic test for KS The diagnosis of KS is usually confirmed on skin biopsy.

Table 259.4  Prognosis of melanoma Stage

Characteristics

5 year survival

1a

Melanoma cells confined to the epidermis

95% +

1b

4 mm and no ulceration

2c

> 4 mm and ulcerated, confined to skin, and no spread

3a

Spread into up to three lymph nodes near the primary, only detectable microscopically Melanoma not ulcerated

3b

Ulcerated melanoma + 1–​3 microscopic lymph node spread or non-​ulcerated melanoma + 1–​3 lymph nodes, which are enlarged, or non-​ulcerated melanoma + local skin spread but no lymph node involvement

3c

Melanoma in lymph nodes + local skin or spread to 1–​3 lymph nodes which are enlarged or spread to 4+ nearby lymph nodes or spread to lymph nodes which have joined together

4

Spread away from origin and local lymph nodes

Men 80% Women 90% Prognosis worsens with higher-​grade tumour (i.e. worse for 2c than for 2a) Men 50% Women more than 50% Prognosis worsens with higher-​grade tumour (i.e. worse for 3c than for 3a)

Men 10% Women 25%

Data from http://​www.cancerresearchuk.org/​about-​cancer/​type/​melanoma/​treatment/​melanoma-​statistics-​and-​outlook.

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Table 259.5  Common differential diagnoses for skin cancers according to type Non-​melanoma skin cancer

Cutaneous melanoma

Actinic keratoses: rough, scaly erythematous papules on chronically sun-​exposed skin • if hyperkeratotic, may simulate an early SCC • Bowen’s disease (intra-​epidermal squamous cell carcinoma): fixed, erythematous, scaly plaque which gradually expands • usually on sun-​exposed skin but characteristically on the lower legs • may be difficult to differentiate from a superficial BCC, although BCCs • often has a thread-​like rolled edge Benign intradermal naevus: usually very long history of a stable lesion • may simulate nodular BCC • Keratoacanthoma: usually very rapidly growing nodule on sun-​exposed skin with • symmetrical configuration, ‘shouldered’ erythematous/​translucent margins, and a central keratotic plug SCCs tend to be more irregular in shape and slower growing and do • not regress spontaneously

Melanocytic naevi: benign or dysplastic • any naevus in which there is a history of change or which is clinically • suspicious should be excised for histological examination Seborrhoeic keratosis (basal cell papillomas): can mimic many of the features suggestive of melanoma but have a • ‘stuck-​on appearance’, and patients often have multiple similar lesions on the body dermoscopy can be a useful adjunct to diagnosis • Dermatofibroma: usually a firm nodule which may be pigmented • often on limbs • a history of insect bite may be given • Vascular lesions: may simulate melanoma, e.g. angiokeratomas (dark red/​black scaly • papules), pyogenic granuloma (rapidly growing, bright red/​purple ulcerated, rounded nodule, surrounding skin is normal)

Abbreviations: BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

CHAPTER 259 Skin cancer

‘Gold-​standard’ diagnostic test for cutaneous melanoma A lesion suspected to be a melanoma should be photographed and then excised completely by a trained specialist. The axis of excision should be orientated to facilitate possible subsequent wide local excision. The excision biopsy should include the whole tumour, with a clinical margin of 2 mm around normal skin, and a cuff of fat. This allows for examination of the entire lesion, such that subsequent definitive treatment can be based on Breslow thickness. With few exceptions, diagnostic shave biopsies or partial removal of lesions must be avoided, as these can lead to incorrect diagnosis due to sampling error.

Acceptable diagnostic alternatives to the gold-​standard tests Although complete excision is the gold standard for diagnosis of melanoma, in a few circumstances, incisional biopsies may be acceptable (e.g. for large lesions on cosmetically sensitive sites). It should be emphasized that, while this approach may assist in confirming whether a lesion is indeed a melanoma, it cannot provide an accurate Breslow thickness, which is required for planning definitive surgical excision, and, occasionally, false negatives may arise from sampling error.

Other relevant investigations Dermoscopy Experienced specialists can make a clinical diagnosis of BCC in many cases. Diagnostic accuracy is enhanced by good lighting and magnification, and the dermatoscope can be helpful in some cases. The dermatoscope allows a closer examination of the surface of pigmented lesions with 10× magnification, and a glass plate/​oil interface or polarized light to minimize reflection from the surface. A dermatoscopic score takes into account features such as asymmetry, number of colours, pigment structure, and irregular border; this scoring can be correlated with risk of malignancy. Dermoscopy is a specialized tool, usually most successfully used by trained and experienced dermatologists.

Radiological imaging Imaging is not routinely indicated to aid diagnosis of non-​melanoma skin cancers or cutaneous melanoma. However, it may be required to establish involvement of underlying structures (e.g. bony involvement), prior to planning definitive treatment. For melanoma, no routine imaging is recommended unless the disease is Stage IIC/​III or above; in these circumstances, staging should be determined using

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whole-​body CT or CT–​PET scans. Ultrasound or CT scanning is indicated for patients with a diagnosis of KS, to exclude visceral or lymphatic involvement.

Investigation of suspicious lymph nodes Sentinel lymph node biopsy Sentinel lymph node biopsy (SLNB) was developed as a means to identify the first lymph node draining the skin in which a melanoma arises. This investigation is usually performed at the same time as definitive wider excision of a primary melanoma. It is usually considered as a staging procedure for melanomas for which the Breslow thickness is between 1 mm and 4 mm, as sentinel node positivity is associated with a worse prognosis in such melanomas. As yet, there is no therapeutic value associated with the procedure. Patients with a positive SLNB usually proceed to complete lymphadenectomy. The procedure is associated with 5% morbidity and, in 5% of cases, it is not possible to identify the sentinel lymph node. As an alternative to SLNB, ultrasound surveillance of lymph node basins can be used but it is only available in specialist centres. Nodes clinically suspicious for metastatic disease should be sampled using fine-​needle aspiration cytology or ultrasound-​guided biopsy. Prior to lymph node dissection, staging CT scan should be performed.

Prognosis, and how to estimate it Prognosis of non-​melanoma skin cancer There are a number of well-​defined prognostic factors, which affect the outcome of non-​melanoma skin cancers (see Table 259.6).

Prognosis of BCC The histological subtype of BCC may influence the prognosis: morphoeic/​ infiltrative, micronodular, and basosquamous variants are associated with aggressive tissue invasion and destruction. Perivascular or perineural invasion are features associated with increased aggression and recurrence. Metastasis is extremely rare (1:50 000), but may occur in the setting of tumours exceeding 5 cm in diameter.

Prognosis of SCC Most patients with primary cutaneous SCC have a very good prognosis. Conversely, metastatic disease has a poor long-​term prognosis; patients with regional lymphadenopathy have a ear > lip (increasing metastatic potential)

Tumour size

Increasing size confers higher risk of recurrence

Tumours >2 cm are twice more likely to recur locally and 3× more likely to metastasize

Tumour depth

–​

Tumours 6 mm in depth or extending into or beyond the subcutis are more likely to recur and metastasize (risk 16%)

Defined clinical margins

Poorly defined lesions are at higher risk of recurrence

Histological subtype

Morphoeic, micronodular, infiltrative, and basosquamous histological subtypes confer higher risk of recurrence

Poorly differentiated tumours have a worse prognosis, with >2× local recurrence rates and 3× metastatic rate compared with well-​differentiated tumours Certain subtypes (e.g. desmoplastic SCC) have a 24% risk of local recurrence vs 1% for non-​desmoplastic SCC

Perivascular or perineural invasion

Confers higher risk of recurrence

More likely to recur and to metastasize (rates up to 50%)

Failure of previous treatments

Recurrent lesions have increased risk of further recurrence Local recurrence is lower with Mohs micrographic surgery

Locally recurrent disease is a risk factor for metastatic disease

Host immunosuppression

Tenfold increased incidence risk

Worse prognosis, increased risk approximately 100-​fold, increased risk of metastasis 5%–​7%

Prognosis of cutaneous melanoma The prognosis of melanoma is dependent on several factors: (a) Breslow thickness (the deepest contiguous point of the tumour in millimetres) (b) mitotic count (the number of mitoses per square millimetre) (c) ulceration status (ulcerated tumours have a worse prognosis) (d) nodal involvement (the prognosis of tumours is dependent on the presence and number of involved nodes) (e) LDH level (f) host immunosuppression (g) site of melanoma (limb melanomas have a better prognosis than truncal melanomas do) (h) age (younger patients have a better prognosis than older patients) (i) gender (males fare worse than females) Factors (a)–​(e) have a significant effect when determining prognosis and are included in the seventh edition of the American Joint Committee on Cancer (AJCC) classification for prognostic staging of melanoma (summarized in Table 259.4). More recently, a website has been set up that provides a tool for predicting the clinical outcome of an individual patient with localized or regional cutaneous melanoma (http://​www.melanomaprognosis.net). The prediction tools can be used to predict the 1-​, 2-​, 5-​, and 10-​year survival rates from initial diagnosis (with a 95% confidence interval) for an individual patient, based on his/​her relevant clinical and pathological information. The predictive models were developed and validated using a combined database (n  =  28 047) from 11 major institutions and study groups participating in the development of the AJCC Melanoma Staging System.

Treatment and its effectiveness Treatment of non-​melanoma skin cancer Although surgical excision remains the gold standard for the treatment of non-​melanoma skin cancer, there are a range of other surgical and non-​ surgical management options for selected non-​ melanoma skin cancers (see Table 259.7). The choice offered to the patient will depend on the anatomical location of the cancer, its size,

its clinical appearance, the histological diagnosis, and the availability of the options.

Treatment of BCC The range of possible treatments for BCC is listed in Table 259.7.

Treatment of SCC Prevention of SCC Individuals at risk of SCC should be given advice regarding photoprotection (e.g. use of protective clothing and effective sunscreens), as this may reduce the incidence of both actinic keratoses and SCC. Although there is good evidence linking SCCs with chronic actinic damage, there is no definite evidence that the treatment of actinic keratosis prevents the development of SCC. These measures are particularly important for immunosuppressed individuals and those individuals who have rare genodermatoses and so are at increased risk of developing SCC. Education on self-​skin surveillance for early detection and treatment should be part of routine care. Topical agents such as imiquimod may have a useful role in preventing the development of skin dysplasia in high-​risk renal transplant recipients but substantive evidence is awaited.

CHAPTER 259 Skin cancer

Abbreviations: BCC, basal cell carcinoma; SCC, squamous cell carcinoma. Adapted: a) with permission from Telfer, N.R., G.B. Colver, and C.A. Morton, Guidelines for the management of basal cell carcinoma, The British journal of dermatology, Volume 159, Issue 1, pp. 35–​48, Copyright © 2008. b) Reproduced with permission from R. Motley, P. Kersey, C. Lawrence, Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma, The British journal of dermatology, Volume 146, Issue 1, pp. 18/​25, Copyright © 2002 John Wiley and Sons.

Management of SCC Management of SCC entails surgical excision with a margin of normal skin removed from around the tumour. For clinically well-​defined, low-​risk tumours (2 cm in diameter; tumours classified as moderately differentiated, poorly differentiated, or undifferentiated; tumours extending into the subcutaneous tissue; tumours on the ear, lip, scalp, eyelids, or nose) should be removed with a wider margin (≥6 mm), and the tissue margins examined histologically or with Mohs micrographic surgery. In cases where the margins of the tumour are ill-​defined (e.g. in poorly differentiated SCCs), tumour extent may not be accurately predicted. After excision of high-​risk SCCs, patients should be kept under regular review for at least 2 years, with particular attention to the possibility of recurrence at

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Table 259.7  Summary of treatments of skin cancers Treatment

BCC

SCC

KS

Melanoma

Cutaneous metastases

Surgical excision

Nodular ++ Morphoeic ++ Superficial +

Well++ Moderate ++ Poor ++

+

Primary cutaneous, recurrent, and metastatic disease

+

Curettage/​shave excision

Superficial subtype ++

Well differentiated +

−

−

−

Cryotherapy /​cryosurgery

Superficial+

In situ (Bowen’s disease)+

+

−

+

Mohs micrographic surgery*

Morphoeic, cosmetically sensitive sites, recurrent BCC ++

High-​risk SCCs (SCC of lip/​ ear, recurrent SCC, SCC arising in non-​sun-​exposed sites or in chronic ulcers/​inflammation)

−

Lentigo maligna

−

Radiotherapy

Primary treatment for BCCs not amenable to surgery or as an adjunctive therapy, e.g. after incomplete surgical excision

Adjunctive for tumours with perineural invasion or where surgical excision is inadequate/​impossible

+

Metastatic disease

+

Topical 5-​fluorouracil

Superficial

Actinic keratosis, Bowen’s disease

−

−

−

Topical imiquimod

Superficial

Actinic keratosis

−

Small lentigo maligna (in the context of a clinical trial)

+

Photodynamic therapy

Superficial BCCs and some nodular subtypes

Actinic keratosis and Bowen’s disease

−

−

+

CHAPTER 259 Skin cancer

Abbreviations: BCC, basal cell carcinoma; KS, Kaposi’s sarcoma; SCC, squamous cell carcinoma. *Mohs micrographic surgery is a surgical technique used to treat skin cancers which allows precise microscopic margin control by using horizontal frozen sections. The advantages are superior cure rates, maximal tissue conservation, ability to trace perineural or infiltrating tumours histologically, and negligible risk of anaesthetic complications because of the almost exclusive use of local anaesthesia.

the original site and in the draining lymph nodes. Lower-​risk tumours may not require such prolonged follow-​up, but all patients should be educated about the risk of further SCCs and the importance of self-​ skin surveillance and photoprotection. In immunologically or genetically predisposed individuals (e.g. organ transplant recipients and patients with xeroderma pigmentosa) who have multiple SCCs, making surgical management difficult, systemic retinoids (acitretin) or nicotinamide  may reduce the rate of development of new lesions. Where appropriate, reduction of immunosuppression or switching to mTOR inhibitor-​based immunosuppression may also reduce SCC risk.

Treatment of KS The aim of treatment of KS is to control the symptoms of the disease, as it is not ‘curable’. Various modalities have been used and are detailed in Table 259.7. In addition, intra-​lesional and systemic chemotherapies are also used (e.g. bleomycin, vinblastine, doxorubicin, etoposide). In the setting of iatrogenic KS, reduction of immunosuppression and switching from calcineurin inhibitors to mTOR-​based immunosuppression (e.g. rapamycin) are additional therapeutic strategies.

Treatment of cutaneous melanoma Prevention of cutaneous melanoma The role of photoprotection in melanoma prevention was recently confirmed in a randomized controlled trial in Australia. This demonstrated that, amongst adults aged 25–​75, regular application of SPF15+ sunscreen in a 5-​year period appeared to reduce the incidence of a new primary melanoma (as well as of SCC) for up to 10 years.

Management of cutaneous melanoma Management of primary cutaneous melanoma Surgery is the only curative treatment for primary melanoma. Following excision for diagnosis and for measurement of microscopic Breslow thickness, a wider and deeper margin is taken to ensure complete removal of the primary lesion, and to remove any micrometastases. Lateral surgical excision margins for invasive melanoma depend on Breslow thickness and are based on five randomized clinical trials including about 3300 patients, and a National Institutes of Health Consensus Panel (see Table 259.8).

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Table 259.8  Recommended lateral surgical excision margins for cutaneous melanoma Tumour thickness

Surgical excision margins (cm)

In situ

0.5

4.00 mm

2.0–​3.0

Management of lymph node basins in melanoma patients should be carried out by specialist skin cancer multidisciplinary teams so that surgical treatment planning and investigations can be run in parallel. Clinically node-​negative patients can be investigated using ultrasound or SLNB in specialist centres in the UK. Patients should have access to a skin cancer nurse specialist. There is no evidence of a survival benefit for adjuvant chemotherapy in patients with melanoma.

Management of secondary cutaneous melanoma Surgery is the treatment of choice for single local or regional metastases. Excision should be clinically and histologically clear but a wide margin is not required. The treatment of locoregional recurrence in a limb is palliative. Multiple small dermal lesions may be treated surgically; CO2 laser and electrochemotherapy with bleomycin may also be useful palliative strategies. Regional chemotherapy with isolated limb infusion (melphalan and dactinomycin D) should be considered for dermal disease which is progressing despite surgery or laser, and for subcutaneous/​deeper limb metastases. Isolated limb perfusion may be suitable for larger volume disease. Surgery should be considered for oligometastastic disease at sites such as the skin, the brain, or the bowel or to prevent ulceration. Radiotherapy may have a palliative role in the treatment of metastases. Patients with Stage IV melanoma should be considered for entry into clinical trials. Due to a better understanding of melanoma cell signalling and immunological response first line agents include immunotherapies either as monotherapy (PD1 inhibitors) or in combination with anti-CTLA4 antibodies. Targeted therapies are second line agents also as monotherapy (BRAF inhibitors) or in combination with MEK inhibitors. Over the next decade, it is likely that further developments will change the face of managing locoregional and metastatic disease.

Treatment of cutaneous metastases In the case of cutaneous metastases, the underlying primary tumour should be treated but, in most cases when skin metastases have developed, the cancer is usually widespread and only palliative care is appropriate. Treatment options include debridement or palliation by debulking or removing symptomatic/​ulcerative lesions and radiotherapy (see Table 259.7).

Green AC and Olsen CM. Cutaneous squamous cell carcinoma: an epidmiological review. Br J Dermatol 2017; 177: 373–​81. Madan V, Lear JT, and Szeimies RM. Non-​melanoma skin cancer. Lancet 2010; 375: 673–​85. Marsden JR, Newton-​Bishop JA, Burrows L, et al. Revised UK guidelines for the management of cutaneous melanoma 2010. Br J Dermatol 2010; 163: 238–​56. Miller AJ and Mihm MC Jr. Melanoma. N Engl J Med 2006; 355: 51–​65.

Further Reading

CHAPTER 259 Skin cancer

Bichakjian CK, Halpern AC, Johnson TM, et  al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol 2011; 65: 1032–​47.

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260 

Skin markers of internal medicine

Charles M. G. Archer and Clive B. Archer

Introduction Some of the most interesting aspects of dermatology are seen when internal medicine and dermatology overlap. Skin lesions may be part of a systemic disease, as occurs in sarcoidosis or SLE, or may be a manifestation or ‘marker’ of an underlying disease or process, as seen in acanthosis nigricans. Here, we will focus on the diagnosis and treatment of selected skin markers of internal medicine.

Erythema nodosum Erythema nodosum (Figure 260.1) is a form of septal panniculitis in which the inflammatory changes also involve the overlying dermis. There are usually painful bruise-​like lesions on the shins. Erythema nodosum may be provoked by a number of stimuli, including streptococcal infection, drugs (including oral contraceptives and sulphonamides), sarcoidosis, and tuberculosis, although often a cause is not found. The patient may be unwell with fever and arthralgia, and the lesions usually resolve in a few weeks.

Granuloma annulare and necrobiosis lipoidica The non-​ infectious granulomatous disorders include granuloma annulare and necrobiosis lipoidica, as well as sarcoidosis.

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Granuloma annulare Granuloma annulare (see Figure 260.2) is a reaction pattern in the skin, with a well-​established morphology and natural history, although the aetiology and pathogenesis are unclear. A  number of potential antigenic trigger factors have been suggested. There is an association between granuloma annulare and diabetes mellitus but this is seen uncommonly. Granuloma annulare can occur at any age but most patients are under 30 years old, and women are affected more frequently than men. Localized granuloma annulare is the commonest form of granuloma annulare and presents as reddish collections of papules which form annular lesions with palpable edges, often over the knuckles and on the elbows. Other areas of the skin may be involved, and a diffuse or generalized pattern occurs uncommonly. In the generalized pattern, there are numerous skin-​coloured or erythematous, slightly palpable, coalescing papules, arranged symmetrically on the trunk and limbs. Annular lesions may be violaceous in colour, and itching is often a feature of the generalized form. Perforating (referring to extrusion of material through the epidermis) and subcutaneous granuloma annulare are uncommon patterns, with the latter sometimes being difficult to distinguish from rheumatoid nodules. It is reasonable to exclude diabetes mellitus in patients with granuloma annulare but this probably occurs in only about 5% cases of localized granuloma annulare, rising to up to 20% in the generalized form. The association of granuloma annulare with diabetes mellitus is debatable, however, and some relatively small studies have not shown a definite association. The distinction from necrobiosis lipoidica, which is more strongly associated with diabetes mellitus, is usually made histologically but granuloma annulare and necrobiosis lipoidica can occur in the same patient. The sporadic occurrence of granuloma annulare and its tendency to remit spontaneously makes it difficult to assess the efficacy

Figure 260.1  Erythema nodosum, with painful bruise-​like lesions on the shins. Please see colour plate section.

Figure 260.2  Granuloma annulare, showing an annular dermal lesion on the dorsum of the hand. Please see colour plate section.

From: Ethnic Dermatology: Clinical Problems and Skin Pigmentation, Archer CB, Copyright 2008, Informa Healthcare, reproduced by permission of Taylor & Francis Books UK.

From: Ethnic Dermatology: Clinical Problems and Skin Pigmentation, Archer CB, Copyright 2008, Informa Healthcare, reproduced by permission of Taylor & Francis Books UK.

Treatment of granuloma annulare, and its effectiveness Potent topical corticosteroids may hasten resolution of localized granuloma annulare, and intra-​lesional triamcinolone can be effective if treatment is required. Cryotherapy has also been used. Psoralen plus UVA (PUVA) therapy seems to be effective for generalized granuloma annulare. Other treatments reported to be of benefit include retinoids, ciclosporin, local injections of low-​dose recombinant interferon gamma, and topical imiquimod or tacrolimus. However, better clinical studies are required in what is a sporadic disorder. In one clinical trial of generalized granuloma annulare treated with oral potassium iodide, the active drug had no advantage over placebo.

Treatment of necrobiosis lipoidica, and its effectiveness Treatment with a super-​potent topical corticosteroid under polythene occlusion is effective in settling the active inflammatory process of necrobiosis lipoidica but the chronic atrophic changes are not reversible and the lesions persist. Early treatment is therefore recommended. Intra-​lesional triamcinolone has been used with good effect, and some dermatologists use perilesional triamcinolone to prevent extension of the process centrifugally. Short courses of prednisolone have been reported to arrest the process but are usually not required. PUVA using a topical psoralen has been beneficial, as has excision and grafting in severe cases. Other treatments which have been tried in the past with limited success include nicotinamide, clofazamine, pentoxifylline, ciclosporin, mycophenolate mofetil, and, more recently, infliximab.

Necrobiosis lipoidica

Other skin disorders in diabetes mellitus

The precise pathogenesis of necrobiosis lipoidica (see Figure 260.3) is unknown but impaired vascularity of the microcirculation is considered to play a role. The occurrence of diabetes mellitus in up 60% patients who have necrobiosis lipoidica was probably overestimated previously in tertiary referral populations. Necrobiosis lipoidica may precede the development of diabetes in about one in ten individuals. However, it does not occur exclusively in diabetes, and the term necrobiosis lipoidica diabeticorum is no longer used. It can occur at any age but usually develops in young adults and in early middle age. There is a female to male ratio of 3:1. Only about 0.3% patients with diabetes mellitus will have necrobiosis lipoidica. Necrobiosis lipoidica occurs as reddish-​ yellow shiny plaques on the shins, with atrophy and telangiectasia, but early lesions are less obvious. Lesions may ulcerate and a chronic course is usual. In most cases, lesions are bilateral, and they are similar in appearance whether occurring in diabetic or non-​diabetic patients. The differential diagnosis includes granuloma annulare, in which there is less necrobiosis on histology. The yellowish appearance may resemble xanthomatous lesions but this will be distinguished on histology.

Skin disorders in diabetes mellitus include diabetic dermopathy, which is the commonest skin disorder associated with diabetes; cutaneous infections which occur as a consequences of diabetic neuropathy; acanthosis nigricans (related to insulin resistance); and, as discussed in ‘Granuloma annulare and necrobiosis lipoidica’, necrobiosis lipoidica and probably generalized granuloma annulare. Anogenital pruritus in diabetes mellitus may be caused by candidiasis or streptococcal infection but diabetes is not a proven cause of generalized pruritus.

Diabetic dermopathy (diabetic shin spots) Diabetic dermopathy occurs in about half of the patients with diabetes, with men being more commonly affected than women. Diabetic dermopathy is thought to be due to microangiopathy and possible neuropathy. Reddish oval macules and slightly scaly plaques are seen on the shins, forearms, and thighs and over bony prominences, later evolving into brownish atrophic scars, where the brown pigment is due to haemosiderin deposition. The presence of these lesions has been suggested to correlate with other internal complications of diabetes, including retinopathy, nephropathy, and neuropathy.

Acanthosis nigricans and insulin resistance Acanthosis nigricans (Figure 260.4), in which there is hyperpigmentation and hyperkeratosis of the flexures (e.g. a velvety appearance in the axillae), exists in two forms. In the absence of obesity, acanthosis nigricans may be an important clinical sign of an underlying

Figure 260.3  Necrobiosis lipoidica, showing atrophic plaques on the shins. Please see colour plate section.

Figure 260.4  Acanthosis nigricans, showing hyperpigmentation and hyperkeratosis of the axillary skin. Please see colour plate section.

From: Ethnic Dermatology: Clinical Problems and Skin Pigmentation, Archer CB, Copyright 2008, Informa Healthcare, reproduced by permission of Taylor & Francis Books UK.

From: Ethnic Dermatology: Clinical Problems and Skin Pigmentation, Archer CB, Copyright 2008, Informa Healthcare, reproduced by permission of Taylor & Francis Books UK.

CHAPTER 260  Skin markers of internal medicine

of treatment; in addition, in many cases, no treatment is needed. Spontaneous remission occurs in about 50% of patients within 2 years but recurrence, usually at the same sites, occurs in 40%.

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adenocarcinoma (e.g. carcinoma of the stomach). The changes of acanthosis nigricans in younger obese patients, in whom the nape of neck and the antecubital fossae are often involved, are associated with insulin resistance (hyperinsulinaemia) and sometimes overt diabetes mellitus. There are considered to be two syndromes of insulin resistance: type A, which occurs in hyperandrogenic women due to a genetic defect affecting insulin receptor function, and type B, which occurs in older women with signs of immunological dysfunction.

Xanthomata There are different forms of xanthoma. Eruptive xanthomata of the skin, often on the buttocks and limbs, may develop in patients with hyperlipoproteinaemia in association with diabetes mellitus. Control of the hyperlipoproteinaemia and diabetes usually leads to resolution of the yellowish papules.

Skin markers of liver diseases

CHAPTER 260  Skin markers of internal medicine

Pruritus in liver disease Generalized pruritus is the most common symptom associated with liver disease. It may precede the onset of jaundice and may be a feature of hepatitis. Itching is most prominent in primary biliary cholangitis, sclerosing cholangitis, and other forms of biliary tract obstruction, being less of a problem in alcoholic cirrhosis, autoimmune chronic active hepatitis, and haemochromatosis. Improvement in hepatic itching by drugs which block the action of opiates suggests that endogenous opiates may be important in the mechanism of itching.

Treatment of pruritus, and its effectiveness Treatment of pruritus is directed at the underlying cause (e.g. drug withdrawal, in drug-​ induced cholestasis; surgery, for mechanical biliary obstruction). Antihistamines are usually ineffective. Other approaches have included colestyramine, rifampicin, and various forms of phototherapy.

Pigmentary changes in liver disease Jaundice is first seen in the sclerae before it becomes generalized. Carotenaemia and drugs, including mepacrine, can also cause yellowing of the skin. A grey hyperpigmentation may occur in chronic liver disease of any cause. There may be a yellowish tinge due to associated jaundice. The pigmentation is usually more prominent on sun-​exposed sites, including the face, with perioral and periorbital accentuation. Pigmentation sometimes localizes to the palmar creases, and men sometimes have increased pigmentation of the areola in association with gynaecomastia.

Vascular changes in liver disease Some of the recognized vascular changes in liver disease are non-​specific, including spider naevi (spider telangiectasias/​spider angiomas) and palmar erythema. Finger clubbing, thought to be due to increased digital pulp blood flow and dilation of arteriovenous anastomoses, occurs in about 15% of patients with cirrhosis.

Hair, nail, and collagen changes in liver disease The body hair is often thinned and men tend to develop a female pubic-​ hair pattern, due to increased production and decreased metabolism of oestrogens and associated with decreased production and increased metabolism of testosterone. Extensive loss of scalp hair may be due to zinc deficiency. Nail colour changes include diffuse white colour; proximal white colour and distal reddish-​pink colour; and white bands. Nail plate changes include clubbing, flattened nails, or koilonychia, associated with poor nutrition or altered iron metabolism.

Porphyria cutanea tarda Porphyria cutanea tarda is associated with chronic liver disease. In this form of porphyria, there is photosensitivity with blisters, scarring, milia (small epidermal cysts), and hyperpigmentation on sun-​exposed

884

areas (e.g. backs of hands and forearms) and hypertrichosis of the face (e.g. the temples).

Skin markers of chronic renal failure Uraemic pruritus Generalized severe pruritus occurs in about one-​third of patients with renal failure (chronic kidney disease), particularly in patients on haemodialysis, with many more patients experiencing less troublesome pruritus. There seems to be a correlation between pruritus and pre-​dialysis plasma urea levels, but a less obvious relationship between itching and dry skin (xerosis) and secondary hyperparathyroidism. The mechanism of pruritus is complicated, since a reduction in uraemia often does not improve the itching, and pruritus is unusual in acute renal failure. Uraemic neuropathy affects about 60% of patients with renal failure or on long-​term haemodialysis and may play a role in uraemic pruritus. The incidence of uraemic pruritus has been reported to be decreasing, which in part may be due to the use of more sophisticated techniques and equipment for dialysis.

Treatment of uraemic pruritus, and its effectiveness In dialysis, lowering the magnesium concentration of the dialysate has been reported to be helpful. In intractable itching, emollients and UVB radiation are reported to be the most effective therapy. Other treatments have included UVA (without psoralen), colestyramine, activated charcoal, and erythropoietin therapy.

Pigmentary changes in chronic renal failure Anaemia presenting as pallor is an early and common sign of chronic renal failure, resulting from reduced haemopoiesis and increased haemolysis. A greyish-​brown discolouration develops in many cases, due to deposition of melanin. Increased nail pigmentation usually confined to the distal nail occurs in a proportion of patients. This distal brown or reddish colour, combined with a proximal white appearance, gives rise to the term ‘half-​and-​half nails’, a distinctive pattern seen in about 10% of patients with renal failure. Purpura due to mild thrombocytopenia or more marked platelet dysfunction is common and may be partly corrected by dialysis.

Calcific arteriolopathy (calciphylaxis) Calcific arteriolopathy (sometimes called ‘calciphylaxis’ or ‘calcific uraemic arteriolopathy’) is a disorder in which patients, usually with renal failure, develop large painful areas of ulceration. Recent studies have shown that the calcification seen in this condition is not the same as that seen in patients with skin necrosis, so the term ‘calciphylaxis’ is now considered inaccurate. The term ‘calcific uraemic arteriolopathy’ indicates the site of the calcification and the usual clinical state of the patients. However, a similar type of arteriolopathy has been reported in patients with minimal or no renal failure, hence our preferred use of the term ‘calcific arteriolopathy’. In addition to renal failure, the other major risk factors include female gender, white race, diabetes mellitus, obesity, warfarin use, and clotting disorders such as protein C and protein S deficiency. It has also been shown that the use of calcium salts and vitamin D in chronic renal failure is a risk factor. There does not seem to be a direct role of hyperparathyroidism in the development of calcific arteriolopathy, the disease having been described in the presence of normal parathormone levels. The usual presentation of calcific arteriolopathy is of areas of ulceration on the legs, buttocks, abdomen, or breasts; these areas are painful and may be extensive. Livedo reticularis around the ulcers may be present. Acral ulceration can also occur, causing autoamputation. The differential diagnosis is any cause of ulceration, and especially vasculitis, in which livedo reticularis may also be present. Increasing awareness of the condition is allowing the diagnosis of calcific arteriolopathy at an earlier, non-​ulcerative stage, before the subcutaneous indurated plaques develop into ulcers. The diagnosis of calcific arteriolopathy is usually by biopsy, with the histology showing calcification of the media of small arterioles

in the skin. The outcome is poor, with a mortality of about 60% for proximal disease and about 20% for distal disease, usually from overwhelming sepsis.

Treatment of calcific arteriolopathy, and its effectiveness Since there is such a high mortality in calcific arteriolopathy, the approach should be to aim for prevention. The control of the hyperphosphataemia is thought to be fundamental to this. Phosphate binders are used, with some evidence showing that the non-​calcium-​ containing binders are better. Parathyroidectomy has been found to be useful in the control of calcific arteriolopathy in some series but not in others. Nephrogenic fibrosing dermopathy (NFD) is a fibrotic disease occurring in patients with renal disease. NFD was initially reported in patients with established renal failure, either on dialysis or having had a transplant, but it has since been reported in patients with chronic renal insufficiency not requiring renal replacement therapy. An association with the IV injection of gadolinium-​based radiocontrast media (particularly containing gadodiamide) has been suggested. The clinical presentation of this rare disorder is of plaques of indurated skin on the extensor surfaces of the limbs, and scleral involvement has been described. The limbs are affected in a symmetrical manner with skin-​coloured papules coalescing to form brawny plaques with a ‘peau d’orange’ appearance, occasionally with swelling of the hands and feet. Patients may complain of pain, pruritus, and causalgia. Most patients do not have systemic involvement but, when this is present, the disease may be rapidly fatal.

Treatment of NFD, and its effectiveness The mainstay of treatment of NFD is improvement of the renal function but transplantation is not guaranteed to cure the disease.

Addison’s disease The autoimmune diseases include Addison’s disease (adrenal insufficiency), in which one sees melanin pigmentation of the buccal mucosa and skin, particularly the palmar creases. This may be associated with vitiligo, alopecia areata, and other autoimmune diseases, including pernicious anaemia and thyroiditis.

Thyroid disease and the skin There are a number of cutaneous manifestations of both hypothyroidism and hyperthyroidism. Skin features associated with hypothyroidism include pale and cold extremities; absence of sweating; puffy oedema of the hands and the face; eczema craquelé and pruritus; xanthomatosis (secondary to hyperlipoproteinaemia); coarse sparse hair; brittle/​striated nails; purpura/​ecchymoses; punctuate telangiectasia on arms and fingertips; and delayed wound healing. Features associated with hyperthyroidism include soft and dry skin, palmar erythema, flushing, increased sweating, fast nail growth, pruritus, urticaria, pretibial myxoedema (see Figure 260.5), acropachy, and diffuse Addisonian hyperpigmentation.

Figure 260.5  Pretibial myxoedema associated with hyperthyroidism. Please see colour plate section. From: Ethnic Dermatology: Clinical Problems and Skin Pigmentation, Archer CB, Copyright 2008, Informa Healthcare, reproduced by permission of Taylor & Francis Books UK.

Pruritus without a rash Individuals presenting with itch in the absence of skin disease should be carefully assessed. It can sometimes be difficult to distinguish secondary changes associated with excoriation from primary skin disease. However, a detailed history (including drug history) and a thorough systemic examination are crucial. Routine initial investigations might include renal function tests, a full blood count with differential and haematinics, thyroid function tests, and liver function tests, with consideration of other investigations, such as a chest X-​ray, HIV testing, and screening for malignancy, dependent on the clinical findings.

Further Reading Caccavale S and Ruocco E. Acral manifestations of systemic diseases: Drug-induced and infectious diseases. Clin Dermatol 2017; 35: 55–​63. Finucane KA and Archer CB. Dermatological aspects of medicine:  Recent advances in nephrology. Clin Exp Dermatol 2005; 30: 98–​102. Gawkrodger D and Ardern-​Jones MR, Dermatology:  An Illustrated Colour Text, (5th edition), 2012. Churchill Livingstone. Wolff K and Johnson RA. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology (6th edition), 2009. McGraw-​Hill Medical.

CHAPTER 260  Skin markers of internal medicine

Nephrogenic fibrosing dermopathy

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261 

Drug-​induced skin disease

Muthu Sivaramakrishnan

Introduction Drug-​induced skin disease is one of the commonest dermatological presentations in both hospitalized and ambulatory patients. It affects 2%–​3% of hospitalized patients and it is estimated that 1 in 1000 hospitalized patients has a serious cutaneous drug reaction. The clinical presentation can mimic any skin disease and should be considered in the differential diagnosis of any acute-​onset symmetrical skin eruption. It is important to make a correct diagnosis, as removal of the offending drug results in clinical resolution in most instances.

Table 261.1  Common drugs causing cutaneous drug reactions Drug reaction

Drugs

Fixed drug eruption

Sulfonamides Tetracyclines Penicillin Quinine Barbiturates NSAIDs

Erythema multiforme

Cephalosporin Sulfonamides Penicillin Rifampicin Barbiturates Carbamazepine Phenothiazines Thiazide diuretics

Stevens–​Johnson syndrome and toxic epidermal necrolysis

Sulfonamides Penicillin Ethambutol Rifampicin Tetracyclines NSAIDs Barbiturates Carbamazepine Lamotrigine Phenytoin Terbinafine Griseofulvin

Exanthematous drug eruption

Penicillin Ampicillin Co-​amoxiclav Sulfonamides Phenytoin Carbamazepine

Drug hypersensitivity syndrome

Anticonvulsants Co-​trimoxazole Minocycline Allopurinol Terbinafine Dapsone

Urticaria and angioedema

Antibiotics Antifungal agents Angiotensin-​converting enzyme inhibitors NSAIDs Muscle relaxants Food additives

Lichenoid drug eruption

Gold salts Antimalarials Penicillamine Frusemide Thiazides Sulfasalazine

Etiopathogenesis Cutaneous drug reactions can be caused by both immunological and non-​immunological mechanisms. The immunological mechanism can be due to the various types of hypersensitivity reactions classified by Gell and Coombs. Non-​immunological mechanisms include irritant reactions caused by topical agents, dose-​dependent toxic reactions, phototoxic reactions, and idiosyncratic reactions.

Clinical features Cutaneous drug reactions can mimic any form of skin disease. Most of the reactions are mild and often settle after removing the offending drug. The commonest clinical presentations are exanthematous reactions; urticaria and angioedema; erythema multiforme; lichenoid eruptions; bullous eruptions; and drug hypersensitivity syndrome. Bullous eruptions present in various forms, including fixed drug eruptions, drug-​ induced vasculitis, Stevens–​ Johnson syndrome, toxic epidermal necrolysis, drug-​ induced porphyrias, pseudoporphyria, pemphigus, and pemphigoid. Severe drug reactions can be recognized from their cutaneous and systemic features. Features of severe cutaneous drug reactions include skin and systemic manifestations. For the skin, extensive reddening, facial swelling, pain, palpable purpura, blisters (especially if extensive), involvement of mucous membranes, and a swollen tongue may be seen. Systemic features include a high temperature; swollen lymph nodes (indicating extensive skin inflammation); joint pains or swelling; respiratory symptoms (particularly breathlessness); and, ominously, low blood pressure.

Individual types of drug-​induced skin disease Common drugs causing cutaneous drug reactions are listed in Table 261.1.

Fixed drug eruption A fixed drug eruption is characterized by the occurrence of one or more erythematous patches, plaques, bullae, or erosions that are present at the same site and were caused by the ingestion of a drug.

Causes of a fixed drug eruption The following agents can cause a fixed drug eruption: • antibacterial agents (e.g. sulfonamides, tetracyclines, penicillin, quinine) • barbiturates • NSAIDs • oral contraceptives • food substitutes

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Lesions are usually single on the limbs but can be multiple and can occur at any site, including mucous membranes. The initial lesion is an erythematous macule developing then into a patch, plaque, or bulla with erosion. The lesions heal with post-​inflammatory pigmentation.

Diagnosis of a fixed drug eruption Diagnosis is usually done by clinical signs but, occasionally, a skin biopsy may be necessary.

Management of a fixed drug eruption With a fixed drug eruption, stopping the offending drug will help the lesions heal in few weeks. Potent topical steroids will be helpful for localized lesions, but systemic steroids may be essential for generalized and painful mucosal lesions.

Erythema multiforme Erythema multiforme is characterized by multiple macules, papules, or urticarial lesions, along with target lesions mainly affecting the distal extremities. It is more often by caused by viral infections (e.g. by herpes simplex virus) but can occasionally be caused by the ingestion of a drug.

Causes of erythema multiforme The following agents can cause erythema multiforme: • antimicrobials (e.g. cephalosporin, sulfonamides, penicillin, rifampin) • barbiturates • carbamazepine • phenothiazines • thiazide diuretics

Clinical features of erythema multiforme In erythema multiforme, the characteristic lesion is a target lesion which is less than 3 cm in diameter, is round in shape, and has three zones: a central area of erythema or purpura, which is surrounded by a pale zone of oedema, which in turn is surrounded by well-​defined erythema. Other lesions may be in the form of macules, papules, or urticarial lesions. The commonest site of involvement is the distal extremities, with rare involvement of mucous membranes (erythema multiforme minor). However, some patients may have a prodromal illness with severe generalized disease and mucous membrane involvement (erythema multiforme major).

Diagnosis of erythema multiforme The diagnosis of erythema multiforme is usually made with clinical signs but a skin biopsy may be necessary on occasion. The cutaneous biopsy may show vacuolar degeneration of lower epidermis, individual necrotic epidermal cells, and dermal, perivascular lymphohistiocytic infiltrate.

Treatment of erythema multiforme When treating erythema multiforme, it is important to stop the offending drug. Ocular involvement requires urgent help from an ophthalmologist. Good skin nursing care is essential in severe cases. Potent topical steroids may be helpful in localized lesions. The use of systemic steroids is debated, although they can help in the relief of systemic symptoms and in severe cases. Thalidomide, dapsone, azathioprine, and ciclosporin may be helpful in recurrent cases.

Stevens–​Johnson syndrome and toxic epidermal necrolysis Stevens–​Johnson syndrome is a severe, acute-​onset disease characterized by a prodromal illness, erythema multiforme of the trunk, and skin blisters involving less than 10% of the body’s surface area. Toxic epidermal necrolysis is also a severe, acute-​onset illness but is characterized by a prodromal illness, sheets of erythema, and skin peeling involving more than 30% of the body’s surface area.

Causes of Stevens–​Johnson syndrome and toxic epidermal necrolysis The following agents can cause Stevens–​Johnson syndrome and/​or toxic epidermal necrolysis: • antibiotics (e.g. sulfonamides, penicillin, ethambutol, rifampicin, tetracyclines, thioacetazone) • NSAIDs • anticonvulsants (e.g. barbiturates, carbamazepine, lamotrigine, phenytoin) • antiretroviral agents • antifungal agents (e.g. terbinafine and griseofulvin) • others (e.g. allopurinol, thiazide diuretics, gold, vaccines)

Clinical features of Stevens–​Johnson syndrome and toxic epidermal necrolysis In Stevens–​Johnson syndrome, patients usually have a severe prodromal illness with fever, myalgia, and arthralgia, following which they develop extensive erythema multiforme lesions on the trunk. They also develop blisters and erosions both on the skin and on mucosal areas. The oral mucosa is commonly involved, followed by the mucosae in the eyes and the genitalia, but any mucosal membrane can be affected. Involvement of lungs and kidneys has been reported. The mortality rate is 5%–​15% in untreated patients, due to renal damage, infection, and toxaemia. In treated patients, the eruption usually heals well but permanent damage can be caused to mucous membranes, particularly in the eyes. In toxic epidermal necrolysis, patients have a severe prodromal flu-​like illness followed by sheets of erythema leading to painful erosions involving the skin and mucous membrane. Mucous membranes are involved in all patients; the oral mucosa is particularly involved, but any mucosal areas can be affected. Acute complications include sepsis, renal failure, induction of a hypercatabolic state, and pneumonitis. Chronic complications are mainly due to permanent damage to mucous membranes. The mortality rate is around 30%–​40% in untreated cases.

Diagnosis of Stevens–​Johnson syndrome and toxic epidermal necrolysis Skin biopsy and histopathology of toxic epidermal necrolysis will reveal full thickness necrosis of skin in established lesions with perivascular mononuclear cells in the dermis. The histology of Stevens–​Johnson syndrome more often resembles erythema multiforme.

Management of Stevens–​Johnson syndrome and toxic epidermal necrolysis In Stevens–​Johnson syndrome and toxic epidermal necrolysis, early diagnosis and stopping the offending drug are the most important steps in management. Patients are best managed in specialized dermatology unit or burns unit (particularly patients with toxic epidermal necrolysis). Fluid and electrolyte replacement and maintaining body temperature is important, as often these patients can develop renal failure and hypothermia. Specialist involvement should be sought early if mucosal areas are involved to prevent complications. Good skin care with emollients and topical antibacterial agents is necessary. Systemic steroids in high doses and early in the disease might be helpful but their use is controversial. IV immunoglobulins early in the disease might help further progression. Appropriate early treatment of complications (like sepsis) is essential.

CHAPTER 261  Drug-induced skin disease

Clinical features of a fixed drug eruption

Exanthematous drug eruptions Exanthematous drug eruptions are the most common of all cutaneous drug reactions (about 75% of all drug rashes) and can occur between 3 days to 2 weeks of ingesting a drug. An exanthematous drug eruption is characterized by an erythematous maculopapular eruption and scaly patches commonly affecting the trunk and extremities. Purpuric lesions of the legs and erosive stomatis can occur in some patients. Some patients may have fever, itching, and peripheral eosinophilia. The commonly implicated drugs are penicillin, ampicillin, co-​ amoxiclav, sulfonamides phenytoin, and carbamazepine. Removal of the offending agent, together with the use of moderately potent to

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potent topical steroids and antihistamines, will usually help to resolve the situation.

stopping the offending drug and administering antihistamines and systemic corticosteroids (in severe cases).

Drug hypersensitivity syndrome

Lichenoid drug eruption

Drug hypersensitivity syndrome, also known as DRESS syndrome (drug rash with eosinophilia and systemic symptoms), consists of fever, lymphadenopathy, organ involvement (e.g. hepatitis, nephritis, pneumonitis, and encephalitis), haematological abnormalities, and a cutaneous rash. The skin eruption is usually in the form of papules or a papulopustular or exanthematous rash leading to erythroderma. Haematological abnormalities include eosinophilia and atypical lymphocytes. This condition is usually caused by anticonvulsants but can also be caused by co-​trimoxazole, minocycline, allopurinol, terbinafine, and dapsone. Treatment includes stopping the offending drug and administering systemic corticosteroids.

A lichenoid drug eruption is characterized by scaly violaceous papules and plaques on the trunk and extremities, sometimes leading to erythroderma. Mucosal involvement is uncommon in a lichenoid drug eruption, unlike the case with lichen planus. The common causative drugs include gold salts, antimalarials, penicillamine, furosemide, thiazides, and sulfasalazine. Quinine and tetracyclines can cause such eruptions on the photo-​exposed areas of the skin. Management involves stopping the offending drug and administering potent topical steroids and systemic corticosteroids (in severe cases).

Urticaria and angioedema

CHAPTER 261  Drug-induced skin disease

Urticaria is characterized by itchy, transient, oedematous papules, and plaques. These lesions are called ‘wheals’ and are caused by superficial oedema in the papillary dermis. Angioedema involves oedema of the deeper tissues, including the dermis and subcutaneous tissue. The common causative drugs in urticaria and angioedema are antibiotics, antifungal agents, angiotensin-​converting enzyme inhibitors, NSAIDs, muscle relaxants, and food additives. Management involves

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Further Reading Burns T, Breathnach S, Cox N, et  al. (eds). Rook’s Textbook of Dermatology (8th edition), 2010. Wiley-​Blackwell. Duong TA, Valeyrie-Allanore L, Wolkenstein P et al. Severe cutaneous adverse reactions to drugs Lancet 2017; 390: 1996–2011. Stern RS. Exanthematous drug eruptions. N Engl J Med 2012; 366: 2492–​501. Wolff K and Johnson RA. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology (6th edition), 2009. McGraw-​Hill Medical.

262 

Psychocutaneous medicine

Anthony Bewley

Introduction The links between the mind and the skin have long been recognized. The skin has been described as the mirror of the mind, and so it is not surprising that the interface between dermatology and psychiatry (‘psychocutaneous medicine’ or ‘psychodermatology’) is emerging as a specific subspeciality of dermatology. Psychodermatological conditions can be classified as either primarily psychiatric disorders which manifest via skin disease, for example delusional infestation, or primarily dermatological disorders, for example psoriasis, which may be caused by, or associated with profound psychiatric morbidity (e.g. anxiety, depression; see Table 262.1).

Delusional infestation Delusional infestation is a well-​recognized uncommon condition in which patients hold a fixed belief that they are infested with organisms (parasites, bacteria, viruses) or fibres. When referred to a purely psychiatric clinic, patients with delusional infestation often default their appointments, but they are also difficult to manage in a standard dermatology clinics. Older terms such as ‘delusional parasitosis’ and ‘acaraphobie’ have been replaced by the term ‘delusional infestation’. Delusional infestation can be classified into primary and secondary disorders. Primary delusional infestation is classified by DSM-​IV as ‘delusional disorder of somatic type’, and in ICD-​10 as ‘persistent delusional disorder’. It is uncommon (about 20 new cases per million population); the female-​to-​male ratio under the age of 50  years is similar, but that for those over 50 is 2:1. There is a bimodal distribution with respect to age, with one peak occurring between 20 and 30 years of age, and then another at over 50, and there are frequent reports of the delusions being shared with a relative or close friend (folie-​a-​deux; 8%–​12% of cases), and occasionally more than one person (folie-​a-​trois). Secondary delusional infestation may follow a real infestation, be associated with recreational drug use (alcohol, cannabis, etc.), be a precursor to dementia, and be associated with other organic disease. But also delusional infestation may be secondary to ‘functional’ psychiatric diseases (such as schizophrenia). It is therefore essential that

Table 262.1  Psychocutaneous medicine Primary psychiatric disorders which present with skin disease

Primary dermatological disorders caused by or associated with psychiatric comorbidity

Delusional infestation Body dysmorphic disorder Dermatitis artefacta OCD (e.g. repeated handwashing) Trichotillomania Neurotic excoriation Others

Psoriasis Eczema Alopecia (e.g. areata) Acne Rosacea Urticaria Vitiligo Visible differences (disfigurements) Inherited skin conditions (e.g. ichthyosis) May be caused, exacerbated by, or associated with: depression • anxiety • body image disorder • social anxiety •

a full medical history (including a dermatological history, a history of substance abuse, and a psychiatric history) and a physical examination are undertaken to identify potential organic disease and make an accurate diagnosis. Many patients bring containers with samples of ‘infested material’ (the ‘matchbox sign’) to the doctor. Patients may take extreme measures to eradicate the organisms from their bodies, and frequently cause severe damage to their skin through applying noxious substances or even burning the skin. Patients with delusional infestation are notoriously difficult to manage due to their lack of insight and resistance to psychiatric referral. Joint working between psychiatrists and dermatologists is therefore vital. Exclusion of organic cause is mandatory. This may include a pruritus screen (thyroid, renal, and liver function tests, blood count, vitamin B12, folate, and syphilis serology). But clinical assessment will inform whether these or other investigations may be relevant. It is important not to confront the patient with the falsity of their delusional belief, as this leads to loss of any therapeutic alliance, and the patient will simply move to find someone who will take their concern ‘seriously’. All samples should be sent for analysis, first, to support the patient, second, to provide a template for discussions about why treatment with antimicrobials is inappropriate, and, last, to exclude genuine infestation. Empathizing with patients is crucial. Patients with delusional infestation have usually seen a large number of doctors, are often frustrated with the perceived lack of help they have received, and are frequently hostile. But it is important not to collude with patients, too. Instead, letting patients know that you understand the seriousness of their condition, and that there are effective therapeutic options for their symptoms, is often enough to engage the patient in a clinical dialogue. Conventional antipsychotics are probably effective. Pimozide was considered the treatment of choice; however, in view of its cardiotoxic side effects, atypical antipsychotics are now considered a better choice. There are no random controlled trials but case reports, case series, and clinical experience suggest that atypical agents such as risperidone, olanzapine, quetiapine, and amilsulpride are effective. Typically, patients respond to smaller doses (e.g. 0.5 mg risperidone twice daily, increasing if necessary to 1 mg twice daily). The prognosis of delusional infestation is highly dependent on the clinical environment. In joint dermatology–​psychiatry clinics, successful treatment of delusional infestation can be expected in over 75% of patients.

Body dysmorphic disorder Body dysmorphic disorder (BDD; also, inaccurately, called dysmorphophobia) is characterized by a preoccupation with a perceived or real visible difference in which the patient’s concern is out of proportion to the ‘defect’. There is a spectrum from patients with overvalued ideas to those whose beliefs are held with delusional conviction (in DSM IV, ‘delusional disorder-​somatic type’; in ICD 10, ‘other persistent delusional disorders’). BDD is common, affecting 1%–​2% of the population (although many of us have a lesser degree of dissatisfaction with our bodies), especially in adolescence, and is known to be associated with mood disorders, obsessive compulsive disease, and social phobia. The condition is extremely disabling for patients and their relatives, as the ‘defect’ may seem, objectively, to be minor and the reaction to the ‘defect’, extreme. Many patients spend long periods in front of mirrors, while others have extensive rituals simply to build enough confidence to look in a mirror. Many become socially isolated, and many seek repeated aesthetic surgery, only to be dissatisfied with the results, or to find another perceived ‘defect’.

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Treatment may be tricky, as most patients lack insight and will not accept psychiatric treatment or referral. Affected individuals are therefore best seen in a joint psychodermatology clinic, where they can be supported, and gradually encouraged to accept psychological interventions. Their surgery-​seeking behaviour can also be contained. The limited evidence base indicates that serotonergic antidepressants (fluoxetine, citalopram, fluvoxamine) may be effective, particularly in higher doses and for longer periods. Importantly, CBT can be effective in BDD patients, and may be pivotal in allowing the patient to regain a healthier perspective of their ‘defect’. Untreated, the condition tends to be chronic, and there is a high suicide risk.

CHAPTER 262  Psychocutaneous medicine

Dermatitis artefacta

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Dermatitis artefacta (DA) describes the condition whereby a patient creates skin lesions but denies knowledge of self-​infliction (as opposed to deliberate self-​harm, where the patient will be able to acknowledge the self-​infliction, and will usually indicate that ‘cutting’ gives the individual a sense of control over their body, and/​ or relieves some emotional tension). In DA, patients produce their artefacts secretly, deny complicity, and may be unaware of their psychological motivations. They and their relatives are often puzzled about the aetiology of their skin lesions, and may be angry with doctors’ inability to diagnose and treat the mysterious problem. The skin lesions, themselves, may be very varied in character (e.g. linear tears, bruises, cuts, non-​healing ulcers) and in severity (minor erosions to widespread, severe, deep ulceration). DA is probably common and under-​reported. It is more common in women (at least 3:1), and the incidence is greatest in the late teens or early twenties. Often, there is a connection between the patient or their family and some aspect of healthcare (such as a recent illness). In addition, studies suggest an association with physical or sexual abuse in some patients. The first rule of managing patients with DA is to be absolutely certain that the diagnosis of DA is accurate and that non-​self-​induced disease has been comprehensively excluded. A non-​confrontational approach is essential. Focusing on how the skin lesions are generated is of less importance than finding out why they are there. Although DA is primarily a dermatological diagnosis, management should involve close cooperation with specialists in mental health. Management is of the skin as well as the underlying psychological issues. General measures such as emollients and topical antibacterials can all be used, depending on the presenting lesions. Occlusion has been used as a diagnostic and therapeutic tool with variable success. Psychological and psychopharmacological approaches are started at the same time as the dermatological treatments. CBT and psychotherapy are probably pivotal, but there is a wide range of efficacy. Patients are often unwilling to accept the psychiatric nature of the disorder and lack the awareness of their circumstances that trigger the drive to produce the lesions. In such circumstances, dermatology/​liaison psychiatry clinics may be beneficial. Often, it is important to simply wait until the patient has enough confidence to relate the underlying psychological issues (there is almost always an underlying issue; this may be relatively minor, such as pressure from examinations, or may be

Box 262.1  Management of the psychosocial aspects of chronic skin disease 1. Listen to the patient. This is by far the easiest and most important aspect of psychosocial care. It is easily overlooked. 2. Engage patients with support groups: • http://​vitiligosociety.org.uk • http://​www.psoriasis-​association.org.uk • http://​www.changingfaces.org.uk 3. Assess any suicidal ideation. 4. Consider a referral to a ‘psychodermatology clinic’. Unfortunately, these are few and far between, but local dermatology units may have either someone with psychodermatological experience, or will be able to refer to a local (usually liaison) psychiatrist. 5. Discuss the possibility of CBT. This may be invaluable for some patients. Person-​centred psychotherapy is probably the most appropriate, as it may focus on thought and behaviour patterns which are unhelpful. 6. Consider psychotropic medication. Sometimes medication for affective disorders may be a useful part of the patient’s holistic care. SSRIs (e.g. citalopram) are usually the medication of choice.

devastating, such as sexual abuse). SSRIs can be used where there is an underlying or associated affective disorder. The prognosis of this condition is probably much, much better when patients are engaged with their healthcare professional team.

Psychological comorbidities of chronic skin disease Psychological comorbidities of chronic skin disease are often underestimated by healthcare professionals. The anxiety, disempowerment, and frustration felt by patients with, for example, psoriasis and vitiligo is only beginning to be recognized. The commonest psychological implication of cutaneous disease is impaired self-​esteem, to the extent that some patients will even consider suicide. Inclusive management of the dermatology patient’s psychosocial comorbidities (Box 262.1) is a newer, under-​recognized and emerging area of holistic care.

Further Reading Brown GE, Malakouti M, Sorenson E, et al. Psychodermatology. Adv Psychosom Med 2015; 34: 123–​34. Mohandas P, Bewley A, and Taylor R. Dermatitis artefacta and artefactual skin disease: The need for a multi-​disciplinary psycho-​cutaneous medicine team to treat a difficult condition. Br J Dermatol 2013; 169: 600–​6. Raff AB and Kroshinsky D. Cellulitis: a review. JAMA 2016; 316: 325–​37.

PART 12 Disorders of the musculoskeletal system

263 

Normal function of the musculoskeletal system Shireen Shaffu and James Taylor

Introduction The musculoskeletal system consists of specialized connective tissue whose primary function is to allow locomotion. The tissues of the musculoskeletal system are bones, muscles, tendons, and ligaments. In particular, the bony skeleton also has the task of protecting vital internal organs, contains the bone marrow, and is an intrinsic part of the metabolic pathways involved in calcium homeostasis. Motion is allowed by specialized articulating structures, the joints. This chapter contains a brief description of all the components.

Bone Bone is a collagen-​rich connective tissue matrix (mainly collagen type I) that is calcified to provide rigidity. Some bones are laid down as a matrix that then calcifies, in a process called membranous ossification (e.g. skull, collarbone), but the majority are laid down as a cartilage model which then gets remodelled and replaced by bone in a process called endochondral ossification (e.g. long tubular bones of the limbs). Initially, the shaft diaphysis calcifies, but the ends of the bones maintain a cartilage architecture which allows further elongation of the bone, resulting in linear growth. These cartilaginous growth plates (epiphyses) eventually calcify as the skeleton matures, so further longitudinal growth ceases. Bone is not an inert tissue; it is in a constant cycle of resorption and formation to allow microarchitectural repair of bone. Bone contains most of the body stores of calcium and therefore is an integral part of calcium homeostasis, which is principally under the control of parathyroid hormone and vitamin D.  These hormones control intestinal absorption of calcium, calcium exchange with the principal body stores in bone, and renal excretion of calcium. Abnormalities of these hormone systems can therefore have substantial impacts on the calcified bone matrix and, therefore, the overall bone strength. There are many genetic disorders which affect bone growth and structure and which result in short stature, disproportionate growth, or deformity (e.g. achondroplasia). Genetic alteration of the collagen 1 production results in very low bone mass prone to fracture, a condition known as osteogenesis imperfecta. The common acquired diseases affecting bone metabolism are: • osteoporosis, which is an idiopathic reduction in bone mass which becomes increasingly prevalent with age; risk factors for premature osteoporosis include early menopause, chronic steroid use, rheumatoid arthritis, thyroid/​parathyroid and adrenal disorders, and malabsorption syndromes of any cause • osteomalacia, which is defined as a failure to calcify the connective tissue matrix of bone due to reduced availability of calcium or phosphorus, most usually as a result of vitamin D deficiency

Cartilage Cartilage is a specialized and largely avascular connective tissue, rich in collagen type II, which in the adult skeleton covers the articulating surfaces of bone of synovial joints. Cartilage is rich in highly charged hydrophilic molecules (glycosaminoglycans) attached to a large hyaluronic acid molecule, which allows cartilage to maintain a high water content. In the growing skeleton, cartilage also forms a matrix scaffold of future long bones, which are further remodelled by endochondral

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ossification into mature bone. Some structures in the body remain as cartilage (e.g. the pinna of the ear and the nasal septum). Idiopathic inflammation of cartilage structures is the hallmark of the rare disease relapsing polychondritis. More commonly in degenerative arthritis (osteoarthritis), there is degeneration of cartilage within the joint; this progresses from fibrillation of the surface to fissuring of cartilage and eventual thinning of the cartilage layer, resulting in exposed bone.

Muscle Muscle is a specialized connective tissue that is able to contract. This is a metabolically active process directed by a neurological signal. Acetylcholine released at the nerve ending crosses the neuromuscular junction and engages a receptor to trigger calcium-​dependent actin/​myosin interactions which allow the muscle fibres to shorten. Further requirements are a supply of oxygen, a source of fuel, such as glycogen, and a well-​maintained balance of potassium and calcium, all of which are essential for normal muscle function. Voluntary muscle (sometimes referred to as striated muscle due to its appearance under the microscope) requires an intact neurological supply and neuromuscular junction to initiate movement. This type of muscle is made up of two principal types of muscle fibre cell: type 1, fast-​twitch muscle fibres, and type 2, slow-​twitch muscle fibres. Some muscles are not under voluntary control. These involuntary muscles (sometimes referred to as smooth muscle due to their appearance under the microscope) are largely controlled by the autonomic nervous system and are generally found in the muscular walls of some arterial, bronchiolar, and intestinal tissues, as well as tissues of the urogenital tract. Some specialized muscles (e.g. cardiac muscle) are able to contract autonomously but still require some neuronal control for appropriate function. Alterations in muscle function are caused by depravation of oxygen or by metabolic abnormalities that alter the metabolism or availability of the muscle’s fuel sources. Biochemical imbalances and neurological disease also result in impaired muscle function. Genetic abnormalities can result in muscular dystrophies or myotonic syndromes. However, the principal manifestation of muscle disorders in rheumatology are due to direct tissue injury by an inflammatory process, myositis.

Tendons Tendons are non-​calcified collagen-​rich connective tissues that attach muscle to bone. Tendons transmit the force generated by muscles to the moving parts of the skeleton through a specialized attachment called an enthesis. Inflammation of these attachment points, enthesitis, is a common feature of the inflammatory spondyloarthritides. The tendon itself can become inflamed, resulting in a condition known as tendonitis, as part of a more general inflammatory disorder, or as a specific localized event. Tendons sometimes have a sheath which can also become inflamed; this condition is referred to as tenosynovitis. However, the principal cause of localized tendon damage is usually secondary to mechanical loading which exceeds the capabilities of the tendon and commonly results in a degenerative process referred to as tendinosis but occasionally progresses to catastrophic failure: tendon rupture.

Ligaments are non-​calcified connective tissues attaching adjoining bones together across a joint. By providing constraints, ligaments can define congruency of adjoining joint surfaces and the number of possible planes of movement. Ligament strains are frequent causes of pain following injury. Ligament rupture often results in instability, and the abnormal motion can accelerate cartilage degradation in the joint due to the alteration in joint biomechanics. Disorders which affect the connective tissue components of tendons and ligament frequently result in hypermobility and, in extreme cases, recurrent dislocation of joints is sometimes associated with arterial fragility and rupture (e.g. Ehlos-​Danlos syndrome—​of which there are many types).

Joints Synovial joints allow significant movement between two adjacent bones. The joint is enclosed by a capsule lined by synovium on its inner surface. Ligaments reinforce the capsule and hold the bones which make up the joint together. The ligaments and the articulating surfaces define the planes of movement possible at that joint. Movement is facilitated by a reduction in friction of the joint surfaces due to the formation of a cartilage cap at the end of each bone, thus allowing cartilage–​cartilage articulation. The synovium is a layer of specialized connective which secretes joint fluid, which in small quantities is present in all joint spaces. Joint fluid provides a boundary fluid layer which further helps to reduce the coefficient of friction between cartilage surfaces. As well as secreting joint fluid, the cells of the synovium also take part in the immune response by taking on tissue macrophage roles and allowing the generation of germinal centres if required. In inflammatory arthritides, the synovium is the target for the inflammatory process which results in synovitis. In synovitis, the synovium thickens due to the accumulation of chronic inflammatory cells involved in the immune response and

the generation of inflammation. The synovitic tissue can have locally invasive effects eroding into the cartilage of the joint; this mass of synovial tissue in contact with cartilage and bone within the joint is often referred to as a pannus. Synovial lining cells also secrete large quantities of joint fluid which can result in a joint effusion. Arthritis is said to exist if the joint is swollen and tender on palpation and if there is limitation of movement on examination. In inflammatory synovitis, the joint will, in addition, often be warm to the touch and, in acute onset, may have overlying skin colour changes (particularly if the joint is close to the skin surface).

Ageing and the musculoskeletal system Any discussion of normal musculoskeletal function should include an understanding of how the normal ageing process affects both normal homeostatic mechanisms for normal musculoskeletal function, and the types of diseases one is likely to encounter at different ages. Our genes programme development in utero and affect the growth and development of the skeleton into the mid-​twenties. Some tissues retain the capability to repair (e.g. soft tissue, bone) and some do not or only retain a limited capacity to repair (e.g. cartilage). In general, genes determine our maximum capacity to develop traits (e.g. bone mineralization, muscle strength/​ endurance). Whether or not an individual achieves this maximum capacity predetermined by our genes depends on subsequent nurture and avoidance of disease (e.g. a child affected by inflammatory arthritis through pre-​teen and teenage life will struggle to achieve maximum bone mineralization and will therefore be at higher risk of osteoporosis in later life).

Further Reading Hochberg MC, Silman AJ, Smolen JS, et al. Rheumatology (6th edition), 2014. Mosby.

CHAPTER 263  Normal function of the musculoskeletal system

Ligaments

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264 

Diagnosis in suspected rheumatological disease Rachel Jeffery

Introduction Musculoskeletal symptoms may be the sole presenting complaint of a rheumatological disease or may be a minor part of a presenting symptom complex. Determining whether or not these symptoms reflect serious pathology requiring specialist management relies on careful history taking and a thorough examination. The majority of rheumatic conditions are chronic, and a holistic approach to patient management is required to establish how the illness affects the physical and psychological functioning of the patient, and to explore how symptoms may be managed. In assessing the patient with musculoskeletal symptoms, you must consider the following questions: • are the symptoms due to an inflammatory process or a non-​inflammatory process? • do the symptoms reflect a primary rheumatological disease or are they secondary to another pathology (e.g. infection or malignancy)? • are the symptoms a complication of the disease or a complication of treatment? • is there evidence of non-​articular disease, which may be relevant to diagnosis or management? This chapter focuses on how elements of the history and examination can help answer these questions. Investigation, dealt with in Chapter  265, provides additional information on diagnosis and prognosis.

History taking When the history is being taken, the age, gender, and ethnicity of the patient should be noted, as well as whether the patient is pregnant, whether the patient smokes, and the presence of any psychosocial factors that may have an impact. Symptoms should be recorded and a history of preceding symptoms, a travel history, a sexual history, and a family history should be taken.

Age When diagnosing rheumatological disease, the following age-​related factors should be taken into consideration: • most autoimmune rheumatic disease can present at any age, although peak incidence varies with condition • osteoarthritis is uncommon below the age of 45, unless there has been specific trauma or congenital deformity at one site • calcium pyrophosphate crystal arthropathy (pseudogout) is rare in patients under the age of 60, unless there is a familial association • malignancy as cause of musculoskeletal or systemic symptoms is more common in those over the age of 65 • polymyalgia rheumatica and giant cell arteritis rarely occur in those 30 min Stiffness improves with exercise, worse with rest

Pain worse on activity Pain better with rest Early morning stiffness 6 weeks) reduces the likelihood of returning to work. Financial problems predict depression, disability, and relationship problems.

Depression Depression is common in chronic rheumatologic conditions and is often missed. It is predicted by level of disability rather than severity of disease. Deformity, negative self-​image, loss of independence, and control also contribute.

Relationships Social support from family, friends, healthcare workers, and patient groups is associated with lower levels of depression. Problems arise when there are reduced opportunity for social contacts; increased isolation and dependence; sexual problems; mood changes; and loss of income.

Coping strategies The belief of self-​control over pain is associated with higher well-​ being and lower disability scores. In contrast, catastrophizing, fear-​ avoidance behaviour, and reduced levels of activity are associated with lower psychological well-​being and higher disability scores.

Symptoms Determining the presence of specific symptom complexes helps to narrow the differential diagnosis and classification and will guide decisions on further investigations and management. Classification criteria for rheumatic disease should not be confused with diagnostic criteria. Once information about pain and stiffness has been obtained, it should be possible to decide whether the condition is more likely to be inflammatory or non-​inflammatory (mechanical; see Table 264.1). This distinction is important, as it will influence the rest of the history taking. For inflammatory conditions, systemic and extra-​articular features, as well as clues as to classification of the condition, will be looked for in both the history and the examination. For non-​inflammatory conditions, aggravating factors and ways of managing the symptoms within the patient’s lifestyle will be considered. In addition, ‘red flags’, which would indicate the need for urgent further investigation to exclude infection and malignancy, need to be excluded (see Box 264.1).

Pain Pain is the most common rheumatological symptom. Several patterns of pain are recognizable: • pain which is worse with or following movement and which is often worse later in the day is suggestive of a mechanical process, such as degenerative arthritis • pain which is worse in the early morning, is often associated with prolonged early morning stiffness, is worse after rest, and is relieved by exercise is suggestive of an inflammatory process • pain associated with neurological symptoms suggests a neuropathic element; radicular pain that is sharp, electric-​shock-​like, and often aggravated by cough (due to raised intrathecal pressure) suggests nerve root entrapment; pain associated with significant neurological dysfunction suggests neural injury and is often worse at night-​time • well-​localized bone pain suggests an injury and, if severe at rest or at night, may be indicative of a malignancy • poorly defined pain localized to a single area but not affected by movement of that area suggests referred pain (e.g. right shoulder pain in cholecystitis; left arm pain in acute coronary syndrome) • musculoskeletal pain associated with systemic/​ constitutional symptoms should prompt a search for infection, malignancy, or features of connective tissue disease or vasculitis

CHAPTER 264  Diagnosis in suspected rheumatological disease

When diagnosing rheumatological disease, the following pregnancy-​ related factors should be taken into consideration:

Box 264.1  ‘Red flags’ pain worse at night • • associated systemic features (fever, sweats) • unexplained weight loss • new neurological symptoms • previous history of malignancy • immunocompromise • extremes of age (70 years)

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• increasing muscle pain during the use of a limb suggests vascular claudication and, when in unusual locations (upper limb or jaw), could suggest a vasculitis • hyperalgesia (more pain than expected from a noxious stimulus) and allodynia (pain from a non-​noxious stimulus) suggests a more complex central pain-​processing problem; this can be generalized pain in fibromyalgia, or localized pain in complex regional pain syndrome

Generalized myalgia (pain in the muscles) and arthralgia (pain in the joints) can occur with systemic illness and fever, due to systemic cytokine release, without the musculoskeletal system being the primary location of inflammation, as in response to a viral’ flu-​like’ illness. A history of associated and preceding symptoms as well as the duration of the symptoms will provide pointers to possible infectious aetiology.

Stiffness

Preceding symptoms, travel, and sexual history

Stiffness is another common symptom of rheumatological disease, but it can be difficult to characterize precisely, as patients will often equate it with pain. Significant stiffness, particularly early morning stiffness of more than 30 minutes duration, is more in keeping with inflammatory disease and will usually improve with activity through the day. Mechanical disorders can cause stiffness but this is often short-​ lived, start-​up pain/​stiffness. Some neurological conditions cause stiffness following upper motor neuron lesions (e.g. cervical cord compression) or extrapyramidal disease (e.g. parkinsonism).

A history of upper or lower respiratory tract infection, acute gastroenteritis, genitourinary symptoms, or risk of exposure to sexually transmitted disease may help identify a reactive arthritis (likely if multiple joints involved) or secondary septic arthritis (essential to consider, particularly if only one joint is involved). In addition, note that an individual who already has one autoimmune disease has a 1 in 5 risk of developing a second one. The spectrum of infectious agents considered will be influenced by the travel history, for example travel to areas endemic for Lyme disease (e.g. New Forest and Norfolk in the UK; Germany; northern parts of North America). HIV infection can be associated with autoimmune disease presentation at seroconversion, as part of the AIDS complex of symptoms and during immune reconstitution on antiretroviral treatment. Diffuse infiltrative lymphocytosis syndrome (DILS), presenting with Sjögren’s type glandular swelling, should not be missed. Psoriasis and spondyloarthropathies can present in HIV infection, and there is a higher risk of septic arthritis.

CHAPTER 264  Diagnosis in suspected rheumatological disease

Swelling Swelling is often reported but must be corroborated by examination (e.g. patients with areas of numbness often report a feeling of swelling). When swelling of a joint is fixed and bony, this suggests osteoarthritis. When swelling of a joint is soft and boggy, it may be inflammatory. When swelling of a limb occurs with pitting on pressure, this suggests oedema.

Colour changes Redness (erythema) associated with a joint or bursa should be considered a sign of infection until proven otherwise. Non-​specific skin redness of a limb should be considered a possible sign of cellulitis. Once infection has been excluded, other possible causes include crystal arthropathy, seronegative spondyloarthropathy, erythema nodosum, ruptured Baker’s cyst, and DVT. Palmar erythema can be seen in rheumatoid arthritis and vasculitis, although other non-​rheumatological causes need to be considered. Vascular changes in Raynaud’s disease typically follow a triphasic colour change of white (the initial vasoconstrictive phase), blue (deoxygenated blood flow), and red (erythralgia, usually painful, as compensatory vasodilatation occurs). Raynaud’s disease is more likely to be primary if it is of young onset (age 40), digital ulceration, persistence even in a warm environment, and systemic symptoms. Unilateral Raynaud’s disease or vascular changes should prompt a search for occlusive causes (extravascular, mural, or intravascular). Livedo reticularis, producing a characteristic purple criss-​cross pattern over the skin, is more commonly pathological if the upper limbs are involved and if it persists in warm environment. This can be associated with vasculitis or antiphospholipid syndrome.

Joint range of movement Joint range of movement is not a particularly helpful feature of the history, as movement may be restricted by pain from any area of the limb. This feature is more useful and specific on examination.

Fatigue Fatigue is a very common symptom in association with chronic rheumatologic conditions, both inflammatory and non-​ inflammatory (reported in up to 90% of patients). The aetiology is multifactorial and often there is a history of sleep disturbance either in the duration or the quality of sleep. This is not always associated with pain and often does not respond to treatment of the underlying condition. Fatigue can affect pain experience, mood, and coping ability and impact on functional outcome.

Systemic symptoms Systemic symptoms of fever, sweats, or unexplained weight loss can occur with severe inflammatory arthritides and systemic autoimmune rheumatic disease, but infection and malignancy must be excluded.

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Family history The following factors should be taken into consideration when taking the family history: • there is a 20% increased risk of autoimmune disease if the patient has a first-​degree relative with an autoimmune disease; the impact of this will depend on the incidence of the disease • in spondyloarthropathies, there is a strong dominant association with HLA-​B27: • of Caucasian patients with ankylosing spondylitis, >90% are positive for HLA-​B27 (the percentage is less for non-​Caucasians) • of patients with reactive arthritis with sacroiliitis, 80% are positive for HLA-​B27 • of patients with peripheral arthritis without sacroiliitis, 25%– 40% are positive for HLA-​B27 • there is a familial association for early onset gout without traditional associated risk factors • periodic syndromes (acute remitting attacks of fever and serositis) have strong family associations • benign joint hypermobility and pathological hypermobility associated with specific syndromes (e.g. Marfan syndrome and Ehlers–​ Danlos syndrome) usually present in familial clusters • in osteogenesis imperfecta, the most common types (Types I and IV) are usually inherited in an autosomal dominant fashion, whereas the more severe forms (including Types II and III) usually occur as the result of sporadic mutations, with no family history • polyarticular generalized nodal osteoarthritis is increasingly recognized as having familial associations The penetrance of phenotype may vary between individuals.

Examination The history will establish whether the symptoms are likely to have an inflammatory or non-​inflammatory cause. The musculoskeletal system is then examined with this in mind, looking for features to confirm or refute the suspected diagnosis. These findings then inform the general examination.

Examination of the musculoskeletal system Inspect the joints and limbs, looking for: • swelling, its localization to the joint or surrounding tissue/​bursa and whether it arises from one compartment or arises more diffusely in the limb • the pattern of joint swelling: whether it occurs in one joint or multiple joints, and the symmetry and size of joint involvement (see Figure 264.1)

ARTHRALGIA/ARTHRITIS

AXIAL

PERIPHERAL & AXIAL

• Inflammatory spondyloarthropathy • Osteoarthritis • Malignancy • Skeletal Hyperostosis

• Inflammatory spondyloarthropathy • Osteoarthritis • Fibromyalgia • Osteomalacia

PERIPHERAL

• Septic arthritis • Crystal arthropathy • Pallindro mic RA • Trauma • OA

Oligoarthritis 2–4 joints

• Psoriatic Arthritis • Reactive Arthritis • Osteoarthritis

Inflammatory causes

Polyarticular >5 joints

• RA • Polyarticular crystal arthropathy • Osteoarthritis • Osteomalacia • Fibromyalgia

Prominent systemic symptoms

• Connective tissue disease • Vasculitis

Non-Inflammatory causes

Figure 264.1  Approach to the diagnosis of joint pain; OA, osteoarthritis; RA, rheumatoid arthritis.

• deformity:  bone distortion (post fracture, osteophytes, remodelling in Paget’s or osteomalacia), subluxation (joint failure due to soft tissue damage), and/​or Boutonniere (fixed flexion of the proximal interphalangeal joint, with hyperextension of the distal interphalangeal joint) or swan neck (fixed flexion of the distal interphalangeal joint, with hyperextension of the proximal interphalangeal joint) deformities of fingers (characteristic of chronic rheumatoid arthritis) • local skin changes or trauma • muscle changes (e.g. wasting, indicating disuse) Palpate the joints and muscles, looking for: • tenderness and the site of tenderness: • tenderness at the joint line is more specific for joint disease • tenderness over entheses occurs in spondyloarthropathies but also with generalized chronic pain syndrome (fibromyalgia) • tenderness over muscles; identify the pattern and localization (see Chapter 63) • specific bony tenderness at one site (suggests a local bone problem) • the nature of the swelling: • is it bony? • is it boggy (suggesting inflammation)? • is there fluid within the joint (fluctuance; e.g. test with a patella tap) and/​or in the surrounding soft tissue (pitting oedema)? • the temperature of the overlying skin:  (e.g. is it raised, due to inflammation, or cold, due to reduced circulation?) Examine the movement of the joints and muscles: • compare the range of movement on both sides and in similarly sized joints, as the exact flexibility will vary between individuals and between joints and will usually reduce with age • mild hyperextension is normal for most joints in children and young adults but is classified as hypermobility when this is more marked

• inability to achieve a normal range of movement is considered restricted movement In addition, confirm the nature of deformity and identify any restrictions. Observing both passive and active ranges of movement makes it possible to distinguish between fixed deformities and restrictions (arising from bone and cartilage changes within the joint, from restrictions from soft tissue surrounding the joint, or from skin restrictions), and reversible deformities (arising from altered muscle balance—​primary to the muscle or secondary to neurological disease—​or from tendon rupture or subluxation)

CHAPTER 264  Diagnosis in suspected rheumatological disease

Monoarthrit is 1 joint

General examination Specific further local and systemic examination will be determined by the findings from the examination of the musculoskeletal system and by features from the history. If systemic/​inflammatory causes are a possibility, then a full systems examination is mandatory. Looking for localizing signs of infection or malignancy is essential.

Neurological system When examining the neurological system, look for the following features: • muscle weakness, which can present as inability to move a joint; this necessitates neurological examination of the limb • numbness or neuropathic pain; if present, a full neurological assessment is indicated • new-​onset headache (unusual for the patient), which is unilateral, involving temple, jaw claudication, visual symptoms (partial or complete loss of vision), with associated systemic symptoms; this suggests giant cell arteritis and requires immediate corticosteroids and further investigation

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• headaches with features of meningitis or encephalitis occurring in a patient with known or suspected autoimmune disease; need to exclude these or treat infective causes

• sclerodactyly and scleroderma changes (systemic sclerosis; changes can be subtle) • lupus pernio (sarcoidosis)

Cardiovascular system

Features suggestive of autoimmune disease but not specific to one condition

When examining the cardiovascular system, look for the following: • infective endocarditis, which can present with joint pains, swelling, heart murmur, and haematuria; note that heart murmur can also be a feature of vasculitis and lupus (Libman–​Sacks endocarditis) or secondary aortic valve incompetence with aortitis from arteritis or ankylosing spondylitis; rheumatic fever is less common with antibiotic treatment of throat infections • signs of right-​sided cardiac failure in association with pulmonary hypertension or constrictive pericarditis, as these are possible complications of connective tissue disease • absence of peripheral pulses (can occur in arteritis) • peripheral oedema in cardiac failure, nephrotic syndrome, or liver disease

CHAPTER 264  Diagnosis in suspected rheumatological disease

Respiratory system When examining the respiratory system, look for the following: • pneumonia; note that, particularly in the elderly and immunocompromised, this may present with systemic features without localizing symptoms • pulmonary fibrosis in association with inflammatory arthritides, connective tissue disease, or vasculitis, or as complication of treatment (methotrexate, leflunomide) • pulmonary embolism; usually associated with antiphospholipid syndrome, but also there is increased risk of this in connective tissue disease and from immobility due to musculoskeletal symptoms • pleural effusion associated with serositis • late-​onset asthma in Churg–​Strauss syndrome

Gastrointestinal system When examining the gastrointestinal system, look for the following features: • hepatosplenomegaly; mild enlargement can occur with autoimmune rheumatic disease, usually in association with reactive lymphadenopathy, although this finding should prompt exclusion of malignancy (lymphoma can occur at increased incidence in association with autoimmune disease, especially Sjögren’s syndrome) • liver disease, as a feature of autoimmune disease or drug therapy • blood or mucous in the stool, or malabsorptive stool, in association with infective or inflammatory colitis, coeliac disease, or upper gastrointestinal dysmotility or bacterial overgrowth (e.g. in systemic sclerosis)

Urogenital system When examining the urogenital system, look for the following features: • peripheral oedema with nephrotic syndrome (suggests lupus, vasculitis, amyloidosis) • the following urine dipstick results: • proteinuria and haematuria, suggesting glomerular inflammation • leucocytes and nitrites, suggesting infection • glucose suggesting diabetes mellitus • genital ulcers (see ‘Oral and genital ulceration’)

Skin, nails, and mucosa Typical diagnostic skin features Typical diagnostic skin features include: butterfly malar rash (SLE) • • discoid rash (discoid lupus) • rheumatoid nodules (seropositive rheumatoid arthritis) • psoriasis and nail dystrophy (psoriatic arthritis) • plantar palmar pustulosis (reactive arthritis) • tophi (gout) • heliotrope rash and Gottron’s papules (dermatomyositis)

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Features suggestive of autoimmune disease but not specific to one condition include: pyoderma gangranosum • • livedo reticularis • photosensitivity • purpura (including palpable); look for the more specific Henoch– Schönlein purpura distribution on lower limb, extensor aspects • erythema nodosum

Other diagnostic clues Other diagnostic clues include: erythema marginatum (streptococcal infection) • • erythema migrans (Lyme disease)

Oral and genital ulceration If there is oral and/​or genital ulceration, note the following: • duration, frequency, severity, and size can help distinguish pathological ulcers • it is important to exclude infectious causes, especially with genital-​ only ulcers (e.g. from herpes simplex, lymphogranuloma venereum) • autoimmune causes include SLE, Behçet’s syndrome, inflammatory bowel disease, reactive arthritis, and Stevens–​Johnston syndrome (including reaction to drugs) • lichen planus can be oral or genital; it is associated with Sjögren’s syndrome

Eyes When examining the eyes, look for the following: • conjunctivitis or episcleritis (red eyes with itching, mild photophobia, and normal visual acuity) • uveitis (red eyes with pain and loss of visual acuity); requires urgent ophthalmology review (NB: in children, uveitis is commonly asymptomatic, and all children with known or suspected inflammatory arthritis or connective tissue disease should be screened and monitored by an experienced ophthalmologist) • dry, gritty eyes with or without dry mouth can occur with primary or secondary Sjögren’s syndrome; Schirmer’s test (the rate of tear chromatography down filter paper) and a wafer test (time to dissolve a thin wafer orally) can give a more quantitative assessment

ENT When examining the ears, nose, and throat, be aware of the following: • rhinosinusitis can occur with vasculitides but it is also a common allergic symptom, so it is non-​specific • nasal crusting, nosebleeds, nasal stuffiness, and conductive hearing loss can occur in Wegener’s granulomatosis • destructive cartilage changes can occur in the nasal septum or upper airways (in Wegener’s granulomatosis and relapsing polychondritis) or pinna (in relapsing polychondritis); other causes such as trauma, surgery, cocaine abuse, or risk of leprosy need to be excluded • parotid and salivary gland enlargement in Sjögren’s syndrome, sarcoidosis, and DILS • lymphadenopathy (with or without hepatosplenomegaly (see ‘Gastrointestinal system’)); exclude malignancy and infection

Prognosis The prognosis of rheumatological disease is predominantly influenced by disease type and natural history, with the outcome modified by the extent of organ involvement and the degree of reversible versus permanent tissue damage. Extent of involvement forms part of the assessment of a patient with rheumatic disease and informs decisions on management. The extent of disability from symptoms is

Further Reading Cawston TE. ‘Structure and function: ‘Joints and connective tissue’, in Warrell, DA, Cox TM, and Firth JD, eds, Oxford Textbook of Medicine (5th edition), 2010. Oxford University Press.

Doherty M and Lanyon PC, ‘Clinical investigation’, in Warrell, DA, Cox TM, and Firth JD, eds, Oxford Textbook of Medicine (5th edition), 2010. Oxford University Press. Hochberg MC, Silman AJ, Smolen JS, et al. Rheumatology (6th edition), 2014. Russell AS and Ferrari R. ‘Clinical presentation and diagnosis of rheumatic disease’, in Warrell, DA, Cox TM, and Firth JD, eds, Oxford Textbook of Medicine (5th edition), 2010. Oxford University Press.

CHAPTER 264  Diagnosis in suspected rheumatological disease

influenced not only by the severity of organ involvement but also by a wider range of functional factors.

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265 

Investigation in rheumatological disease

Rachel Jeffery, Pradip Nandi, and Kenny Sunmboye

Introduction In suspected rheumatological disease, the findings on careful clinical assessment, as detailed in Chapter 264, are crucial to the interpretation of test results. Investigation should not be used as a screening tool, but rather to clarify the differential diagnosis. In established disease, investigation should also be used to assess the extent and severity of organ involvement, establish prognosis, and guide treatment choices.

Full blood count The full blood count is often affected by rheumatological diseases and their treatments. The haemoglobin concentration may be low because of anaemia of chronic disease, iron deficiency, or macrocytic anaemia. For example, in uncontrolled rheumatoid arthritis (RA), anaemia of chronic disease may be seen. If there is coexisting celiac disease, the patient may have an iron-​deficiency anaemia. A  macrocytic anaemia may be seen if there is folate deficiency related to methotrexate toxicity.

White blood cell count The white blood cell count is useful in monitoring for neutrophilia from infection and neutropenia related to active disease or disease-​ modifying anti-​rheumatic drugs (DMARDs). The platelet count may be raised in active RA. Felty’s syndrome, a complication of untreated or poorly controlled RA, is associated with neutropenia, splenomegaly, and thrombocytopenia. SLE may result in leucopenia, lymphopenia, and thrombocytopenia

Liver function tests Liver function tests are used to monitor for liver injury due to DMARDs such as methotrexate and leflunomide.

Acute phase reactants Acute phase reactants are described as ‘positive’ or ‘negative’ depending on whether they rise or fall in the presence of an inflammatory state. They are usually driven by cytokines such as interleukin-​ 6, tumour necrosis factor alpha, interferon gamma, and transforming growth factor beta. Positive acute phase reactants include the erythrocyte sedimentation rate (ESR), C-​reactive protein (CRP), and ferritin. Negative acute phase reactants include albumin and transferrin. The two most widely used acute phase reactants are ESR and CRP. Both are elevated in most inflammatory diseases, and are helpful in assessing disease activity. In polymyalgia rheumatica, giant cell arteritis, and RA, ESR and CRP are indicators of severity, prognosis, and response to treatment. However, in early psoriatic arthritis and ankylosing spondylitis, these acute phase reactants can be normal. In SLE, a raised ESR with a normal CRP is typical; a raised CRP in SLE may reflect infection, lupus serositis, or vasculitis. Procalcitonin is an emerging positive acute phase reactant which may have utility in differentiating bacterial infection from disease progression.

Uric acid The plasma level of uric acid is useful in the diagnosis of gout. In a patient with risk factors for gout, and an acutely swollen joint or

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joints, the presence of a raised uric acid confirms the diagnosis of gout. However, it is important to note that plasma uric acid may be normal during an acute attack of gout, and so this does not exclude the diagnosis. In this setting, an aspirate of the swollen joint is needed for crystal analysis.

Rheumatoid factor, and anti-​cyclic citrullinated peptide antibodies Rheumatoid factor (RF) is an antibody against the Fc portion of IgG in the patient’s serum. The most commonly measured and clinically useful class of RF is IgM RF. Five per cent of a healthy population can be RF positive, and the prevalence increases with age. Testing for RF is useful in the diagnosis and management of RA, but RF positivity is not a necessary diagnostic criterion. RF positivity is associated with more severe joint disease, systemic disease (extra-​articular features), and responsiveness to biological DMARDs such as rituximab. RF can also be seen in a number of other rheumatic diseases, as well as in non-​rheumatic diseases. Anti-​cyclic citrullinated peptide (anti-​CCP) antibodies are directed against citrulline residues formed in post-​translational modification of arginine. In patients with RA, anti-​CCP antibodies have a sensitivity comparable to that of RF but with a much higher specificity of 95%–​ 98%. The presence of anti-​CCP antibodies can predate the onset of RA and may be positive in patients who are RF negative. Thus, these antibodies, if present, can help in making the diagnosis of RA, given their high specificity. Their presence is also associated with a more severe disease course and more extra-​articular features. Unlike RF, anti-​CCP antibodies are rarely found in patients with non-​rheumatic disease.

Antinuclear antibodies Antinuclear antibodies (ANAs) are autoantibodies that bind to components of the cell nucleus and (despite their name) cytoplasm. The most commonly used technique to detect ANAs is indirect immunofluorescence, in which HEp-​2 cells (obtained from a human epithelial tumour line) are made permeable and incubated first with the patient’s serum, and then with anti-​human antibodies conjugated to a fluorescent molecule. The cells are then examined by microscopy, and the staining pattern noted. The results are reported as positive or negative and include a titre. The presence or absence of ANAs is not sufficient to confirm or exclude any rheumatic disease. For example, nearly all patients with untreated SLE have a positive ANA test but not all people with a positive ANA have SLE. Given the low prevalence of SLE, the positive predictive value of a positive ANA for SLE is also low, at around 11%. ANA titres of 1:160 or more are usually regarded as significant. However, amongst healthy people, 25%–​30% have a positive ANA test with a titre of 1:40, 10%–​15% have a titre of 1:80, and 5% have a titre of 1:160 or more. The positivity of the test also increases with age, particularly in women. An ANA titre of 1:40 is seen in 25%–​30% of relatives of patients with rheumatic disease. In Raynaud’s phenomenon, a positive ANA test increases the risk of developing an associated rheumatic disease from 19% to 30%, and a negative test decreases this risk to 7%. Table 265.1 summarizes the prevalence of ANAs in rheumatic diseases.

Table 265.1  Utility of autoantibodies in the diagnosis of rheumatological disease Sensitivity (True positive rate)

Specificity (True negative rate)

SLE

93%

57%

Systemic sclerosis

85%

54%

Polymyositis/​dermatomyositis

61%

63%

Rheumatoid arthritis

41%

56%

Sjӧgren’s syndrome

48%

52%

Secondary Raynaud’s phenomenon

64%

41%

Sjögren’s syndrome antibodies Antibodies associated with Sjögren’s syndrome include the anti-​SS-​ A/​Ro and anti-​SS-​B/​La antibodies. They are of importance in making a diagnosis of Sjögren’s syndrome, as they are rarely seen in healthy people, although they may be present in other rheumatic diseases such as RA, SLE, and polymyositis.

Adapted with permission from Daniel H. Solomon, Arthur J. Kavanaugh, Peter H. Schur, Evidence-​based guidelines for the use of immunologic tests: Antinuclear antibody testing, Arthritis & Rheumatology, Volume 47, Issue 4, pp. 434–​444, Copyright © 2002 John Wiley and Sons.

Extractable nuclear antigens In a patient with a positive ANA test, it is important to determine the target antigen of the ANA. These target antigens, also called extractable nuclear antigens, are soluble nuclear and cytoplasmic components that leach from the cell when extracted with saline. Table 265.2 summarizes the prevalence of extractable nuclear antigen antibodies in rheumatic diseases.

Scleroderma-​associated antibodies Scleroderma-​ associated antibodies include anticentromere antibodies, the anti-​ Scl-​ 70 antibody, and anti-​ U3-​ ribonucleoprotein antibodies.

Anticentromere antibodies

SLE-​associated autoantibodies

Anticentromere antibodies are associated with limited cutaneous systemic sclerosis, which was previously called CREST (calcinosis, Raynaud’s phenomenon, oesophageal dysmotility, sclerodactyly, telangectasia) syndrome, and have high specificity but limited sensitivity for the diagnosis. They are rarely found in patients with other connective tissue diseases or in healthy people, Their presence distinguishes patients with limited systemic sclerosis from those with diffuse systemic sclerosis or primary Raynaud’s phenomenon.

SLE-​associated autoantibodies include:

Anti-​Scl-​70

• anti-​double-​stranded DNA antibodies: • most strongly associated with SLE • important in the diagnosis and assessment of the disease, as their levels correlate with disease activity • also associated with the development of lupus nephritis • the anti-​Smith antibody: • high specificity but low sensitivity for SLE • associated with renal involvement and poor prognosis • antiribonucleoprotein antibody: • high specificity for mixed connective tissue disorder and is an essential criterion in making this diagnosis • often present before the onset of disease

The anti-​Scl-​70 antibody is also very useful in diagnosing diffuse systemic sclerosis. This antibody is highly specific for diffuse disease, although not very sensitive. Anti-​Scl-​70 and anticentromere antibodies rarely coexist in the same person. The presence of anti-​Scl-​70 antibodies is useful in predicting a greater likelihood for the development of diffuse cutaneous involvement and pulmonary fibrosis.

Anti-​U3-​ribonucleoprotein antibodies Anti-​ U3-​ ribonucleoprotein antibodies are antinucleolar antibodies which have high specificity but low sensitivity for scleroderma.

Myositis-​associated antibodies Table 265.2  Autoantibodies and their associated rheumatological disease Antibody

Associated condition

Sensitivity (True positive rate)

Specificity (True negative rate)

Anti-​dsDNA Ab

SLE

57%

97%

Anti-​Smith Ab

SLE

25%-​–​0%

High*

Anti-​Ro/​SS-​A Ab

Sjӧgren, SCLE, neonatal lupus syndrome

8%–​70%

87%

Anti-​La/​SS-​B Ab

Sjӧgren, SCLE, neonatal lupus syndrome

16%–​40%

94%

Anti-​Scl-​70 Ab

Systemic sclerosis

20%

100%

Anticentromere Ab

Limited cutaneous systemic sclerosis

65%

99.9%

Anti-​U3-​RNP Ab

Scleroderma

12%

96%

Abbreviations: Ab, antibody; anti-​dsDNA, anti-​double-​stranded DNA antibody; RNP, ribonucleoprotein; SCLE, subacute cutaneous lupus erythematosus. *Precise data not available. Adapted from Sheldon J., Laboratory testing in autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology, volume 18, issue 33, pp. 249–​269, copyright © 2004 with permission from Elsevier.

Tests for myositis-​associated antibodies are helpful in the diagnosis of polymyositis and dermatomyositis (Table 265.3). They have high specificity but low sensitivity for these diseases.

Antineutrophil cytoplasmic antibodies

CHAPTER 265  Investigation in rheumatological disease

Disease

• anti-​SS-​A/​Ro and anti SS-​B/​La antibodies: • female patients with SLE who become pregnant must have blood testing for these antibodies because of the associated risk of congenital heart block in the fetus or neonate, or neonatal lupus

Neutrophils contain enzymes including proteinase 3 (PR3), myeloperoxidase (MPO), and elastase, which are components of the immune response. Antibodies directed against these enzymes are associated with certain small vessel vasculitides. Antineutrophil cytoplasmic antibodies (ANCAs) are detected by indirect immunofluorescence and have two main patterns of immunofluorescent staining in patients who are ANCA positive:  cytoplasmic (cANCA) and perinuclear (pANCA). Following the finding of cANCA or pANCA positivity, an enzyme immunoassay (i.e. ELISA) is done to determine the presence or absence of antibodies directed against either PR3 or MPO. A  cANCA staining pattern in combination with a positive PR3 ANCA result from an ELISA is highly specific (99%) for small vessel vasculitis. A  pANCA staining pattern in combination with a positive MPO ANCA is also highly specific for small vessel vasculitis. However, a pANCA staining pattern on indirect immunofluorescence can be seen in a number of non-​rheumatic diseases. Table 265.4 summarizes the sensitivities of ANCA in selected rheumatic and non-​rheumatic diseases.

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Table 265.5  Adverse effects of disease-​modifying agents in rheumatological disease

Table 265.3  Myositis-​associated antibodies Antibodies

Significance

Anti-​Jo1 antibody

Associated with rarer antisynthetase syndrome: interstitial lung disease, non-​erosive symmetrical arthritis, Raynaud’s phenomenon, and mechanic’s hand

Anti-​signal recognition particle antibody

Associated with acute onset severe illness with minimal evidence of inflammation on muscle biopsy, requiring aggressive immunosuppression

Anti-​Mi2 antibody

Associated with classical dermatomyositis (erythroderma/​ shawl sign)

DMARD

Major adverse effects

Methotrexate

• oral ulcers (patient may need to increase dose of folic acid) marrow suppression (patient may need • folinic-​acid rescue therapy) hepatotoxicity (presents as deranged LFTs) • pulmonary toxicity (ask patient about • symptoms of dyspnoea) rashes • alopecia •

Sulphasalazine

CHAPTER 265  Investigation in rheumatological disease

Human leukocyte antigen B27 Human leukocyte antigen B27 (HLA-​B27) is a Class I surface antigen encoded by the B locus in the major histocompatibility complex on Chromosome 6.  HLA-​B27 is strongly associated with the seronegative spondyloarthritides, including psoriatic arthritis, ankylosing spondylitis, reactive arthritis, and inflammatory-​ bowel-​ disease-​related arthritis. HLA-​B27’s association with this group of diseases is strongest in ankylosing spondylitis. It is important to note, however, that the presence of HLA-​B27 alone cannot be taken as indicating rheumatic disease: 8% of the healthy white population is HLA-​B27 positive, while 4% of the healthy African-​American population is HLA-​B27 positive. HLA-​B27 should only be tested in an individual with a strong clinical suspicion of seronegative spondyloarthritis.

Hydroxychloroquine

Blood tests for monitoring DMARDs

Azathioprine TPMT levels (pretreatment)

Patients with rheumatic disease require monitoring via blood tests, to prevent medication-​related complications. Table 265.5 highlights important DMARDs, with some comment on their adverse effects.

Urinalysis Urinalysis is an effective method of detecting renal involvement in rheumatological disease (e.g. SLE, scleroderma) or a renal complication of therapy (e.g. gold and d-​penicillamine in RA (see Table 265.6). Urinary Bence Jones protein (monoclonal free kappa or lambda light chains) should be measured if the differential diagnosis includes myeloma (because of bone pain, increased plasma alkaline phosphatase, renal impairment, or a monoclonal band on serum protein electrophoresis).

Table 265.4  Prevalence of antineutrophil cytoplasmic antibodies findings in vasculitic disease Disease

cANCA/​PR3

pANCA/​ MPO

Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis)

85%

10%

Microscopic polyangiitis

45%

45%

Allergic granulomatosis and angiitis (formerly Churg–​Strauss syndrome)

10%

60%

Idiopathic crescentic glomerulonephritis

25%

65%

Polyarteritis nodosa

5%

15%

Anti-​GBM disease (Goodpasture’s disease)

20%–​30%

Abbreviations: cANCA, cytoplasmic antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane; MPO, myeloperoxidase; pANCA, perinuclear antineutrophil cytoplasmic antibody; PR3, proteinase-​3. Adapted from Sheldon J., Laboratory testing in autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology, volume 18, issue 33, pp. 249–​269, copyright © 2004 with permission from Elsevier.

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Ciclosporin Creatinine clearance (pretreatment)

Leflunomide BP check (preferably 100 000 leucocytes/​mm3

In suspected septic joint, urgent aspiration and immediate Gram staining is essential Even few drops of fluid are adequate for WCC (count, differential), Gram staining, culture, and sensitivity and, if an adequate amount of fluid is available, then crystals Negative joint aspiration does not rule out septic arthritis; the entire clinical picture needs to be taken into consideration In suspected septic arthritis, consider routine FBC, renal function tests, liver function tests, CRP level, blood culture, synovial fluid culture, and urine culture Immunosuppression, steroid therapy, and diabetes are risk factors for septic arthritis

Crystal arthropathy

Can be slightly turbid

20 000–​50 000 leucocytes/​mm3

Monosodium urate crystals cause gout (monosodium urate crystals are negatively birefringent, needle-​shaped crystals seen in polarized microscopy) Calcium pyrophosphate dihydrate crystals are associated with pseudogout, and the deposition of these crystals may be superimposed on osteoarthritis X-​ray may show chondrocalcinosis in pseudogout Other causes are calcium oxalate crystals (if the patient is on dialysis) and calcium phosphate crystals (Milwaukee shoulder/​knee) Important reminder: crystals and infection can coexist

Haemorrhagic synovial fluid

Bloody, fluid Haematocrit >10% will appear grossly bloody

Predominantly RBC

Can be due to trauma, bleeding disorder, or pigmented villonodular synovitis

CHAPTER 265  Investigation in rheumatological disease

Table 265.6  Urinary dipstick findings in rheumatological disease

Abbreviations: FBC, full blood count, RBC, red blood cell; WCC, white-​cell count.

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CHAPTER 265  Investigation in rheumatological disease

Table 265.8  Findings on peripheral-​joint radiography Disease

Value of peripheral-​ Finding joint radiography

Comment

Early inflammatory arthritis

May be uninformative in early disease

May show soft-​tissue swelling and/​or periarticular osteoporosis

High-​frequency ultrasound or MRI may be more useful

Established rheumatoid arthritis or other inflammatory arthritis

Evidence of joint damage and structural deformity

In established rheumatoid arthritis, may show loss of cartilage, and bone erosion In a rheumatoid arthritis hand, MCP joints and PIP joints are more affected than DIP joints Erosion suggests late-​stage disease, but erosion can be seen in other conditions (e.g. psoriatic arthritis, gout) In connective tissue disease, a peripheral-​joint X-​ray will show a non-​erosive arthropathy

High-​frequency ultrasound may be still of value for active disease

Osteoarthritis

Usually the first-​line investigation

A plain X-​ray may reveal loss of joint space, subchondral sclerosis, and cyst and osteophyte formation

In osteoarthritis of the hand, DIP joints are more affected than PIP joints; in the thumb, the carpometacarpal joint is commonly affected Other joints (e.g. hip, knee (medial compartment common), spine) may also be affected

Crystal arthropathy

Some value

In gout, soft-​tissue swelling or punched-​out erosion may be seen Nodular deposits of calcium urate can occur in the synovium In calcium pyrophosphate dihydrate crystal deposition (pseudogout), cartilage or meniscal calcification can be seen, especially in the knee

Joint aspiration for the presence of crystals is the gold-​standard investigation

Osteoporosis

Limited value

A plain X-​ray may show diffuse osteopenia with cortical thinning

FRAX score and DEXA scan

Osteomalacia

Value in advanced stages

A plain X-​ray may show Looser zones (pseudofractures)

Looser zones most commonly seen in the medial femoral neck, the axillary border of scapula, the ribs, and the pubic rami Rare in the Western world

Paget’s disease

Diagnostic value

A plain X-​ray may show enlarged, sclerotic bones with a trabecular pattern

Stress fracture Bone softening Sarcomatous changes (1%) may occur

Abbreviations: DIP, distal interphalangeal; MCP, metacarpophalangeal; PIP, proximal interphalangeal.

CT CT is superior to plain radiography in assessing disorders of the bone cortex (e.g. cortical fractures or metastases). It can detect fractures of the cervical spine, the hip, the wrist, and the foot when these are not evident on plain radiographs.

MRI MRI shows non-​calcified tissues that cannot be assessed by plain radiography or CT. Thus, it can demonstrate abnormalities present in synovium, tendons, and muscles and which may precede joint

involvement. For example, in early RA, pre-​erosive changes like bone marrow oedema, synovitis, and tendinosis can be seen on MRI. In suspected myopathy or myositis, MRI can be used to identify muscle inflammation and the best site for biopsy.

Dual X-​ray absorptiometry Dual X-​ray absorptiometry (also called ‘DEXA scan’) measures bone mineral density (BMD) and is used to confirm or refute a diagnosis of osteoporosis and predict the fracture risk in patients with radiographic osteopenia or vertebral deformity.

Table 265.9  Findings on spinal radiography

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Disease

Value of spinal X-​ray

Findings

Comment

Spondyloarthropathy-​like ankylosing spondylitis

Useful

An X-​ray of sacroiliac joint may pick up early or advanced sacroiliitis In ankylosing spondylitis, an X-​ray might show ‘squaring of endplates’, Romanus lesions, osteopenia, calcification, and, in late stages, bamboo spine

MRI may be useful early in diagnosis (other causes of sacroiliitis are inflammatory bowel disease, psoriatic spondyloarthropathy, and Reiter’s syndrome)

Degenerative spinal disease

Limited value

Presence of osteophytes Lower cervical/​lumbar findings

MRI is useful for radiculopathy

Osteoporosis

Limited value

X-​ray of spine in an osteoporotic individual may show a wedge fracture Fracture to site previously may result in kyphosis of the spine

FRAX score and DEXA scan

Table 265.10  Findings on chest radiography Disease

Possible findings

Comment

Rheumatoid arthritis

Rheumatoid nodules (typically peripheral location in lower zones) Interstitial lung disease Pleural effusion (usually unilateral) Pneumonitis as complication of methotrexate therapy

Chest X-​ray should be done as a baseline before methotrexate started

Pleural effusion (often bilateral) Acute pneumonitis Interstitial lung disease Pericardial effusion (enlarged cardiac silhouette)

SLE may present with pulmonary disease

Ankylosing spondylitis

Apical fibrosis

Apical fibrosis also seen in tuberculosis, in sarcoidosis, and after radiotherapy

Systemic sclerosis

Interstitial lung disease Oesophageal dilatation

Pulmonary involvement occurs in >80% of patients Echocardiography is needed to screen for pulmonary hypertension

GPA (formerly Wegener’s granulomatosis)

Nodules that may be cavitary Lobar or segmental atelectasis Pleural opacities

Upper respiratory tract involvement (nasal, sinus, or ear) occurs in 90% of patients with GPA

Bone scan A bone scan using technetium-​99m-​labelled methyl diphosphonate can be useful in the diagnosis of bone metastases, infection, occult fracture, and other bone disorders (e.g. fibrous dysplasia). In Paget’s disease, a bone scan may show intense activity but, in sarcomatous change, there may be lower uptake.

PET–​CT

Abbreviations: GPA, granulomatosis with polyangiitis; SLE, systemic lupus erythematosus.

The T-​score compares individual results to those in a young population (aged 20–​30) of the same gender and ethnic background, while the Z-​score compares individual results to those in an age-​matched population. BMD is classified by the WHO as being

PET–​CT can be used to diagnose large vessel vasculitis (e.g. Takayasu arteritis). It can also be used to screen for cancer in patients with dermatomyositis and polymyositis.

Echocardiography Echocardiography can be used to assess for cardiac and aortic involvement in diseases such as SLE, ankylosing spondylitis, and vascular Ehlers–​Danlos syndrome. It is also used to screen for pulmonary hypertension complicating diseases such as systemic sclerosis.

Further Reading Cawston TE. ‘Structure and function: Joints and connective tissue’, in Warrell DA, Cox TM, and Firth JD, eds, Oxford Textbook of Medicine (5th edition), 2010. Oxford University Press. Doherty M. ‘Clinical investigation’ in Warrell DA, Cox TM, and Firth JD, eds, Oxford Textbook of Medicine (5th edition), 2010. Oxford University Press. Hochberg MC, Silman AJ, Smolen JS, et  al. Rheumatology (6th edition), 2014. Mosby. Russell AS and Ferrarri R. ‘Clinical presentation and diagnosis of rheumatic disease’, in Warrell DA, Cox TM, and Firth JD, eds, Oxford Textbook of Medicine (5th edition), 2010. Oxford University Press.

CHAPTER 265  Investigation in rheumatological disease

SLE

normal (T-​score within one standard deviation (SD) of the BMD of an average 25-​year-​old) or indicating the presence of osteopenia (T-​score between −1 and −2.5 SD), osteoporosis (T-​score below −2.5 SD), or established osteoporosis (T-​score below −2.5 SD, with one or more fragility fractures). The risk of bone fracture is slightly increased in patients with osteopenia and considerably increased in those with osteoporosis.

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266 Osteoarthritis Michael Doherty

Definition of osteoarthritis Osteoarthritis (OA) is a disorder of synovial joints and is characterized by the combination of (1) focal hyaline cartilage loss, and (2) accompanying subchondral bone remodelling and marginal new bone formation (osteophyte). It has genetic, constitutional, and environmental risk factors and presents a spectrum of clinical phenotypes and outcomes. OA commonly affects just one region (e.g. knee OA, hip OA). However, multiple hand interphalangeal joint (IPJ) OA, usually accompanied by posterolateral firm swellings (nodes), is a marker for a tendency towards polyarticular generalized nodal OA.

Etiology of OA OA is a dynamic, metabolically active condition involving all joint tissues. It is regarded as the inherent repair process of synovial joints. A variety of insults may trigger the need to repair, and often this slow but efficient process compensates for the insults, resulting in an anatomically remodelled but functioning asymptomatic joint. However, in some cases, due to overwhelming insult or inefficient repair, the OA process cannot compensate, resulting in pain, disability, and presentation as a patient with clinically relevant OA. Risk factors vary according to joint site, and differ according to development and progression. For example, high bone mineral density (BMD) is a risk factor for development of hand, knee, and hip OA, but low BMD is a risk factor for more rapid progression of hip and knee OA. There are three main categories of risk factors: • genetic factors: OA shows strong heritability (40%–​60% for hand, knee, and hip OA), although the specific associations are currently poorly defined (specific associations, such as COL2A1 mutations, are identified for some rare monogenic disorders causing premature polyarticular OA (e.g. Stickler’s syndrome)) • generalized, constitutional factors, such as age, obesity, female gender, bone density, and low muscle strength • localized mechanical factors that cause abnormal joint loading, such as abnormalities of joint shape (dysplasia) or alignment; trauma; meniscectomy; instability; and occupational/​recreational overloading Some factors (e.g. obesity, muscle function, and occupation) may be modified and thus offer scope for primary, secondary, and tertiary prevention.

Typical and less common symptoms of OA The two main symptoms of OA are pain and restricted activity and function. The pain is characteristically worse on usage/​movement and is relieved by rest, typically being worst at the end of the day and best in the morning. The joint may feel stiff in the morning or after rest (‘gelling’) but, unlike inflammatory joint pain, it quickly ‘loosens up’ on moving. Pain is usually restricted to just one or a few joints. It is often variable, with ‘good days’ and ‘bad days’, and any progression is slow over many months or years. Restricted activity and function often reflects pain severity but may be the presenting symptom, even in the absence of marked pain. The severity of pain and functional impairment are greatly influenced by psychosocial factors (anxiety, depression), daily activity requirements, and the presence of comorbidity. Cartilage changes in OA facilitate crystal deposition, so superimposed symptoms of acute crystal synovitis are not uncommon (especially at the knee, for calcium pyrophosphate dihydrate

906

crystal deposition disease, and at peripheral lower and upper limb joints in gout). Less common symptoms are mechanical locking and rapid progression of hip (less commonly, knee) symptoms.

Demographics of OA OA has a higher prevalence than that of all other arthropathies considered together. Structural OA is frequently asymptomatic, so radiographic OA is always more prevalent than symptomatic OA. In general: • OA increases markedly with age (especially after 40) and is more common in women than men at all sites other than the hip (equal prevalence) • the prevalence is highest for hand OA, then knee OA, and then hip OA, with other joints (e.g. feet, shoulders, elbows) affected less commonly • although hand OA is most prevalent, it only occasionally causes significant disability, and symptomatic knee and hip OA present the major burden • knee OA alone is the single most common cause of disability in those aged over 65, and knee and hip OA together affect >20% of the older population With the increasing proportion of older people, large-​joint OA will become an even more important healthcare problem.

Natural history of OA, and complications The natural history of OA, as well as its complications, varies according to joint site.

Natural history of hip OA Symptomatic hip OA commonly progresses, eventually requiring surgery. Superior pole OA (i.e. maximal cartilage narrowing superiorly) is the usual pattern in men and usually progresses more rapidly, with superolateral femoral head migration, than other patterns. Medial and axial hip OA, mainly restricted to women, often associate with nodal OA and have a better prognosis.

Natural history of knee OA Symptoms are often intermittent and sometimes improve and the correlation between clinical outcome and radiographic change is less strong than at the hip. In those that worsen, clinical progression is variable but is usually only slowly progressive and the transition from mild to severe typically takes many years.

Natural history of hand OA The overall prognosis is good. Nodal hand OA typically improves symptomatically once nodes are fully developed, often after several years. The exception is thumb-​base involvement (first carpometacarpal joint and trapezioscaphoid joint), which sometimes progresses to require surgery.

Complications of OA Complications of OA include poorly controlled pain, joint restriction, and deformity.

Approach to diagnosing OA The diagnosis of OA is essentially clinical and depends on a full history and examination. Patients are usually over age 40 and have predominantly usage-​related or ‘mechanical’ (non-​inflammatory) symptoms

restricted movement, with or without pain • • bony joint enlargement • coarse, palpable crepitus, sometimes also audible, on movement (mainly large joints) • weakness and wasting of muscles acting over the joint • deformity (instability is uncommon, due to capsular thickening) • varying degrees of inflammation (effusion, increased warmth) There may be joint-​line tenderness, but periarticular tenderness is also common with knee and hip OA.

Diagnosing hip OA Pain from hip OA is typically felt maximally deep in the anterior groin but may be referred over a wide area including the lateral thigh and buttock, anterior thigh, knee, and as far down as the ankle. Pain is mainly a problem when walking but can occur at rest and disturb sleep. The gait is typically an antalgic limp, with less time spent weight bearing on the arthritic side. The usual first sign is painful restriction of internal rotation with the hip flexed, although, with advanced OA, there may be more widespread restriction, a fixed flexion and external rotation deformity, and leg length narrowing due to marked cartilage and bone attrition.

Diagnosing knee OA Knee OA is usually bilateral and symmetrical, mainly targeting the medial tibiofemoral and patellofemoral compartments. Pain is usually well localized to the affected compartment, and quadriceps weakness, with frequent ‘giving way’, is common. Patellofemoral OA causes localized anterior knee pain which is worse on inclines or stairs, particularly when going down. Examination may reveal restricted flexion/​extension, coarse crepitus, joint-​line tenderness (with or without periarticular tenderness, especially over the upper medial tibia region), and small-​to-​moderate knee effusions. With advanced OA, there may be bony swelling (femoral condyles, tibial plateaux), flexion and varus (bow-​legged deformity), or, less commonly, valgus (knock-​knee deformity).

Diagnosing nodal hand OA Nodal hand OA is a polyarticular arthropathy of hand IPJs and is characterized by multiple Heberden’s nodes (see Figure 266.1) and Bouchard’s nodes (proximal IPJs), mainly affecting women and often with a family history. It causes intermittent pain and stiffness and is well localized to the involved joints; it commonly starts around menopause but becomes less symptomatic once nodes are fully developed. Typical end-​stage deformity is lateral (ulnar/​radial) deviation without instability. Thumb-​base OA may cause more persistent, aching pain which is maximal at the thumb base but often radiates distally up the thumb and proximally to the wrist. Advanced cases may show

thumb-​base ‘squaring’ caused by subluxation, osteophyte, and bone remodelling.

Other diagnoses that should be considered OA and gout co-​associate, so gout should be considered in patients with OA if they develop typical acute attacks of crystal synovitis, if they have more pronounced symptoms and signs of joint inflammation, or if their established finger nodes become more swollen and symptomatic in older age. Other types of inflammatory arthritis (e.g. rheumatoid arthritis, seronegative spondyloarthritis) can be distinguished usually by pronounced early morning and inactivity stiffness, involvement of several or multiple joints, and frequent systemic upset. However, some cases of OA may have a lesser inflammatory component, and combined synchronous symptoms in hands and other sites. The presence of predominantly soft tissue rather than bony swelling and high inflammatory markers in the blood are more suggestive of inflammatory arthritis. In patients with apparently young-​onset OA (occurring at age 2 if bilateral; Grade >3 if unilateral)

3

Genetic background Presence of HLA-​B27, or familial history of ankylosing spondylitis, reactive arthritis uveitis, psoriasis, or inflammatory bowel disease

2

Response to treatment Good response to NSAIDs within 48 hours, or relapse of pain within 48 hours if NSAIDs discontinued

2

*A patient is considered to have spondyloarthritis if the sum of the points is 6 or more. A total point score of 5 or more is classified as probable spondyloarthritis. Adapted by permission from BMJ Publishing Group LTD [The assessment of Spondyloarthritis international society (ASAS) handbook: a guide to assess spondyloarthritis, J Sieper M Rudwaleit, X Baraliakos, J Brandt, J Braun, R Burgos-​Vargas, M Dougados, K-​G Hermann, R Landewe, W Maksymowych and D van der Heijde, Annals of the Rheumatic diseases, 2009;68;ii1-​ii44].

Box 268.2  European Spondyloarthropathy Study Group criteria Inflammatory spinal pain or synovitis (asymmetrical or pre­ dominately lower limbs), and one or more of the following: positive family history • • psoriasis • inflammatory bowel disease • urethritis, cervicitis, or acute diarrhoea within 1 month of the onset of arthritis • buttock pain alternating between right and left gluteal areas • enthesopathy • sacroiliitis Adapted by permission from BMJ Publishing Group LTD [The assessment of Spondyloarthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis, J Sieper, M Rudwaleit, X Baraliakos, J Brandt, J Braun, R Burgos-​ Vargas, M Dougados, K-​G Hermann, R Landewe, W Maksymowych and D van der Heijde, Annals of the Rheumatic disease, 2009;68;ii1-​ii44]

While spondyloarthropathies share common clinical features, each condition has a distinct set of symptoms. However, inflammatory back pain is a central feature, common to all the spondyloarthropathies and the most typical symptom. The term is applied to back or neck pain present most days for more than 3 months (except in reactive arthritis, where it may be acute). The pain, which is insidious in nature, improves with exercise, and worsens or does not improve with rest. Pain occurring at night is consistent, and the age of onset is typically before 40 years. Ankylosing spondylitis presents with typical symptoms of inflammatory back pain in a young person (often male) and is typically insidious, often leading to diagnosis being delayed for many years. Associated symptoms, requiring careful questioning, include: alternating buttock pain • • enthesitis (e.g. heel pain), with plantar fasciitis or Achilles tendonitis • decreased spinal movements • fatigue or systemic features • history of uveitis (painful red eye), inflammatory bowel disease, or psoriasis. Reactive arthritis is characterized by inflammatory spinal pain and/​ or peripheral arthritis within 4–​6 weeks of specific infections, principally bacterial gastroenteritis and genitourinary infection (usually chlamydia). Gastrointestinal symptoms vary in severity according to the triggering infection—​severe with shigella, often mild with yersinia—​ while chlamydia infection is often asymptomatic, although symptoms of urethritis/​cervicitis should be sought. Enthesitis is common, and dactylitis (diffuse swelling of a digit) may occur. Extra-​articular features include mucocutaneous lesions, such as oral or penile ulcers, and keratoderma blennorrhagica (hyperkeratotic psoriatic lesions on hands and feet), as well as conjunctivitis or, occasionally, uveitis. Psoriatic arthritis symptoms include peripheral inflammatory arthritis, which is often asymmetric and can occur with or without inflammatory back pain. Peripheral arthritis is subdivided into oligo-​and polyarthritis, with the latter being commonest, and some patients have only distal interphalangeal joint disease. The presence of psoriasis at presentation or at any time in the past, or a family history of psoriasis, is key. Other spondyloarthropathy features, including dactylitis and enthesitis, occur frequently. Arthropathy of inflammatory bowel disease (enteropathic arthritis) may present with typical axial and peripheral features of spondyloarthropathy, in addition to intestinal symptoms or a known diagnosis of inflammatory bowel disease. Other extra-​intestinal manifestations include mouth ulcers, fatigue, systemic features, erythema nodosum, and pyoderma gangrenosum. Undifferentiated spondyloarthropathy can include any of the symptoms of other forms of spondyloarthropathy, but the condition fails to satisfy classification criteria for any of them. Juvenile spondyloarthropathy symptoms can include the spectrum of clinical characteristics of adult spondyloarthropathy. They tend to occur in children over 10 years of age, mostly boys, often with a family history of spondyloarthropathy.

Demographics of the disease Spondyloarthropathy may present at any age but young adults are primarily affected. The prevalence of spondyloarthropathy as a whole is 1%–​2% in the Caucasian population.

Natural history, and complications of the disease Spondyloarthropathies are often progressive chronic conditions with long-​term complications, both musculoskeletal and extra-​articular. However, they may also be self-​limiting, as in reactive arthritis, with 75% cases in remission at 2 years. Spondyloarthropathies often follow a relapsing–​remitting course with short or extended symptom-​ free periods. In ankylosing spondylitis, chronic spinal inflammation leads to bony ankylosis, resulting in progressive restriction of spinal movement.

Significant morbidity and mortality results from spinal disease, and complications arising include spinal fractures with or without neurological complications. The fractures occur due to spinal osteoporosis, which is often marked and related to chronic inflammation. Iritis may result in visual loss, while less common manifestations, including conduction defects, aortic valve incompetence, upper lobe lung fibrosis, renal complications, and amyloidosis, may result in poor outcomes. Reactive arthritis is self-​limiting in the majority of cases but may relapse or persist. Persistent arthropathy, axial involvement, and extra-​articular manifestations may represent evolution into other forms of spondyloarthropathy in predisposed patients. Psoriatic arthritis complications depend on the pattern of joint involvement and its severity, with a wide spectrum of outcomes ranging from mild, non-​destructive polyarthritis to severe joint destruction with bone loss (arthritis mutilans; rarely seen now). Progressive joint destruction, or axial disease combined with significant skin disease, can produce significant disability and considerable psychosocial morbidity.

Approach to diagnosing the disease The diagnosis of spondyloarthropathies can be difficult, due to the evolution of symptoms over time, as well as the overlap between different forms. In approaching the diagnosis of the disease you should: • take a thorough history to identify key or classical features (e.g. a classical description of inflammatory back pain, with dactylitis or monoarticular joint swelling, and a preceding history of recent diarrhoea, is highly suggestive of reactive arthritis) • consider the appropriate demographic group (e.g. ankylosing spondylitis primarily affects males under 40) • perform relevant clinical examination looking for characteristic joint and entheseal inflammation, together with extra-​ articular manifestations (see Figure 268.1) • obtain appropriate investigations, including radiology and blood tests, as well as others Radiology includes plain X-​rays and/​or MRI of the following: • sacroiliac joints: note that • plain X-​rays demonstrate chronic changes and are not suitable for early diagnosis but are useful in established disease; sclerosis, erosions, bony bridges, and ankylosis are common findings • MRI is helpful in early diagnosis, with demonstration of bone marrow oedema, capsulitis, synovitis, and enthesitis, as well as of later progression to the more chronic changes • spine: look for ankylosis, syndesmophytes, and spinal fractures in more advanced disease • affected peripheral joints: look for evidence of periarticular osteopenia, erosions, and chronic joint deformity, as well as periosteal reaction or enthesitis (Sieper et al., 2009)

CHAPTER 268  Seronegative spondyloarthropathy

Typical symptoms of the disease

Blood tests can be used as follows: • to find evidence of the acute phase response (e.g. elevated erythrocyte sedimentation rate (ESR) or C-​ reactive protein levels (CRP) and decreased haemoglobin levels) • HLA-​B27 typing • to find serological evidence of infection by organisms associated with reactive arthritis (e.g. yersinia, campylobacter, and salmonella) Other tests include: • culture of stool, and culture/​PCR of urine or genital tract, with or without rectal swabs for organisms associated with reactive arthritis • skin biopsy, where clinical diagnosis is uncertain • colonoscopy, to investigate possible inflammatory bowel disease

Other diagnoses that should be considered Given the wide and varied presentation of spondyloarthropathies, other inflammatory arthritides (e.g. rheumatoid arthritis) should be considered when inflammatory peripheral arthritis predominates. A monoarthritis should always raise the suspicion of septic arthritis

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Pathophysiology

Mechanism

Sign/Symptom/Lab Finding

Complications

Aortitis, Aortic regurgitation, conduction abnormalities

Inflammation of connective tissue in large vessels and heart valves

Cardiac

Secondary Amyloidosis (rare)

Deposition of amyloid proteins in glomeruli

Renal

As Inflammation resolves, fibrotic tissue replaces the lung interstitium Compression of sacral nerve roots innervating the bladder and rectum

Apical lung fibrosis

Inflammation in the lung interstitial tissue

Ligamentous inflammation and fibrosis

Bladder and bowel incontinence

Respiratory (rare)

Neurological

Authors: Payam Pournazari Reviewers: Yan Yu Scott Rapske Liam Martin* *MD at time of publication

​ eproduced with permission from The Calgary Guide to Understanding Disease, a collaborative student/​faculty project of the University of Calgary. For this, and other materials which illuminate the connection between pathophysiology and R clinical manifestation of disease, visit www.thecalgaryguide.com. Copyright (c) 2012 The Calgary Guide to Understanding Disease.

Figure 268.1  Ankylosing spondylitis: extra-​articular manifestations; AS, ankylosing spondylitis; GI, gastrointestinal.

Legend:

Usually asymptomatic

Inflammatory ulceration of ileum and colon may be seen on endoscopy (Not Inflammatory Bowel Disease (IBD), but IBD is more common in AS patients)

Inflammation of the iris, the anterior part of the eye’s middle layer (uvea)

Anterior Uveitis

GI

Ocular

Extra-articular manifestations

Immune systemic activation in Ankylosing Spondylitis

Ankylosing Spondylitis: Extra-articular Manifestations

CHAPTER 268  Seronegative spondyloarthropathy

‘Gold-​standard’ diagnostic test There is no ‘gold-​standard’ diagnostic test for seronegative spondyloarthropathy; diagnosis is made using the framework detailed in ‘Approach to diagnosing the disease’.

Acceptable diagnostic alternatives to the gold standard As there is no ‘gold-​standard’ diagnostic test for seronegative spondyloarthropathy, there are also no acceptable diagnostic alternatives to the gold-​standard test; instead, diagnosis is made using the framework detailed in ‘Approach to diagnosing the disease’.

Other relevant investigations For seronegative spondyloarthropathy, only investigations used to clarify the diagnosis and exclude the differentials are relevant.

Prognosis and how to estimate it The prognosis of seronegative spondyloarthropathy depends principally on its form; for any given disease, severity varies considerably, and it is not currently possible to give an accurate prognosis. In the early phase of ankylosing spondylitis, elevated acute phase reactants, hip involvement, and osteoporosis are markers of poor prognosis. As the disease progresses, extra-​articular manifestations, spinal fracture, continued elevation of ESR/​CRP, and anaemia are associated with a worse outcome. Patients who have reactive arthritis and are HLA-​B27 positive tend to have more severe and more persistent disease, with a higher likelihood of axial disease and extra-​articular manifestations. Indicators of poor outcome in psoriatic arthritis include polyarticular involvement, early decline in functional abilities, and HIV positivity (Watts et al., 2009).

Treatment and its effectiveness Management of spondyloarthropathy is according to disease subset, its activity, and the possibility of progression. Initial conservative management includes NSAIDs and non-​ pharmacological measures such as education and physiotherapy. An escalation in treatment is often required and tailored according to the presence of peripheral or axial disease, as well as severity of symptoms and initial response to treatment. Recently, international criteria for the management of ankylosing spondylitis have been established (Sieper et al., 2009). Both pharmacological and non-​pharmacological management should run in parallel. In recent times, the use of anti-​tumour necrosis factor (anti-​TNF) agents has dramatically improved the quality of life of patients with ankylosing spondylitis, as these agents treat both peripheral and axial symptoms as well as extra-​articular manifestations.

Psoriatic arthritis treatment aims for peripheral joint remission, symptom control, and prevention of disease progression. Initial management with NSAIDs, escalating to both oral and intra-​articular steroids, is appropriate. Disease-​modifying anti-​rheumatic drugs (DMARDs), including methotrexate, sulfasalazine, and leflunomide, have been shown to be beneficial for peripheral disease but not for axial disease. For polyarthritis, very active oligoarthritis, or enthesopathy, DMARDs are introduced early in disease, as for the treatment of rheumatoid arthritis, although the rationale for doing this is less well established than in rheumatoid arthritis. Anti-​TNF agents, used when DMARDs fail to control peripheral disease, treat both peripheral and axial symptoms. Additional biologic drugs, especially those targeting IL-17 and IL-23 are proving useful in psoriatic arthritis and ankylosing spondylitis. The management of reactive arthritis involves treatment of the triggering infection, although there is no definitive evidence that this approach affects the outcome of the condition. Arthritis is controlled initially with full-​dose NSAIDs, aspiration of affected joints, and intra-​ articular steroids. Short courses of oral steroids may be required. If synovitis fails to resolve by 4–​6 months, particularly in HLA-​B27-​ positive patients, or if there are flares, treatment with DMARDs (e.g. sulfasalazine, methotrexate, or leflunomide) may be used. In a proportion of these cases, the DMARD can be discontinued after ~2  years if the patient is asymptomatic, but 5%–​10% of reactive arthritis patients have persistent disease which continues to require DMARD treatment; in severe cases, the use of anti-​TNF agents can be effective without unmasking latent infection. Spondyloarthropathy associated with inflammatory bowel disease requires optimal management of the colitis/​ enteritis. NSAIDs may aggravate inflammatory bowel disease and worsen anaemia and so must be used with caution. Intra-​articular steroids are useful for individual active joints. DMARDs such as sulfasalazine and methotrexate must be tailored to treat both joint and bowel symptoms (note that drugs that are used in inflammatory bowel disease but do not contain a sulfonamide component (e.g. mesalazine) are ineffective for arthritis). When DMARDs are inadequate, anti-​TNF drugs can be used and are also effective for Crohn’s disease. Undifferentiated spondyloarthropathy can also be managed via these strategies, according to whether peripheral or axial disease predominates. Juvenile spondyloarthropathy requires a multidisciplinary approach to treatment, which generally uses the same agents as for adult disease. As for all patients with juvenile arthritis, monitoring for eye disease is recommended, although anterior uveitis, which is the commonest complication, is usually symptomatic.

Further Reading

CHAPTER 268  Seronegative spondyloarthropathy

or a crystal arthropathy. Sarcoidosis can also present with dactylitis and/​or enthesitis. In addition, mechanical back pain and diffuse idiopathic skeletal hyperostosis are diagnoses to be considered as alternatives to inflammatory spinal pain.

Braun J and Sieper J. Ankylosing spondylitis. Lancet 2007; 369: 1379–​90. Sieper J, Rudwaleit M, Baraliakos X, et  al. The Assessment of SpondyloArthritis International Society (ASAS) handbook:  A guide to assess spondyloarthritis. Ann Rheum Dis 2009; 68 (Suppl. 2): 1–​44. Taurog JD, Chhabra A, and Colbert RA. Ankylosing Spondylitis and Axial Spondyloarthritis. N Engl J Med 2016; 374: 2563–​74. Watts R, Clunie G, Hall F, et al. Oxford Desk Reference Rheumatology, 2009. Oxford University Press.

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269 

Systemic lupus erythematosus

Robert Stevens and Chee-​Seng Yee

Definition and etiology of the disease Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune inflammatory disorder of unknown etiology. Numerous abnormalities within the innate and adaptive immune system have been described. The hallmark of this disease is B-​cell hyperactivity resulting in autoantibody production, abnormal T-​cell function, impaired clearance of immune complexes (resulting in their deposition in tissues), complement activation, and defective cellular apoptosis. However, these abnormalities of the immune system are not uniform across patients and within the same patient at different stages of the disease, resulting in heterogeneity in its presentation and progress. The pathogenesis is complex, involving genetic, environmental, and hormonal factors.

Genetic factors SLE is considered a complex genetic trait, with a lack of correlation between phenotype and genotype. The genetic basis is supported by the fact that there are ethnic differences in disease incidence/​ prevalence, the disease has a tendency for familial clustering, a higher concordance rate in monozygotic twins than in dizygotic twins, and several genetic associations. Genetic factors are a major determinant of susceptibility to the disease and possibly of disease severity as well.

Environmental factors Environmental factors are thought to be involved in triggering the autoimmune process in a genetically susceptible individual. The three main environmental factors are UV light, infections (especially with Epstein–​Barr virus), and drugs. Many drugs have been implicated in drug-​induced lupus but the most recognized are procainamide and hydrallazine.

Hormonal factors The role of oestrogen is suggested by the strong female preponderance of this disease, the timing of disease onset (occurring mainly after puberty), and the increased risk of flare of disease during pregnancy.

Fatigue is the most common symptom of SLE and can be disabling. Another contributory factor is fibromyalgia, which is common in SLE patients and tends to be persistent, even when the disease is under controlled.

Non-​specific mucocutaneous manifestations Non-​specific mucocutaneous manifestations of SLE include: mucosal ulcers (nasal or oral) • • photosensitivity • cutaneous vasculitis (e.g. purpuric rash, urticaria, subcutaneous nodules, and ulcers)

Lupus-​specific mucocutaneous lesions Lupus-​specific mucocutaneous lesions are characterized by deposition of IgG along the dermal–​epidermal junction (known as positive lupus band test); this occurs both in obvious lesions and in normal-​ appearing skin. Lesions can be classified into three types: • acute cutaneous lupus, which can be erythematous (including malar rash), exanthematous (resembling erythema multiforme), or bullous • subacute cutaneous lupus, which can be psoriasiform or annular/ polycyclic • chronic cutaneous lupus, which can lead to scarring; this commonly manifests as discoid lesions with follicular plugging or, in the case of lupus profundus, as tender subcutaneous nodules

Musculoskeletal disorders Musculoskeletal manifestations of SLE include: arthralgia/​myalgia, which is very common but non-​specific • • inflammatory arthritis, which is usually non-​erosive • Jaccoud’s arthropathy, which is a deforming arthropathy that can be rheumatoid-​like but is correctable

Serositis Both pleurisy and pericarditis can occur in SLE.

Demographics and epidemiology

Renal manifestations

SLE has been reported worldwide, with differences in the incidence, prevalence, pattern of organ involvement, and severity of disease across different ethnic groups. Any age can be affected but it predominantly affects women of childbearing age, with a female to male ratio of 11:1. This is an uncommon disease, with a prevalence of about 1 in 2000 and an incidence of 7 per 100 000 per year amongst adult women in the UK. It is more common in those of Afro-​Caribbean and South Asian descent than in those of Caucasian descent. There appears to be a trend towards increasing prevalence and incidence of the disease over time.

Renal involvement in SLE is commonly asymptomatic or non-​specific, especially in the early stages. It is most commonly picked up with urine dipstick testing (e.g. as proteinuria, haematuria, and/​or pyuria). Hence, it is crucial that urine dipstick testing is performed as part of the routine assessment of SLE patients.

Clinical manifestations SLE is a chronic disease that is characterized by periods of exacerbations with variable course. Recognized triggers of flare of disease activity are UV light, infection, oestrogen, and stress. SLE is a multisystem disease that can affect any parts of the body, with protean manifestations. As any organ system can be involved, the disease may present in variable combinations of organ system manifestations that can vary both between patients and within the same patient over time.

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Fatigue

Haematological disorders The following haematological disorders are common in SLE but are usually asymptomatic: anaemia (this is usually the anaemia of chronic disease) • • leucopenia with neutropenia and/​or lymphopenia • thrombocytopenia

Approach to diagnosis There is no specific diagnostic test for SLE. Although classification criteria have been devised by the American College of Rheumatology, the criteria were developed for research studies and are not intended for diagnostic purposes.

Evidence of systemic involvement As there is no diagnostic test, a good clinical assessment is essential to determine the pattern of systemic involvement. A high index of suspicion is required, particularly when there is multisystem involvement and the following common manifestations of SLE are present: • mucocutaneous features (especially mouth ulcers, alopecia, rash, and photosensitivity) • inflammatory arthritis • renal involvement (as indicated by proteinuria and active urinary sediment) • pleurisy or pericarditis • haematological manifestations (especially haemolytic anaemia, leucopenia, neutropenia, lymphopenia, and thrombocytopenia) As renal and haematological involvement may be asymptomatic, it is important to perform the following tests during the diagnostic workup: • a urine test for proteinuria and active urinary sediment (a urine dipstick test on its own is not sufficient, as it is not accurate and is associated with a high level of false-​positive results) • a full blood count Other investigations will be dictated by patient’s presentation and are performed mainly to exclude other causes for the manifestation(s). These include: biopsy (e.g. renal biopsy, skin biopsy) • • imaging (e.g. MRI of the head/​spine; high-​resolution CT of the chest) • electrophysiological tests (e.g. nerve conduction studies, electromyography) • blood tests (e.g. Coomb’s test, hepatitis serology, muscle enzymes)

Presence of autoantibodies As B-​cell hyperactivity is the hallmark of SLE, the absence of autoantibodies in an untreated patient makes the diagnosis unlikely (good negative predictive value). Autoantibodies that are specific to SLE are anti-​double-​stranded DNA antibodies (present in 60%–​70% of cases) and anti-​Sm antibodies (present in 10%–​30% of cases). Autoantibodies to be tested for include: • antinuclear antibody (ANA), which is the most common type of autoantibody found in SLE (>95% of cases) • extractable nuclear antigens, including anti-​Ro, anti-​La, and anti-​Sm • anti-​double-​stranded DNA antibodies • antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) Two further important points to note regarding autoantibodies are that:

diseases (e.g. Sjögren’s syndrome, dermatomyositis, polymyositis, and systemic sclerosis), termed overlap syndrome and mixed connective tissue disease) • antiphospholipid syndrome (note that this can occur as part of SLE (secondary antiphospholipid syndrome)) • sarcoidosis • other inflammatory arthritis (such as rheumatoid arthritis and seronegative spondyloarthropathy)

Assessment of disease In assessing SLE patients, there are three outcome domains to be considered: disease activity, damage, and the health status of patient. Disease activity is the immune-​mediated process that is potentially reversible or ‘inflammation’, while damage is an irreversible process or ‘scarring’. Damage can be a result of uncontrolled disease activity but, more commonly, it is multifactorial, due to a combination of disease activity, treatment, and comorbidities. Examples of damage are myocardial infarctions, joint erosions, and scarring alopecia. The health status of the patient is the person’s sense of physical, emotional, and social well-​being associated with the disease or its treatment; it is perhaps better known as the ‘health-​related quality of life’. These three outcome domains are managed differently; hence, it is crucial to differentiate these domains with regards to attribution of manifestations. In particular, immunomodulators are used to treat manifestations of disease activity but not manifestations of damage or health-​related quality of life. Assessing SLE can be challenging, particularly when trying to attribute clinical manifestations to disease activity. This is due to the lack of a good biomarker and the complexity of this multisystem disease, with its myriad of presentations that can vary between patients and within the same patient over time.

Complications Organ damage Organ damage caused by SLE includes skin scarring (including scarring alopecia), avascular necrosis of bone (especially hip), chronic kidney disease, and pulmonary fibrosis.

Premature atherosclerosis SLE patients are at much higher risk of developing cardiovascular disease, compared to the general population. Furthermore, in women, the premenopausal protective effect for cardiovascular disease appears to be abrogated by the disease. It should be noted that the traditional Framingham risk calculator underestimates the risk of cardiovascular disease in SLE patients. It has been suggested that SLE patients should be considered to have the same level of risk for cardiovascular disease as those with diabetes mellitus.

• ANA is not specific to SLE, as many different conditions can cause a positive result for the ANA test, and up to 5% of the normal population is positive for ANA; hence, a positive ANA test does not equate to a diagnosis of SLE • a patient being treated for SLE can become negative for autoantibodies

Malignancy

Other diagnosis to be considered

Pregnancy comorbidities

As SLE is a multisystem disease with protean manifestations, of which most are not specific to the disease itself, the clinical presentation can mimic other conditions. The main differential diagnoses are other multisystem conditions, in particular:

Comorbidities seen during pregnancy in SLE patients include:

• sepsis (it is important to note that SLE patients have an increased risk of infection (in part due to immunosuppressive treatment) and that infection itself could trigger a flare of disease activity) • primary systemic vasculitis (e.g. antineutrophil cytoplasmic antibody-​associated vasculitis, and Behçet’s syndrome) • other connective tissue diseases (note that it is not uncommon for there to be overlapping features of other connective tissue

Prognosis

CHAPTER 269  Systemic lupus erythematosus

The two key features of SLE are systemic involvement and the presence of autoantibodies.

SLE patients have an increased risk of cancer, compared to general population. This is even more so for: non-​Hodgkin’s lymphoma • • lung cancer • cervical cancer

neonatal lupus syndrome • • pregnancy loss • flare of disease activity

Before the advent of corticosteroids, the 5-​year survival for SLE was less than 55%. Over the last few decades, survival has improved considerably; currently, the 10-​year survival rate is ~90%. However, SLE patients still have much lower life expectancy, compared to the general population, and this is most pronounced in those under the

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age of 45. The most common causes of deaths are cardiovascular disease, infection, and malignancy. The more damage a patient has accumulated, the higher is the risk of death.

Treatment The treatment of SLE is aimed at controlling disease activity (through immunomodulation), prevention of development of damage, and management of complications. The treatment options for disease activity are:

CHAPTER 269  Systemic lupus erythematosus

symptomatic treatment (e.g. NSAIDs) • • antimalarials (e.g. hydroxychloroquine, chloroquine, and mepacrine) • corticosteroids (e.g. topical, oral, intra-​lesional, or parenteral) • immunosuppressives (in particular, azathioprine, methotrexate, mycophenolate, and cyclophosphamide) • biologicals (e.g. rituximab and belimumab) • plasmapheresis • IV immunoglobulins • others (e.g. thalidomide, prasterone, dapsone, and retinoids)

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The management of disease activity is tailored to the patient, and the major determinant of treatment option is the level of disease activity. Severe disease activity is defined as manifestations that are life-​threatening or result in significant organ dysfunction, such as seizure, nephrotic syndrome, and inability of the patient to perform the activities of daily living. On the other end of the spectrum, mild disease activity refers to minor manifestations that cause some discomfort but leave the patient able to continue with their daily routines. Severe disease activity requires treatment with high-​dose corticosteroids and usually with immunosuppressives and/​or biologicals. IV immunoglobulins and plasmapheresis are mainly reserved for life-​ threatening manifestations. Moderate disease activity is commonly treated with lower doses of corticosteroids, and immunosuppressives may be added in. Antimalarials are also commonly used and have been shown to be

effective in controlling mucocutaneous manifestations and inflammatory arthritis. For certain manifestations, local treatment with corticosteroids (and occasionally immunosuppressives) could be used, such as intra-​articular injection of methylprednisolone for inflammatory arthritis, and corticosteroid cream for discoid rash. Thalidomide, retinoids, and dapsone are used for the treatment of refractory skin lesions. Prasterone (an androgen) has been shown to have steroid-​ sparing properties and reduce the number of SLE flares. Mild disease activity usually only requires symptomatic treatment. Due to their low toxicity, antimalarials are also used to treat recurrent or persistent milder mucocutaneous and musculoskeletal manifestations. There is also evidence supporting the ubiquitous use of hydroxychloroquine, as long-​term usage is associated with lower cardiovascular events and improved survival. Apart from managing disease activity, other measures that deserve special mention are: • photoprotection (in the form of protective clothing and high-​factor (at least SPF 30) sun cream); many SLE patients are photosensitive, and UV light is a well-​recognized trigger of disease activity flare • smoking cessation; this is important, as SLE patients have an increased risk of cardiovascular disease and lung cancer • aggressive management of cardiovascular risk factors, given the increased risk of cardiovascular disease in SLE • physiotherapy and occupational therapy; these non-​pharmacological measures may help with inflammatory arthritis, fatigue, and fibromyalgia (commonly associated with SLE)

Further Reading Lisnevskaia L, Murphy G, and Isenberg D. Systemic lupus erythematosus. Lancet 2014; 384: 1878–​88. Rahman A and Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008; 358: 929–​39.

270 

Crystal arthropathy

Michael Doherty

Definition of crystal arthropathy Three main crystals associate with arthritis: monosodium urate (MSU) • • calcium pyrophosphate, the usual cause of cartilage calcification (chondrocalcinosis (CC)) • basic calcium phosphates (BCP), including hydroxyapatite Gout is a true crystal deposition disease caused by MSU. Calcium pyrophosphate crystal deposition (CPPD) is the umbrella term for calcium pyrophosphate deposition. Calcium pyrophosphate crystals cause inflammation in acute calcium pyrophosphate crystal arthritis and chronic calcium pyrophosphate crystal inflammatory arthritis. However, osteoarthritis (OA) commonly associates with calcium pyrophosphate (OA with CPPD) and BCP crystals and, in this context, it is unclear if the crystals are pathogenic.

Aetiology of crystal arthropathy Crystals only form when the saturation point for crystallization is exceeded. A  serum uric acid (SUA) of 360 µmol/​L (6.0 mg/​dl) approximates to the saturation point for MSU. Extracellular pyrophosphate (ePPi) in cartilage is the key determinant of CPPD but cannot be measured clinically. Uric acid (UA), produced from xanthine by xanthine oxidase (XO), is the end product of purine breakdown. About two-​thirds of UA is produced endogenously, with the rest coming from dietary purines. UA is excreted mainly via the kidney. Risk factors for SUA elevation and gout are shown in Table 270.1. MSU preferentially deposits in and around joints, mainly feet, knees, hands, and elbows.

Most ePPi comes from the breakdown of nucleoside triphosphates, although some comes from intracellular pyrophosphate transported outside by the progressive ankylosis protein homolog protein, which is encoded by the ANKH gene. ePPi is converted to orthophosphate by alkaline phosphatase (with magnesium as a cofactor). Moderate increases in ePPi stimulate, but high levels inhibit, BCP crystal formation, making ePPi a key regulator of normal mineralization (bones, teeth) and an inhibitor of unwanted BCP (cartilage, urine, saliva). High ePPi levels in hyaline and fibrocartilage predispose to CPPD, particularly in knees. Risk factors for CPPD are shown in Table 270.2.

Typical symptoms of crystal arthropathy, and less common symptoms Acute gout and acute calcium pyrophosphate crystal arthritis Acute gout and acute calcium pyrophosphate crystal arthritis present as acute mono-​arthritis characterized by: • rapid-​onset severe pain (‘worst ever’), reaching a maximum in 6–​24 hours • marked tenderness—​even to clothing over the joint • swelling, effusion, increased warmth (± erythema) The ‘attack’ resolves within a few days or weeks. Occasionally, several joints are affected simultaneously. Milder, short-​lived episodes

Table 270.2  Risk factors for calcium pyrophosphate dihydrate deposition disease Table 270.1  Risk factors for gout

Risk factor

Mechanism

Risk factor

Mechanism

Ageing

Hereditary, genetic risk

Inefficient renal excretion (>95%) due to polymorphisms related to URAT1 and other renal ion transporter systems Overproduction due to purine enzyme mutation (very rare)

Unclear; possible increase in pyrophosphate, alteration of tissue factors

Prior joint insult

Increased production of ePPi by hypertrophic chondrocytes

Osteoarthritis

Increased production of ePPi by hypertrophic chondrocytes Reduction in normal crystal inhibitors (e.g. proteoglycans) Increase in promotors of crystallization (e.g. osteopontin, collagen X)

Metabolic disease:

All of the following lead to increased ePPi levels: Iron inhibits alkaline phosphatase; iron is also a nucleating factor Ca++ inhibits alkaline phosphatase and increases the ionic product Reduced breakdown of ePPi to orthophosphate Reduced breakdown of ePPI by alkaline phosphatase

Metabolic syndrome: • obesity • hypertension • hyperlipidaemia • insulin resistance

Increased endogenous production Reduction in renal efficiency of urate clearance Reduction in renal efficiency of urate clearance Reduction in renal efficiency of urate clearance

Dietary risk factors:

• excessive beer, spirits • diet high in red meat,

Increased exogenous uric acid production (from guanosine in beer) Increased exogenous uric acid production

• hyperparathyroidism

Reduction in renal efficiency of urate clearance Reduction in renal efficiency of urate clearance

Diuretics

Possibly due to diuretic-​induced hypomagnesaemia

Familial CPPD

Rare; families with polyarticular CC and variable arthropathy Some cases due to a mutation in the ANKH (CCAL2) gene

shellfish, offal, etc.

Renal impairment: • chronic renal impairment • drugs (e.g. diuretics, ciclosporin) Ageing, osteoarthritis

• haemochromatosis

Altered balance between tissue inhibitors/​ promotors for crystal nucleation and growth (particularly in osteoarthritis) Age-​related reduction in renal efficiency of urate clearance

• hypophosphatasia • hypomagnesaemia

Abbreviations: CPPD, calcium pyrophosphate dihydrate deposition; ePPi, extracellular pyrophosphate.

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in men (~5:1) and increases with age, rising to 7% prevalence in older men. Usually, it presents after age 30 and is rare before the menopause (oestrogen is uricosuric). Knee CC is rare under the age of 50, but increases from 4% in those aged 50–​60 to 20% in those over the age of 80, affecting both sexes equally.

(A)

(B)

Natural history, and complications of crystal arthropathy Untreated gout typically progresses through an asymptomatic phase to presentation with acute gout, to recurrent attacks separated by asymptomatic inter-​critical periods and, finally, to chronic tophaceous gout. Evolution is slow, usually taking several decades to reach tophaceous gout. Renal complications include nephrolithiasis (UA, but also common calcium stones) and chronic interstitial nephritis (due to MSU deposition). There is growing evidence that high SUA is an independent risk factor for cardiovascular disease and renal impairment, unrelated to MSU deposition. The natural history of CPPD is variable. Acute attacks usually occur only a few times in a patient’s lifetime.

CHAPTER 270  Crystal arthropathy

Approach to diagnosing crystal arthropathy For typical attacks, clinical features alone permit a diagnosis. Factors such as age, the joint involved, comorbidity, drug history and presence of joint damage/​OA usually allow distinction between MSU and calcium pyrophosphate. However, for atypical presentations and chronic disease, crystal identification becomes increasingly important.

Figure 270.1  Tophi on a finger (A) and toes (B) of a patient with chronic tophaceous gout; in some cases, the white colour of monosodium urate crystals can be seen, allowing distinction from rheumatoid nodules.

(‘petite attacks’) are common. Gout also causes acute self-​limiting bursitis, tenosynovitis, or cellulitis. Acute gout targets the first metatarsophalangeal joint (1MTPJ), the mid-​foot, the ankle, the knee, the wrist, the metacarpophalangeal (MCP) joints, the finger joints, and the elbows. First attacks often affect feet (1MTPJ especially). Acute calcium pyrophosphate crystal arthritis targets knees and, less commonly, wrists, MCP joints, elbows, and shoulders (rarely, it occurs in other joints). Both conditions can be triggered by intercurrent illness, surgery, or joint trauma. Initiation of urate-​lowering drugs can trigger gout.

Recurrent and chronic tophaceous gout Acute attacks usually recur, become more frequent, and involve new sites. With continuing deposition, enlarging crystal concretions (tophi) damage cartilage and bone, causing chronic pain, stiffness, and disability. Tophi may be clinically evident (Figure 270.1) mainly over extensor surfaces of feet, knees, hands, and elbows, sometimes discharging pus-​like fluid containing white MSU. Occasionally, tophi occur without preceding attacks.

OA with CPPD and chronic calcium pyrophosphate crystal inflammatory arthritis OA with CPPD is identical to OA (see Chapter  266). It may be asymptomatic or associate with usage-​related pain and functional limitation, with or without superimposed attacks. Chronic calcium pyrophosphate crystal inflammatory arthritis resembles OA but with more inflammation (stiffness, effusion) and involvement of joints (e.g. wrists, MCP joints) atypically affected by OA.

Demographics Gout is the most common inflammatory arthritis in men, and in women aged >65. Overall prevalence is 1.4% but it is more common

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Other diagnoses that should be considered For atypical attacks, the following require consideration: • septic arthritis (see Chapter 271): this is subacute and progressive; crystals and sepsis can coexist so, if sepsis is suspected, microbiological investigation should still be undertaken, despite identification of synovial fluid (SF) crystals • psoriatic and reactive arthritis (see Chapter 264) • palindromic rheumatism: this produces progressive synovitis with adjacent inflammation and erythema over 1–​3  days and which resolves in a similar amount of time • acute haemarthrosis: this presents a tense effusion with no periarticular inflammation or erythema Both chronic gout and chronic calcium pyrophosphate crystal inflammatory arthritis may superficially resemble rheumatoid arthritis. A routine search for SF crystals should be undertaken in any undiagnosed inflammatory arthritis.

‘Gold-​standard’ diagnostic test The gold-​standard test for crystal arthropathy is crystal identification in SF or a tophus aspirate, using compensated polarized microscopy. MSU crystals are needle shaped and brightly birefringent (negative sign). Calcium pyrophosphate crystals are smaller rhomboid crystals with weak (positive) or no birefringence.

Acceptable diagnostic alternatives to the gold standard In the absence of crystal confirmation, diagnosis may be supported by imaging, via radiographs or ultrasound.

Radiographs Radiographs may show CC (Figure 270.2) and, occasionally, synovial/​capsular calcification, with or without OA. Radiographic changes in gout occur late and are mainly those of OA. More specific are para-​articular ‘punched-​out’ cortical erosions and well-​defined cysts (intra-​osseous tophi; see Figure 270.3).

is the preferred treatment in hospital; also, the SF can be examined to confirm the diagnosis and, if required, exclude sepsis • an oral NSAID (naproxen, diclofenac, etoricoxib) plus a proton-​pump inhibitor; although widely used, NSAIDs often are contraindicated in older patients due to comorbidity (e.g. renal impairment) or concomitant drugs (e.g. warfarin, diuretics) • oral colchicine: this alkaloid effectively reduces the neutrophil-​ driven inflammation of crystal synovitis; its main side effect of severe diarrhoea is dose dependent, so use only low doses (0.5 mg twice daily for elderly or those with renal impairment; up to three to four times daily for more robust patients) • systemic steroids: A short course of prednisolone (e.g. 15 mg daily for 5 days) or single intramuscular injection of methylprednisolone (80–​120 mg) may be considered for oligo-​articular attacks and for patients with contraindications or intolerance to NSAIDs and colchicine, if aspiration/​injection is impractical

Ultrasound Crystals can produce hyperechogenicity in cartilage of peripheral joints (e.g. 1MTPJs, knees). MSU occurs at the cartilage surface, whereas CPPD targets the midzone, allowing differentiation. Elevated SUA is a strong risk factor for gout but is unhelpful in diagnosis.

Other relevant investigations Renal function and SUA are relevant to gout, and X-​rays of clinically abnormal joints help assess damage. Metabolic screening (of e.g. calcium, ferritin, alkaline phosphatase, magnesium) is recommended for polyarticular CC and for patients presenting with CC but are under the age of 60.

Prognosis, and how to estimate it A therapeutic aim for troublesome gout is elimination of the crystals. Therefore, the main prognostic factor, as for CPPD, is the degree of irreversible damage (OA), which is assessed clinically and by radiographs.

Treatment and its effectiveness Acute gout and acute calcium pyrophosphate crystal arthritis The following treatments are recommended for acute gout and acute calcium pyrophosphate crystal arthritis: rest the joint and apply ice packs • • if possible, aspirate the affected joint and inject a long-​acting steroid (e.g. methylprednisolone) into it; this gives rapid relief and

Figure 270.3  Foot radiograph of a patient with chronic tophaceous gout, showing cyst-​like bone lesions, cortical erosion, cartilage loss, and the soft-​tissue swelling of the clinically evident tophi.

Long-​term management of gout The following are recommended for long-​term management of gout: provide information concerning gout and its management • • modify risk factors (e.g. advise the patient to lose weight, if the patient is obese, and to reduce excessive intake of high purine foods, beer, and spirits; stop diuretics, if possible) • initiate urate-​lowering therapy (ULT):  this is indicated for frequent attacks, tophi, joint damage, or urolithiasis, with the aim being to reduce SUA well below the saturation point (360 µmol/​l), to prevent further crystal formation and dissolve existing crystals; with the increasing realization that microtophi (seen on ultrasound or MRI) are widespread at first presentation, the trend is towards earlier definitive treatment (see ‘Drugs used for ULT’) • treat comorbidity:  treatment of hypertension, hyperlipidaemia, and insulin resistance helps lower SUA; the antihypertensive losartan and the lipid-​lowering agent fenofibrate have an additional beneficial, mild, uricosuric effect

Drugs used for ULT Allopurinol, the first-​line ULT, is a purine, non-​specific, XO inhibitor that reduces UA production. Its active metabolite oxypurinol is excreted via the kidney. The recommended starting dose is 100 mg daily (50 mg in older patients or those with impaired renal function). SUA is measured every 3–​4 weeks, and the dose increased in 100 mg increments (50 mg if elderly or with renal impairment) until this is achieved (maximum 900 mg; algorithms allow calculation of the lower maximum in renal impairment). The reduction in UA following the initiation of ULT can partially dissolve MSU crystals, encouraging crystal shedding and triggering of attacks. The patient should be warned of this and told to continue ULT if an attack occurs. This triggering is minimized by slow upward titration, or by prophylaxis for several months using daily colchicine (0.5 mg 12 hourly) or NSAIDs (plus a proton-​pump inhibitor). Allopurinol is usually well tolerated but 10% of patients experience gastrointestinal upset, a headache, or mild rashes. Vasculitic rashes and allopurinol hypersensitivity syndrome are serious but rare (mainly in renal impaired patients). Annual SUA monitoring is advised to ensure continuing effective treatment. ULT usually is required indefinitely. Febuxostat is a new, non-​purine, specific XO inhibitor that undergoes hepatic metabolism, requiring no dose adjustment in renal impairment. It is recommended for patients intolerant of allopurinol or in whom allopurinol is contraindicated (e.g. those with severe renal disease). It usually provokes attacks at the starting dose (80 mg), so prophylaxis with colchicine/​ NSAID is advised. It has just two dose options (120 mg daily being the maximum). Uricosuric drugs such as sulfinpyrazone or prebenecid have restricted availability, are less efficient than allopurinol, require high fluid intake to avoid UA crystallization in renal tubules, and are contraindicated in patients with renal impairment or urolithiasis. Benzbromarone (50–​200 mg daily) is a very efficient uricosuric that is effective and safe in mild-​to-​moderate renal impairment. Because

CHAPTER 270  Crystal arthropathy

Figure 270.2  Radiographic knee chondrocalcinosis, with predominant involvement of the fibrocartilaginous menisci.

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of rare hepatotoxicity, it has limited availability and is used on a named-​patient basis.

Long-​term management of CPPD No drugs are available to modify CPPD. Principles of management of OA with CPPD are identical to those for OA (see Chapter  266). For frequent flares or chronic calcium pyrophosphate crystal inflammatory arthritis, oral colchicine (0.5 mg twice daily) or NSAIDs (plus a proton-​pump inhibitor) may be helpful, and hydroxychloroquine or low-​dose methotrexate is sometimes used empirically.

Further Reading

CHAPTER 270  Crystal arthropathy

Mulay SR and Anders HJ Crystallopathies. N Engl J Med 2016; 374: 2465–​76.

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Neogi T. Gout. N Engl J Med 2011; 364: 443–​52. Qaseem A, Harris RP, and Forciea MA. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med 2017; 166: 58–​68. Richette P and Bardin T. Gout. Lancet 2009; 375: 318–​28. Zhang W, Doherty M, Bardin T, et al. EULAR evidence-​based recommendations for calcium pyrophosphate crystal associated arthritis. Part I: Diagnosis. Ann Rheum Dis 2011; 70: 563–​70. Zhang W, Doherty M, Pascual E, et al. EULAR evidence-​based recommendations for calcium pyrophosphate crystal associated arthritis. Part II: Management. Ann Rheum Dis 70: 571–​5.

271 

Infection of joints and bones

Benjamin Bloch

Definition and classification of infection Infection can arise at any time within the bone or soft tissues, and sepsis should always be a consideration in the assessment of an acutely swollen, painful joint. A variety of organisms can be responsible (Table 271.1). An acute infection is an orthopaedic emergency, and prompt assessment should always be sought. Infection can affect either joints (septic arthritis) or bones (osteomyelitis). Septic arthritis can affect either a native joint or a prosthetic one, and the presentation can be acute or chronic. Similarly, osteomyelitis can present acutely or chronically, and can be due to haematogenous spread (particularly affecting the long-​bone metaphyses in children, and the vertebral bodies in adults), direct inoculation via trauma or surgery, or communication from a contiguous infection site.

Presentation Acute septic arthritis is usually as a result of haematogenous infection, and presents typically with pain, swelling, restriction of movement, Table 271.1  Causative organisms Infection

Acute

Chronic

Native septic arthritis

Staphylococcus aureus Streptococcus pyogenes Neisseria gonorrhoeae Gram-​negative organisms such as Escherichia coli and Pseudomonas sp. (in elderly and immunocompromised patients) Anaerobes (rare; associated with penetrating trauma)

In addition to those causing acute infection: Mycobacterium tuberculosis • low-​virulence organisms • (e.g. coagulase-​negative staphylococci)

Prosthetic septic arthritis

Staphylococcus aureus (including MRSA) Streptococcus pyogenes Enterococcus sp. Gram-​negative organisms (Escherichia coli, Pseudomonas sp.)

Coagulase-​negative staphylococci Staphylococcus aureus (including methicillin-​ sensitive Staphylococcus aureus and MRSA) Streptococcus pyogenes Enterococcus sp. Corynebacteria Gram-​negative bacilli Anaerobes Mycobacteria (rare) Fungi (even rarer) Up to 50% of infections are polymicrobial

Staphylococcus aureus Streptococcus pyogenes Streptococcus pneumoniae Haemophilus influenzae type b (more common in children) Salmonella (sickle cell) Pseudomonas aeruginosa

Staphylococcus aureus Streptococcus pyogenes Escherichia coli Pseudomonas aeruginosa Enterobacter sp. >30% of infections are polymicrobial

Osteomyelitis

and fever. Care should be taken when assessing patients who are immunocompromised or taking immunosuppressive drugs, as their inflammatory response may be depressed and they may not show the same pyrexia, leucocytosis, or elevation of serum C-​reactive protein (CRP) levels as healthy patients would. Chronic septic arthritis is rare, but generally presents with a more prolonged course, and may not have as dramatic a rise in blood parameters as acute septic arthritis. In these cases, other organisms such as mycobacteria or atypical bacteria should be considered. Septic arthritis following a prosthetic joint replacement may present acutely or some time after the joint is replaced. Acute presentations tend to be due to local contamination and will present with a hot, red, swollen joint that is usually discharging, as the wound will not have healed fully. A  joint replacement that becomes infected many years down the line will have done so either due to an indolent infection that has been present long term or, more commonly, due to haematogenous spread from another source. Acute osteomyelitis is more commonly seen in children, and is typically rapid in onset and severe in presentation. In adults, acute osteomyelitis is usually associated with the presence of lowered resistance to infection due to conditions such as diabetes or immunosuppression secondary to chemotherapy, HIV/​ AIDS, or post-​ transplant suppression. Finally, those patients with sickle cell disease are at risk of developing salmonella osteomyelitis. The cardinal signs of osteomyelitis are pain, fever, acute tenderness, and inflammation. Radiographs will look normal in the acute stage, and MRI is more useful for diagnosing osteomyelitis. Chronic osteomyelitis is a more indolent process, often as a result of open fractures, surgery, or (in the foot) the sequelae of diabetes. Patients often have sinuses or scars of previous surgery, and will present with recurrent flares of pyrexia, redness, and swelling. The sinus may recommence drainage. The overlying tissues are usually of poor quality and are tethered and adherent to the underlying bone. Plain radiographs may show the typical features of sequestrum (sclerotic, avascular bone) and involucrum (new bone formation as a result of lifting of the periosteum. Further imaging can include the use of radioisotope bone scans, which will show increased uptake in osteomyelitis, and CT and MRI scans are both useful for preoperative planning, particularly in showing the surgeon how much of the bone is involved.

Diagnosis and treatment In all cases, a history and examination is the starting point. The duration of symptoms is important, as it may guide further treatment. Haematological investigations include a full blood count, particularly looking at the white-​cell count, the erythrocyte sedimentation rate, and the CRP level. Radiological investigations generally start with plain X-​rays of the affected bone or joint. However, acute infections rarely show any changes on plain radiographs and, if there is any doubt about the diagnosis, an MRI scan can be beneficial. For those joints that are deep, such as the hip, an ultrasound scan can help to detect an effusion and these can also be aspirated under ultrasound guidance. Septic native joints should be aspirated, and the fluid sent for microscopy, culture, and sensitivities. It is possible to aspirate the shoulder, elbow, wrist, knee, and ankle without radiological guidance. The aspirate should also be examined for the presence of crystals, but infection can, of course, coexist with crystal arthropathy. Whenever possible, aspiration should be done before the administration of antibiotics, to maximize the possibility of identifying the responsible organism.

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CHAPTER 271  Infection of joints and bones

A prosthetic joint should never be aspirated without prior orthopaedic discussion, and it should be done in the operating theatre in a clean environment. The treatment of an acutely septic joint is urgent washout and debridement. In the case of an acutely infected prosthetic joint, it may be possible to salvage the joint by aggressive debridement and exchange of easily accessible parts such as polyethylene bearings. A chronically infected prosthetic joint is likely to need a planned revision, and this may be done either as a single-​stage revision or as a two-​stage revision in which the first stage is removal of the infected replacement and implantation of a temporary spacer, usually with antibiotics given both locally and systemically. In the case of osteomyelitis, a biopsy of the infection may be required for diagnostic purposes, and this drainage can also be therapeutic. Acute osteomyelitis, if appropriately treated, can be arrested before it becomes chronic and the bone becomes necrotic. Chronic osteomyelitis exhibits the radiographic changes of sequestrum (dead bone) and involucrum (an encasing sheath of live bone walling off the sequestrum). Both acute and chronic osteomyelitis require prolonged antibiotic treatment, usually of 6 weeks’ duration, and microbiological advice should be sought for the most appropriate regime. The treatment of chronic osteomyelitis is more complex and requires aggressive surgical debridement of dead bone, removal of

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infected metalware, and reconstruction of any bony defects. This may involve the use of bone grafts or Ilizarov frames and bone transport techniques, and amputation may be required. Chronic osteomyelitis is commonly seen in diabetic patients with ulcers, particularly affecting the metatarsal heads and the calcaneus. In these patients, following initial debridement, the most appropriate treatment may be amputation. Depending on the level of involvement, it may be possible to preserve part of the foot through the use of ray or partial foot amputations but, if not, then a below-​knee amputation would be required. Management of these patients is best done in a multidisciplinary setting, with input from diabetologists, vascular surgeons, orthopaedic surgeons, prosthetists, and podiatrists.

Further Reading Mathews CJ, Kingsley G, Field M, et al. Management of septic arthritis: A systematic review. Postgrad Med J 2008; 84: 265–​70. Mathews CJ, Weston VC, Jones A, et al. Bacterial septic arthritis in adults. Lancet 2010; 375: 846–​55. Matthews PC, Berendt AC, McNally MA, et al. Prosthetic joint infection. BMJ 2009; 338: b1773. Solomon L, Warwick D, and Nayagam S. Apley’s System of Orthopaedics and Fractures (9th edition), 2010. Hodder Arnold.

272 Vasculitis Raashid Luqmani, Joanna Robson, and Ravi Suppiah

Definition of the disease The vasculitides are a heterogeneous group of disorders that can range from mild inflammation of blood vessels in the skin, to organ-​ and life-​threatening diseases. The term ‘vasculitis’ is a pathological description of blood vessel wall inflammation which leads to ischaemia and infarction of the target organs. Definitions and classifications of the primary vasculitides are mainly based on the predominant calibre of the blood vessels involved but incorporate clinical, pathological, and laboratory features. The secondary vasculitides usually occur in the context of other connective tissue diseases and are not discussed further in this section. Anti-​glomerular basement membrane disease (previously known as Goodpasture’s disease) is not usually included in the primary vasculitides, but has compatible clinical features of pulmonary capillaritis and glomerulonephritis. The definitions of the most common types of primary vasculitis proposed at the Chapel Hill Consensus Conference are given in Table 272.1. The 2013 conference advised changing the name of ‘Wegener’s granulomatosis’ to ‘granulomatosis with polyangiitis’ and ‘Churg–​Strauss syndrome’ to ‘eosinophilic granulomatosis with polyangiitis’.

Aetiology Hepatitis B virus infection and resulting immune complex deposition cause hepatitis B-​related polyarteritis nodosa. Hepatitis C virus is the cause of over 90% of mixed cryoglobulinaemia. For all other forms of primary vasculitis, the aetiology is unknown. Antineutrophil cytoplasm antibodies (ANCAs) may play a role in the pathogenesis of granulomatosis with polyangiitis and microscopic polyangiitis; furthermore, Staphylococcus aureus infection is implicated in granulomatosis with polyangiitis.

Symptoms

Anti-​glomerular basement membrane disease has a poor untreated outcome (most cases will die from pulmonary haemorrhage and renal failure). Henoch–​Schönlein purpura in childhood is usually a self-​limiting disease but in adulthood only has 75% survival at 5 years (mainly due to renal disease). Kawasaki disease is associated with coronary aneurysms in 15%–​25% of untreated cases; in the short term, these can be fatal in approximately 1% of children and, in the remainder, can cause complications such as premature atherosclerotic disease and myocardial infarction later in life.

Approach to diagnosing the disease A high index of suspicion and a detailed history and examination are the key to making an accurate diagnosis. In some cases, the clinical history will be highly suggestive. For example, in a patient over the age of 50, the presence of a new-​onset headache with temporal tenderness, jaw claudication, and raised inflammatory markers implies giant cell arteritis. The temporal artery biopsy is the gold standard but may be negative in around 40% of cases. Other patients can present in a more subtle way, and a systematic approach is required to evaluate these patients. It is very important to consider the differential diagnoses and avoid either missing the diagnosis of vasculitis or, conversely, over-​diagnosing it. Ideally, patients should be identified before potentially organ-​and life-​threatening features develop, but this can be difficult in the early, non-​specific stages. A  systematic approach to the patient with multisystem disease is shown in Table 272.4. Where there is a high clinical suspicion, a biopsy from an affected organ is then obtained to try and confirm the diagnosis and exclude other conditions.

Other diagnoses that should be considered

The specific symptoms listed in Table 272.2, some alone but especially in combination, may occur in patients with systemic vasculitis. Non-​specific symptoms such as fever, weight loss, myalgia, and arthralgia are common but not very discriminatory between vasculitis and other conditions.

The differential diagnosis of primary systemic vasculitis is wide and can be broadly divided into the following categories: infection (e.g. HIV, subacute bacterial endocarditis), malignancy (e.g. lymphoma, atrial myxoma), drugs (e.g. cocaine, ciprofloxacin, allopurinol), secondary forms of vasculitis (e.g. connective tissue diseases), and other miscellaneous causes (e.g. thromboembolic disease, calciphylaxis, amyloid).

Demographics of the disease

‘Gold-​standard’ diagnostic test

The demographics depend on the type of systemic vasculitis and are shown in Table 272.3. We have not discussed isolated cutaneous vasculitis any further.

Although there is no gold standard for the diagnosis of systemic vasculitis, a confirmatory biopsy from an involved organ such as a kidney, a lung, or a nerve demonstrating active vasculitis should always be sought. In practice, histological findings can be inconclusive, possibly because of early disease, patchy involvement in a particular organ, or the effect of previous treatment with corticosteroids or other immunosuppressants (which may have to be started promptly in severe life-​or organ-​threatening disease). Histology and microbiology are important to exclude as far as is possible the presence of infection or malignancy but clinical judgement is still essential, especially when the pathological findings are non-​diagnostic. ANCA testing can be very helpful in patients with clinical features suggestive of systemic small vessel vasculitis, but its indiscriminate use is not encouraged. Furthermore, not all cases of granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, or microscopic polyangiitis are ANCA positive. There is a strong association between the presence of anti-​glomerular-​basement-​membrane antibodies and Goodpasture’s disease.

Natural history and complications of the disease The natural history of untreated multisystem vasculitis is likely to be death within the first year. Giant cell arteritis can result in blindness from ischaemic optic neuropathy (in up to 60% of untreated patients) and, rarely, strokes (especially brainstem infarcts). Takayasu arteritis can result in limb ischaemia, gangrene, aortic aneurysms, aortic dissections, aortic ruptures, and potentially death. The ANCA-​associated vasculitides, especially granulomatosis with polyangiitis and microscopic polyangiitis, are associated with acute renal failure from rapidly progressive glomerulonephritis and/​ or fulminant pulmonary haemorrhage due to pulmonary capillaritis, both of which can cause long-​term morbidity such as end-​stage renal failure or death.

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CHAPTER 272 Vasculitis

Table 272.1  Definitions for vasculitides adopted by the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides CHCC2012 name

CHCC2012 definition

Large vessel vasculitis (LVV)

Vasculitis affecting large arteries more often than other vasculitides. Large arteries are the aorta and its major branches. Any size artery may be affected.

Takayasu arteritis (TAK)

Arteritis, often granulomatous, predominantly affecting the aorta and/​or its major branches. Onset usually in patients younger than 50 years.

Giant cell arteritis (GCA)

Arteritis, often granulomatous, usually affecting the aorta and/​or its major branches, with a predilection for the branches of the carotid and vertebral arteries. Often involves the temporal artery. Onset usually in patients older than 50 years and often associated with polymyalgia rheumatica.

Medium vessel vasculitis (MVV)

Vasculitis predominantly affecting medium arteries defined as the main visceral arteries and their branches. Any size artery may be affected. Inflammatory aneurysms and stenoses are common.

Polyarteritis nodosa (PAN)

Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with antineutrophil cytoplasmic antibodies (ANCAs).

Kawasaki disease (KD)

Arteritis associated with the mucocutaneous lymph node syndrome and predominantly affecting medium and small arteries. Coronary arteries are often involved. Aorta and large arteries may be involved. Usually occurs in infants and young children.

Small vessel vasculitis (SVV)

Vasculitis predominantly affecting small vessels, defined as small intraparenchymal arteries, arterioles, capillaries, and venules. Medium arteries and veins may be affected.

ANCA-​associated vasculitis (AAV)

Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles, and small arteries), associated with myeloperoxidase (MPO) ANCA or proteinase 3 (PR3) ANCA. Not all patients have ANCA. Add a prefix indicating ANCA reactivity, e.g., MPO-​ANCA, PR3-​ANCA, ANCA-​negative.

Microscopic polyangiitis (MPA)

Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent.

Granulomatosis with polyangiitis (Wegener’s) (GPA)

Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries, and veins). Necrotizing glomerulonephritis is common.

Single-​organ vasculitis (SOV)

Vasculitis in arteries or veins of any size in a single organ that has no features that indicate that it is a limited expression of a systemic vasculitis. The involved organ and vessel type should be included in the name (e.g., cutaneous small vessel vasculitis, testicular arteritis, central nervous system vasculitis). Vasculitis distribution may be unifocal or multifocal (diffuse) within an organ. Some patients originally diagnosed as having SOV will develop additional disease manifestations that warrant redefining the case as one of the systemic vasculitides (e.g., cutaneous arteritis later becoming systemic polyarteritis nodosa, etc.).

Eosinophilic granulomatosis with polyangiitis (Churg-​Strauss) (EGPA)

Eosinophil-​rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.

Immune complex vasculitis

Vasculitis with moderate to marked vessel wall deposits of immunoglobulin and/​or complement components predominantly affecting small vessels (i.e., capillaries, venules, arterioles, and small arteries). Glomerulonephritis is frequent.

Anti-​glomerular basement membrane (anti-​GBM) disease

Vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-​ GBM autoantibodies. Lung involvement causes pulmonary hemorrhage, and renal involvement causes glomerulonephritis with necrosis and crescents.

Cryoglobulinemic vasculitis (CV)

Vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) and associated with serum cryoglobulins. Skin, glomeruli, and peripheral nerves are often involved.

IgA vasculitis (Henoch–​Schönlein) (IgAV)

Vasculitis, with IgA1-​dominant immune deposits, affecting small vessels (predominantly capillaries, venules, or arterioles). Often involves skin and gastrointestinal tract, and frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may occur.

Hypocomplementemic urticarial vasculitis (HUV) (anti-​C1q vasculitis)

Vasculitis accompanied by urticaria and hypocomplementemia affecting small vessels (i.e., capillaries, venules, or arterioles), and associated with anti-​C1q antibodies. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are common.

Variable vessel vasculitis (VVV)

Vasculitis with no predominant type of vessel involved that can affect vessels of any size (small, medium, and large) and type (arteries, veins, and capillaries).

Behçet’s disease (BD)

Vasculitis occurring in patients with Behçet’s disease that can affect arteries or veins. Behçet’s disease is characterized by recurrent oral and/​or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal, and/​or central nervous system inflammatory lesions. Small vessel vasculitis, thromboangiitis, thrombosis, arteritis, and arterial aneurysms may occur.

Cogan’s syndrome (CS)

Vasculitis occurring in patients with Cogan’s syndrome. Cogan’s syndrome characterized by ocular inflammatory lesions, including interstitial keratitis, uveitis, and episcleritis, and inner ear disease, including sensorineural hearing loss and vestibular dysfunction. Vasculitic manifestations may include arteritis (affecting small, medium, or large arteries), aortitis, aortic aneurysms, and aortic and mitral valvulitis.

Vasculitis associated with systemic disease

Vasculitis that is associated with and may be secondary to (caused by) a systemic disease. The name (diagnosis) should have a prefix term specifying the systemic disease (e.g., rheumatoid vasculitis, lupus vasculitis, etc.).

Vasculitis associated with probable aetiology

Vasculitis that is associated with a probable specific aetiology. The name (diagnosis) should have a prefix term specifying the association (e.g., hydralazine-​associated microscopic polyangiitis, hepatitis B virus–​associated vasculitis, hepatitis C virus–​associated cryoglobulinemic vasculitis, etc.).

Reproduced with permission from J. C. Jennette et al., 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, Arthritis & Rheumatology, Volume 65, Issue 1, pp. 1-​11, Copyright © 2012 John Wiley and Sons.

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Table 272.2  Symptoms that may suggest a diagnosis of vasculitis Vessel size

Symptoms

Comments

Large vessel

New-​onset/​unaccustomed headache Jaw claudication Tongue pain Limb claudication Sudden onset of blindness

Any of these symptoms alone should raise the suspicion of vasculitis

Medium vessel

New-​onset hypertension Abdominal ischaemic symptoms Ischaemic chest pain Polyneuropathy

Hypertension in itself is not very discriminatory, but in combination with abdominal ischaemia and polyneuropathy is very suggestive

Small vessel

Pulmonary haemorrhage or haemoptysis New-​onset asthma or treatment-​resistant asthma Chronic upper respiratory symptoms (e.g. nasal crusting, discharge) Sensory or motor peripheral neuropathy (mononeuritis multiplex) Haematuria, proteinuria, and/​or oliguria Inflammatory arthritis Purpura

A combination of these symptoms is suggestive of vasculitis but other causes such as infection should be excluded first

Disease

Incidence per million population

Age distribution

Notes

Giant cell arteritis

37–​350 (for patients older than 50 years of age)

Almost always over the age of 50

Incidence is in the higher range in northern Europe, and in the lower range in central and southern Europe Female-​to-​male ratio is 3:1

Takayasu arteritis

0.4–​2.6

Usually below the age of 40, but cases reported as old as 60

Prevalence is thought to be higher in Turkey and Asia but there is no epidemiological data to support this

Kawasaki disease

55–​146 (for children less than 5 years of age and living in the UK)

Usually children under 5

Incidence is lowest in children of Caucasian ancestry and highest in children of Asian origin A significantly higher incidence is reported in China and Japan

Polyarteritis nodosa

0.0–​0.9

Any age, but peak in 40–​60-​year-​old age group

Incidence has been dramatically reduced in the past two decades due to widespread vaccination and better screening of blood products for hepatitis B virus

Granulomatosis with polyangiitis

4.9–​10.5

Any age

Prevalence is higher in northern Europe

Microscopic polyangiitis

2.7–​11.6

Any age

Prevalence is higher in southern Europe

Eosinophilic granulomatosis with polyangiitis

0.5–​4.2

Any age

Henoch–​Schönlein purpura

62–​240 (for children under the age of 17 and living in the UK)

Usually children under 15, but can occur in adults

CHAPTER 272 Vasculitis

Table 272.3  Incidence of vasculitis in Europe

Lowest incidence observed in children of black Caribbean descent, and highest in children with Asian ancestry

Table 272.4  A systematic approach to the assessment of the patient with systemic vasculitis General: Myalgia, arthralgia/​arthritis, fever >38°C, weight loss Skin

Infarcts, purpura, ulcers, gangrene

Respiratory

Wheeze, nodules or cavities, effusions, infiltrates, haemoptysis, haemorrhage, respiratory failure

Mucous membranes/​eyes

Mouth or genital ulcers, uveitis, scleritis, episcleritis, retinal changes

Cardiovascular

Valvular disease, loss of pulses, pericarditis, IHD, cardiomyopathy, CCF

Ear nose and throat

Bloody nasal discharge, crusts, granulomata, deafness, subglottic stenosis, sinusitis

Gastrointestinal

Peritonitis, bloody diarrhoea, ischaemic abdominal pain

Neurological

Headache, meningitis, confusion, seizures, cranial nerve and peripheral nerves, spinal cord lesions, CVA

Renal

Hypertension, proteinuria, haematuria, rise in creatinine

Abbreviations: CCF, congestive cardiac failure; CVA, cerebral vascular accident; IHD, ischaemic heart disease. Reproduced from Annals of the Rheumatic Diseases, Mukhtyar C, et al, Modification and validation of the Birmingham Vasculitis Activity Score (version 3), volume 68, issue 12, pp. 1827–​1832, copyright © 2008 BMJ Publishing Group Ltd.

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Table 272.5  Mortality in systemic vasculitis: Five-​year survival compared with age-​matched population Diagnosis

5-​year survival (%)

Granulomatosis with polyangiitis

75

Microscopic polyangiitis

45–​75

Eosinophilic granulomatosis with polyangiitis

68–​100

Adult-​onset Henoch–​Schönlein purpura

75

Polyarteritis nodosa

75–​80

Kawasaki disease

>99

Giant cell arteritis

100

Takayasu arteritis

70–​93

Acceptable diagnostic alternatives to the gold standard Temporal artery ultrasound is more sensitive but less specific than temporal artery biopsy for the diagnosis of giant cell arteritis. In Takayasu arteritis and in polyarteritis, the use of MRI and magnetic resonance angiography for diagnosis and monitoring of the disease is now replacing invasive conventional angiography. PET scans may prove valuable in suspected large vessel disease but have a considerable radiation load, especially when used in conjunction with CT.

Data from Phillip R and Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol, 2008. 26(5 Suppl 51): p. S94–​104.

CHAPTER 272 Vasculitis

Table 272.6  Recommendations for the treatment of vasculitis Vasculitis type

Recommendations for treatment

Large vessel vasculitis (giant cell arteritis and Takayasu arteritis)

For suspected giant cell arteritis, treatment should be initiated even before the biopsy or scan has been obtained and may be continued despite a negative biopsy or scan if the clinical suspicion is high Early use of high-​dose corticosteroids (approximately 1 mg/​kg of prednisolone (maximum 60 mg) per day or equivalent) to achieve remission; continue with this high dose for 1 month Taper steroids to achieve a target daily dose of 10–​15 mg per day by 3 months Do not use alternative-​day steroids, as this is more likely to lead to relapse of disease Immunosuppressive therapy (e.g. methotrexate or azathioprine) can be considered as an adjunct to treatment with corticosteroids There is growing evidence of benefit from anti-cytokine therapy, targeting interleukin-6, and in some cases from targeting interleukin -12 Adequate bone protection (e.g. bisphosphonates) should be considered because patients are likely to require several years of glucocorticoid therapy

Small or medium vessel vasculitis (including granulomatosis with polyangiitis; microscopic polyangiitis; eosinophilic granulomatosis with polyangiitis; polyarteritis nodosa (not hepatitis B related); and non-​infectious essential mixed-​ cryoglobulinaemia vasculitis)

Induction therapy in generalized disease (to induce remission): cyclophosphamide and rituximab are equivalent in efficacy for treatment of GPA and MPA • • IV pulse cyclophosphamide 15mg/kg (maximum 1.2g) fortnightly for first three doses, then 3 weekly for the next 3–7 doses; less commonly, continuous oral cyclophosphamide 2mg/kg/day (maximum 200mg/day) for 3–6 months may be given daily prednisolone 1 mg/​kg per day (maximum 60 mg/​day) for the first months, and then taper to a target of 15 mg/​day by the • end of the third month consider an initial pulse of IV methylprednisolone (0.5–​1.0 g) as a single dose at the start of therapy, in addition to oral steroids • plasma exchange should be used as an adjunct to cyclophosphamide and steroid therapy in patients with severe renal disease • (creatinine >500 µmol/​l) trimethoprim/sulfamethoxazole (800/​160 mg on alternate days) should be used to prevent Pneumocystis jiroveci infection, which • can result from severe immunosuppression oral or IV mesna should be given to patients receiving pulse cyclophosphamide, to reduce the risk of bladder toxicity • consider rituximab, mycophenolate mofetil, 15-​deoxyspergualin, anti-​thymocyte globulin, infliximab, or IV immunoglobulin in • patients who are refractory to induction therapy with cyclophosphamide Induction therapy in limited disease (to induce remission): methotrexate (20–​25 mg/​day) can be used as an alternative to cyclophosphamide to induce remission in patients with mild disease • and normal renal function Maintenance therapy (to maintain remission once this is achieved with induction therapy) in limited and generalized disease: azathioprine (2 mg/​kg per day), methotrexate (20–​25 mg/​week), mycophenolate mofetil (2–3g per day), or leflunomide (20–​30 • mg/​day) should be used to maintain remission; continue for a minimum of 18 months taper glucocorticoids to 10 mg/​day by 6 months and then slowly taper further by 18 months • the addition of trimethoprim/sulfamethoxazole (800/​160 mg twice daily) may reduce the risk of relapse in granulomatosis with • polyangiitis

Hepatitis B-​associated polyarteritis nodosa

Combination therapy utilizing high-​dose glucocorticoids, antiviral therapy, and plasma exchange Hepatitis B can usually be cured with antiviral therapy

Hepatitis C-​ associated mixed-​ cryoglobulinaemia vasculitis

Antiviral therapy; usually, long-​term dual therapy with ribavirin and interferon alfa, due to chronic persistence of infection despite antiviral therapy

Henoch–​Schönlein purpura

In children, supportive therapy only Adults may be managed using immunosuppressive therapy +/​− plasma exchange as for small vessel vasculitis, although there is no evidence base for effectiveness

Kawasaki disease

IV immunoglobulin 2 g/​kg as a single infusion as soon as diagnosis is made High-​dose aspirin 80–​100 mg/​kg per day in four divided doses for a minimum of 14 days and patient afebrile for >72 hours, then reduce dose to 3–​5 mg/​kg per day for 6–​8 weeks; if there is evidence of coronary aneurysm, continue low-​dose aspirin indefinitely

Data from: Lapraik C, Watts R, Bacon P, et al. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxford), 2007. 46(10): p. 1615–​6. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis, 2009. 68(3): p. 318–​23. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis, 2009. 68(3): p. 310–​7. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-​term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation, 2004. 110(17): p. 2747–​71.

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Baseline investigations in all patients with suspected vasculitis should include a full blood count, tests for urea and electrolytes, liver function tests, inflammatory markers, urinalysis, a chest radiograph, and an ECG. Further investigations, such as CT scans, can then be arranged as indicated from the pattern of organ involvement.

Prognosis and how to estimate it Historically, patients with untreated systemic vasculitis had an 80% mortality rate. Improved recognition of these diseases and immunosuppressive therapy has reversed this to a 5-​ year survival of approximately 80%. Table 272.5 summarizes the outcome from a variety of studies of vasculitis over the last 50 years. Early deaths are usually secondary to uncontrolled vasculitis and highlight the need for aggressive early therapy in life-​or organ-​threatening disease. The other major cause of early death is infection. Due to more patients surviving the initial presentation, the effects of immunosuppressive therapy and comorbidities such as cardiovascular disease become important causes of death in the long term. A five-​factor score (FFS) which comprises renal impairment, proteinuria, cardiomyopathy, CNS involvement, and gastrointestinal involvement predicts prognosis in polyarteritis nodosa and eosinophilic granulomatosis with polyangiitis. Patients with a FFS of 0 have a 5-​year mortality of 12%, whereas, in patients with three or more factors, the mortality is 46%.

Treatment and its effectiveness The treatment recommendations differ between the types of vasculitis but, in general, large vessel vasculitis is treated with moderate-​to-​high doses of corticosteroids alone, whereas most small and medium-​ sized vessel vasculitides require stronger immunosuppression in

conjunction with steroids. The choice and intensity of immunosuppressive treatment for small vessel vasculitis is dependent on the severity of disease and the distribution of the organs involved. The exceptions are childhood-​onset Henoch–​Schönlein purpura, which is normally self-​limiting, and Kawasaki disease (which requires aspirin and IV Ig). Antiviral strategies are necessary for the vasculitides associated with an infectious cause such as hepatitis B-​associated polyarteritis and hepatitis C-​related mixed-​cryoglobulinaemia vasculitis. Modern treatment strategies are usually very effective at treating acute disease, but patients are still prone to recurrent flares and long-​term sequelae from low-​grade, grumbling disease, from relapse, or from the therapy itself. Table 272.6 is based on the current recommendations from the European League Against Rheumatism and the American Heart Association.

Further Reading Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-​Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore), 1996; 75: 17–​28. Lane SE, Watts R, and Scott DG. Epidemiology of systemic vasculitis. Curr Rheumatol Rep 2005; 7: 270–​5. Lapraik C, Watts R, Bacon P, et  al. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxford) 2007; 46: 1615–​16. Mukhtyar C, Guillevin L, Cid MC, et  al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009; 68: 318–​23. Mukhtyar C, Guillevin L, Cid MC, et  al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009; 68: 310–​17. Phillip R and Luqmani R. Mortality in systemic vasculitis: A systematic review. Clin Exp Rheumatol 2008; 26: S94–​S104.

CHAPTER 272 Vasculitis

Other relevant investigations

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273 Osteomalacia Kassim Javaid

Definition of the disease Osteomalacia is a disorder of bone mineralization and is due to a lack of vitamin D.

Aetiology of the disease Vitamin D is a prohormone formed by the action of UV radiation on the vitamin’s precursor (7-​dehydrocholesterol) in the skin. It then undergoes two hydroxylation steps to become an active hormone: the step to become 25-​hydroxyvitamin D (25-​OH vitamin D) occurs in the liver, and the second conversion takes place in the kidney to produce 1,25-​dihydroxyvitamin D (1,25-​OH vitamin D; also known as calcitriol), which is the active form. Conversion to calcitriol also occurs in most tissues for auto-​/​paracrine functions. The commonest cause of osteomalacia is vitamin D deficiency due to a lack of UVB skin exposure. This is likely in those with darker skin, a reduced cutaneous exposure to the sun due to cultural clothing or lifestyle restrictions, or an ageing-​associated reduced cutaneous capacity to metabolize vitamin D. Other causes include malabsorption (due to coeliac disease or pancreatic insufficiency), obesity, and chronic kidney disease. Rarer causes include Fanconi syndrome, distal renal tubular acidosis, drugs (e.g. phenytoin, carbamazepine, aluminium), cancer, and monogenic diseases that present in early life (e.g. X-​linked hypophosphataemic rickets, autosomal dominant hypophosphataemic rickets).

Typical symptoms of the disease, and less common symptoms The typical symptoms of osteomalacia are non-​specific bone pain, proximal myopathy (which can be severe), fatigue, and polyarthralgia. The presence of unexplained groin pain may reflect an underlying insufficiency fracture of the proximal femur. Hypocalcaemia is uncommon but may lead to fits if severe. In patients with vitamin D deficiency, serum calcium is usually maintained by a secondary rise in parathyroid hormone (PTH), which resorbs bone to release calcium. If however, there is then a sudden substantial pharmacological block to resorption with drugs, such as with IV bisphosphonates or RANKL inhibitors, subclinical vitamin D deficiency can lead to clinically severe hypocalcaemia. Oncogenic osteomalacia is due to ectopic production of fibroblast growth factor (FGF23) by benign, small, mesenchymal tumours. Patients present with profound proximal weakness with skeletal complications of vitamin D deficiency. Treatment is aimed to remove the tumour(s) with supportive with use of phosphate supplements and calcitriol. However, tumour localization can be challenging and may involve whole-​body MRI, 18F-​labelled FDG-​PET, and octreotide scintography.

Demographics of the disease Clinical osteomalacia is uncommon and usually seen in specific ethnic groups. In contrast, biochemical vitamin D deficiency (35 ml/​min per 1.73 m2, normocalcaemia, and a 25-​hydroxyvitamin D level of more than 50 nmol/​l. Zoledronic acid is highly effective in this disorder, and a single infusion appears to result in a sustained improvement in symptoms for many years. It is unusual for the markers of bone turnover (ALP or other bone turnover markers) to not suppress after treatment; if this is the case, one would want to exclude vitamin D deficiency and then repeat the infusion. For those with ongoing joint symptoms, where it is unclear if symptoms are due to Paget’s disease or secondary osteoarthritis, if pain persists following zoledronic acid infusion, it is likely that secondary osteoarthritis is established. The patient’s treatment pathway should then focus on analgesics, physiotherapy, and referral for

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CHAPTER 274  Paget’s disease of bone

consideration of arthroplasty. For those unable to take zoledronic acid, 30 mg daily of oral risedronate for 2 months is recommended. Other treatments such as calcitonin are no longer used except in exceptional circumstances. Treatment of asymptomatic Paget’s disease of bone is controversial, and some wait for symptoms to occur before initiating treatment.

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Further Reading Ralston SH. Paget’s disease of bone. N Engl J Med 2013; 368: 644–​50. Singer FR. ‘Paget’s disease of bone’, in De Groot LJ, Chrousos G, Dungan K, et al., eds, Endotext, 2000. MDText.com, Inc.

275 

Osteoporosis and fragility fracture

Kassim Javaid

Definition of the disease Osteoporosis is defined as a systemic bone disease with reduction in both bone density and microarchitectural integrity, resulting in an increase in fragility fracture risk.

Aetiology of the disease Osteoporosis is a multifactorial disease, through effects on bone formation and resorption on both the peak bone mass achieved during early adulthood and on rates of bone loss in later adulthood. Regulation of bone mass is currently thought to involve mechanosensing by osteocytes, which regulate osteoblast activity through sclerostin and DKK1 inhibition of the WNT pathway. Osteoblasts then regulate osteoclast proliferation and activity through a balance of pro-​osteoclastic RANKL and anti-​osteoclastic osteoprotegerin. There is a significant genetic component for osteoporosis, with studies identifying pathways including WNT, RANKL, osteoprotegerin, and the oestrogen receptor. Environmental factors are thought to influence fracture risk across the life course, including vitamin D deficiency during in utero life, inadequate physical exercise, and vitamin D and calcium deficiency during childhood. In later adulthood, the commonest cause is sex hormone deficiency, including deficiency due to menopause, premature menopause (menopause occurring before the age of 45), testosterone deficiency, drug-​induced gonadal deficiency (via the use of progesterone-​only contraception, aromatase inhibitors, or androgen deprivation therapy), glucocorticoid excess (iatrogenic or due to Cushing’s disease), current smoking, excess alcohol intake (greater than 3 units per day), and secondary diseases (malabsorption (e.g. coeliac disease), inflammatory diseases (e.g. inflammatory arthritides, inflammatory bowel disease, asthma), endocrine disorders (e.g. hyperparathyroidism, hyperthyroidism, diabetes)). Falls are an important risk factor for fracture and it is important to differentiate contributors such as syncope, poor balance, poor gait, postural hypotension, medication, and neurological diseases. Finally, there are rare genetic causes of osteoporosis, such as osteogenesis imperfecta and Turner’s syndrome.

Typical symptoms of the disease, and less common symptoms Osteoporosis is clinically silent until a fragility fracture occurs, as defined as due to a fall from standing height or less. The commonest sites are the distal forearm, the proximal femur, the thoracic/​lumbar vertebra, the ribs, and the proximal humerus. However, recent evidence such a fracture in an older person from any level of trauma should raise the suspicion of osteoporosis. Fractures of the digits, the face, the skull, the scaphoid, and the ankle, by some, are not usually considered osteoporotic. While fractures in the young typically heal with limited ongoing morbidity and excess mortality, osteoporotic fractures are associated with poorer healing and excess mortality (hip, spine, and pelvis). The morbidity after fracture depends on the site and includes chronic back pain for vertebral fracture, and wrist pain and weakness after distal forearm fracture. Progressive kyphosis from vertebral fracture reduces respiratory reserve.

Demographics of the disease There are 3 million patients with osteoporosis in the UK, with over 200 000 fractures per year and 80 000 hip fractures. Fractures are commoner in those over 65 years and in women. A 50-​year woman

has a 1:2 lifetime risk of future fracture, with the risk being 1:5 for men. While, with an ageing population, the absolute number of fractures is set to rise, for reasons not completely understood, the age-​ specific rate of fracture is reducing in the USA and Northern Europe while still increasing in other parts of the world.

Natural history, and complications of the disease Initially, patients present with peripheral fractures and then vertebral fractures before proximal femoral fractures. Half of patients with a proximal femoral fracture have a history of previous first fracture. Without therapy, bone mineral density (BMD) progressively declines with age. The outcomes after hip fracture are 50% fail to return home, with a significant reduction capacity to independently mobilize, and a 30% 1-​year mortality. Further, only half of patients with a distal forearm fracture report a satisfactory recovery. Vertebral fractures lead to chronic back pain but only rarely lead to neurological compromise.

Approach to diagnosing the disease The key issue is the ascertainment of primary versus secondary fracture prevention. The next stage is to determine BMD at the hip and spine using DEXA and then to exclude secondary causes and establish the most appropriate therapy according to patient-​specific factors. The identification of a fragility fracture after the age of 40 years substantially increases the risk of future fracture and guides therapy. However, identification of occult vertebral fragility fractures can be challenging and requires radiological confirmation. The presence of one of the risk factors listed in ‘Aetiology of the disease’ warrants DEXA measurement. Those over 75  years with a fracture or with two or more risk factors can start treatment without a BMD test if DEXA imaging is clinically not appropriate. It is also important to rule out secondary causes of osteoporosis as well as ensure that patients are calcium and vitamin D replete.

Other diagnoses that should be considered Osteoporosis is effectively a disease of exclusion. Important diagnoses to exclude include those diseases listed in ‘Aetiology of the disease’ as well as myeloma, malabsorption, osteomalacia, hyperthyroidism, chronic-​kidney-​disease-​associated metabolic bone disease, and Cushing’s syndrome.

‘Gold-​standard’ diagnostic test The gold-​standard diagnostic test for osteoporosis is a BMD T-​score for the lumbar spine, total hip, or femoral neck area of −2.5 or lower, as measured by DEXA. Some DEXA scanners can also measure the lateral and anterior posterior thoracolumbar X-​ray as part of instant vertebral assessment, which often detects occult vertebral fractures. Care must be taken to exclude fractured vertebra(e) from the BMD assessment and to ensure optimal positioning.

Acceptable diagnostic alternatives to the gold standard Patients over 75  years old with a fragility fracture or two or more risk factors for osteoporosis can start treatment. Peripheral DEXA and ultrasound may also be used as screening tools in experienced departments or as part of research.

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Other relevant investigations Other investigations that are relevant to osteoporosis include measurements of: serum calcium • • serum phosphate • serum alkaline phosphatase • serum 25-​hydroxyvitamin D • serum parathyroid hormone • thyroid-​stimulating hormone

Prognosis and how to estimate it The prognosis of osteoporosis can now be assessed using the online FRAX tool. This uses readily ascertained risk factors with or without BMD measurement to provide an estimate of the 10-​year risk of major fracture and hip fracture. Caveats for its use are that it does not include measurements of the lumbar spine BMD, dose of glucocorticoids, or measures of fracture number or site. There is some evidence that FRAX predicts fracture risk both off and on therapy.

Other tests include: a renal profile • • a liver profile • full blood count • erythrocyte sedimentation rate

Treatment and its effectiveness Treatment for osteoporosis is aimed at reducing future fracture risk. As there is no symptomatic benefit from therapy, and oral treatment requires complex administration regimens, it is important to ensure adequate patient information using the National Osteoporosis Society literature. The first line of treatment is to ensure patients are calcium (>800 mg/​ day) and vitamin D (25-​ h ydroxyvitamin

Optional investigations include: a coeliac screen • • a myeloma screen • the urinary calcium/​creatinine ratio

CHAPTER 275  Osteoporosis and fragility fracture

24-​hour urinary calcium excretion • • 24-​hour urinary cortisol

Table 275.1  NICE guidance for primary and secondary prevention of osteoporotic fragility fractures in postmenopausal women Age

50/​54

55/​65

65/​69

70/​74

75+

Alendronic acid

T-​score ≤ −2.5, 1 CRF*, and 1 BRF†

T-​score ≤ −2.5, 1 CRF, and 1 BRF

T-​score ≤ −2.5, and 1 CRF

T-​score ≤ −2.5, and 1 CRF/​BRF

2 CRFs/​BRFs

Risedronate

Not recommended

Not recommended

T-​score ≤ −3.5, and 1 CRF T-​score ≤ −3, and 2 CRFs

T-​score ≤ −3.5 T-​score ≤−3.0, and 1 CRF T-​score ≤−2.5, and 2 CRFs

T-​score ≤ −3.0 T-​score ≤ −2.5, and 2 CRFs

Denosumab

Not recommended

Not recommended

T-​score ≤ −4.5, and 1 CRF T-​score ≤ −4.0, and 2 CRFs

T-​score ≤ −4.5 T-​score ≤ −4.0, and 1 CRF T-​score ≤ −3.5, and 2 CRFs

T-​score ≤−4.0 T-​score ≤−3.0, and 2 CRFs

Strontium

Not recommended

Not recommended

T-​score ≤ −4.5, and 1 CRF T-​score ≤ −4.0, and 2 CRFs

T-​score ≤ −4.5 T-​score ≤ −4.0, and 1 CRF T-​score ≤−3.5, and 2 CRF

T-​score ≤ −4.0 T-​score ≤ −3.0, and 2 CRFs

Primary prevention

Secondary prevention Alendronic acid

T-​score ≤ −2.5

T-​score ≤ −2.5

T-​score ≤ −2.5

T-​score ≤ −2.5

No DEXA threshold

Risedronate

T-​score ≤ −3.0, and 1 CRF T-​score ≤ −2.5, and 2 CRFs

T-​score ≤ −3.0 T-​score ≤ −2.5, and 2 CRFs

T-​score ≤ −3.0 T-​score ≤ −2.5, and 1 CRF

T-​score ≤ −2.5

No DEXA threshold

Denosumab

Intolerant to alendronate or risedronate

Intolerant to alendronate or risedronate

Intolerant to alendronate or risedronate

Intolerant to alendronate or risedronate

Intolerant to alendronate or risedronate

Strontium or raloxifene

T-​score ≤ −3.5, and 1 CRF

T-​score ≤ −4.0 T-​score ≤ −3.5, and 1 CRF

T-​score ≤ −4.0 T-​score ≤ −3.5, and 1 CRF T-​score ≤ −3.0, and 2 CRFs

T-​score ≤ −3.0 T-​score ≤ −2.5, and 2 CRFs

T-​score ≤ −3.0 T-​score ≤ −2.5, and 1 CRF

T-​score ≤ −4.0, and ≥ 3 fractures

T-​score ≤ −4.0 T-​score ≤−3.5, and ≥ 3 fractures

T-​score ≤ −4.0 T-​score ≤−3.5, and ≥ 3 fractures

T-​score ≤ −4.0 T-​score ≤−3.5, and ≥ 3 fractures

Teriparatide

Abbreviations: BRF, bone risk factor; CRF, clinical risk factor for parental hip fracture. *Clinical risk factors for parental hip fracture: alcohol ≥4 units/​day; rheumatoid arthritis. † Bone risk factors: BMI < 22 kg/​m2; diseases like Crohn’s disease or ankylosing spondylitis; prolonged immobility; untreated premature menopause. Data from NICE: Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (2008) http://​www.nice.org.uk/​guidance/​ta160. NICE: Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (2008) http://​www.nice.org.uk/​guidance/​ta161. NICE: Denosumab for the prevention of osteoporotic fractures in postmenopausal women (2010). http://​www.nice.org.uk/​guidance/​ta204.

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6 weeks, despite antibiotic therapy, usually after an invasive dental procedure. However, cases are usually cancer patients receiving 3–​12-​times-​higher doses of bone agents than are used in osteoporosis therapy. Currently, the risk of ONJ is considered rare in osteoporosis therapy. Teriparatide is a humanized 1-​34 parathyroid hormone analogue. It is the only pure anabolic agent available and is given as a daily subcutaneous injection, for 18 months. It is usually reserved for those with severe osteoporosis, as evidenced by a T-​score less than −3.5, the presence of more than two fractures, and intolerance/​fracture on treatment with oral agents. The higher cost of teriparatide is offset by its observed greater fracture reduction, especially at the spine. The duration of therapy with bone-​specific therapies is only clear for teriparatide, for which 24  months is the licensed duration. In the absence of evidence, currently, the recommendation is 5 years’ treatment and then a drug holiday for 2 years before considering another cycle of therapy. In those with a vertebral fracture, 10-​year cycles are appropriate. For those who refracture while on treatment, a switch in therapy, usually to a parenteral therapy, should be considered. Atypical subtrochanteric fractures are a growing concern in the field of osteoporosis. They are typically preceded by atypical thigh pain and lead to a spontaneous or minimal-​trauma horizontal femoral fracture with a characteristic breaking on one side and relatively thickened femoral shaft cortices. They appear to be associated with prolonged use of bisphosphonates. Key principles in their management are effective orthopaedic intervention, given that the bone is likely to be brittle; early imaging of the contralateral side with radiographs; MRI of the whole femur, to exclude a contralateral fracture; and cessation of bisphosphonate therapy. If the patient remains at risk of fracture at other sites, strontium ranelate or teriparatide therapy should be considered. The role of denosumab in this patient group is not known. The estimated rate of subtrochanteric fracture is 5 per 10 000 patient years of treatment, and the risk rapidly diminishes with cessation of bisphosphonate therapy. Vertebroplasty and kyphoplasty are used to manage painful vertebral fractures but currently undergoing NICE reappraisal, as two sham-​controlled trials have not replicated the benefits of usual care-​ controlled trials.

Further Reading Lewiecki EM. ‘Osteoporosis:  Clinical evaluation’, in De Groot LJ, Chrousos G, Dungan K, et al., eds, Endotext, 2000. MDText.com, Inc. National Institute for Health and Clinical Excellence. Osteoporosis: Assessing the risk of fragility fracture. 2012. Available at http://​ www.nice.org.uk/​guidance/​cg146 (accessed 8 Sep 2017). Seibel MJ, Cooper MS, and Zhou H. Glucocorticoid-​induced osteoporosis: Mechanisms, management, and future perspectives. Lancet Diabetes Endocrinol 2013; 1: 59–​70.

CHAPTER 275  Osteoporosis and fragility fracture

D >50 nmol/​l) replete. Diet is a good source of calcium, with 600 mg in a pint of milk, and 200 mg in a small pot of yoghurt or a small matchbox of cheese. The ideal intake is 800–​1200 mg/​day. Vitamin D is difficult to find in the diet and often requires use of supplements. Next requires selection of the optimal bone therapy and the National Institute for Health and Clinical Excellence (NICE) have produced intervention thresholds based on primary versus secondary prevention, BMD, clinical risk factors, and patient tolerability (see Table 275.1). Most of the agents show fracture reductions in the range of 30% for non-​vertebral fracture, and 50%–​70% for vertebral fracture. The first-​line agent is 70 mg oral alendronate weekly. This is an amino bisphosphonate that inhibits farnesyl transferase and osteoclast function. As it has a very poor bioavailability (0.7%), there are four keys aspects for administration: (1) to take it first thing in the morning after an overnight fast with a large glass of tap water; (2) not to take any other drink, food, or medication for the next 30 minutes; (3) to remain upright (standing, sitting, and/​or walking) for the next 30 minutes; and (4) to take any calcium supplements in the afternoon on the day that the oral bisphosphonate is taken. Alendronic acid is contraindicated in those with significant upper gastrointestinal pathology, hypocalcaemia, an estimated glomerular filtration rate (eGFR) of less than 30 ml/​min, and pregnancy. Dyspepsia is common and should be managed by switching to another agent rather than adding an proton-​pump inhibitor (PPI), as there is evidence that PPI use blunts the fracture reduction benefit. Alternative oral therapies include risedronate (35 mg weekly with similar administration and contraindications) and strontium ranelate. Strontium ranelate 2 g is taken in the middle of a 4-​hour calcium-​and magnesium-​free dietary fast. Typically, it is given at bedtime after a 2-​hour fast. It is an insoluble powder that patients suspend in water and then take. Common unwanted effects are loose stool to diarrhoea. Rarely, a DRESS syndrome (drug rash with eosinophilia and systemic symptoms) can occur, and patients should be advised to stop and consult their doctor if they develop a rash on treatment. Given the poor adherence to oral therapies, three groups of parenteral therapy are available. Denosumab is a monoclonal antibody that binds RANKL and inhibits osteoclast proliferation and function. It is given every 6 months as a subcutaneous injection and has efficacy with an eGFR of greater than 15 ml/​min. Unwanted effects are uncommon and we await Phase 4 analyses for more information. Zoledronic acid is an IV bisphosphonate given as a short infusion every year for 3–​6  years. It is slightly renally toxic and so is contraindicated in patients with an eGFR of less than 35 ml/​min. It commonly causes flu-​like symptoms for up to 7 days but, in some cases, it leads to an acute inflammatory response in specific organs, causing iritis or colitis. Both denosumab and zoledronic acid as well as oral bisphosphonates have been associated with osteonecrosis of the jaw (ONJ). This is an exposure of the mandible for more than

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276 

Genetic bone and joint disease

Susan Price

Introduction Genetic conditions affecting the skeleton and supporting structures are individually rare and heterogeneous. This chapter suggests approaches to assessing patients for suspected skeletal dysplasia, osteogenesis imperfecta, Marfan syndrome, and Ehlers–​ Danlos syndrome.

Skeletal dysplasia Aetiology of skeletal dysplasia Skeletal dysplasias are caused by abnormalities of bone growth and modelling. Many are linked to mutations in genes for particular collagens or for growth factors and their receptors.

Typical symptoms of skeletal dysplasia, and less common symptoms Skeletal dysplasias predominantly cause short stature and deformity. However, the affected sites are linked to different complications. Conditions affecting the epiphyses (the area of secondary ossification at the ends of long bones) affect articulation and predispose to early arthritis, requiring joint replacement. The metaphysis is adjacent to the epiphysis and is the main growth region. Conditions affecting metaphyses (including achondroplasia) shorten long bones, compromising eventual height. The diaphysis is the central shaft and is affected by conditions, like osteogenesis imperfecta, that alter the early collagen bone model. The term ‘spondylo’ is used where the spine is affected. The spine may be short, with kyphosis or scoliosis. The skeletal dysplasias can be classified clinically, radiologically, or by the causative genetic mutation. One such classification, which is regularly revised, is from the International Skeletal Dysplasia Society and is referred to as the International Nomenclature and Classification of the Osteochondrodysplasias.

Demographics of skeletal dysplasia Each specific type of skeletal dysplasia is individually rare. The commonest non-​lethal type is achondroplasia, with an incidence of 1/​10 000 to 1/​30  000.

Natural history of skeletal dysplasia, and complications of the disease In achondroplasia, disordered endochondral bone formation can result in compression of the cervical cord and medulla at the foramen magnum, spinal stenosis, atlantoaxial subluxation, and macrocrania, with or without hydrocephalus.

Approach to diagnosing skeletal dysplasia When diagnosing skeletal dysplasia, take a three-​generation history with details of adult height, joint replacement, and specific questions about consanguinity. Document whether growth was normal in pregnancy and try to obtain early growth records. Ask about fractures and developmental delay. Assess whether the growth problem is proportionate or disproportionate. Measure span, height, and lower segment length. If the growth problem is disproportionate, is the shortening proximal (rhizomelic) or distal (mesomelic)? Is there any bowing of the bones or contractures? There are many other features that can be linked to specific dysplasias, particularly polydactyly or abnormal thumbs; cleft

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palate; abnormal teeth and hair; cataract or myopia; and congenital heart disease. Many patients with skeletal dysplasia will have lax joints.

Other diagnoses that should be considered aside from skeletal dysplasia When considering a diagnosis of skeletal dysplasia, exclude other causes of short stature (e.g. chromosomal or syndromic causes). These will often have proportionate short stature. Storage disorders and a wide range of other metabolic and hormonal conditions can affect growth.

‘Gold-​standard’ diagnostic test for skeletal dysplasia A definitive diagnosis of skeletal dysplasia is generally made after specialist review of a skeletal survey; this is often most helpful in childhood. Mutation analysis may then be possible. A skeletal survey should include the following X-​rays: skull AP and lateral • • chest PA • spine AP and lateral • pelvis with hips • unilateral humerus, radius, ulna, femur, tibia, and fibula • hand carpal bones and phalanges

Acceptable diagnostic alternatives to the gold-​standard test for skeletal dysplasia When skeletal dysplasia is suspected, an acceptable diagnostic alternative to a skeletal survey is a descriptive diagnosis based on family history and examination findings, with patients classified according to the following clinical diagnostic groups: • those with short limbs but in whom the trunk less affected: hypochondroplasia, achondroplasia, and pseudoachondroplasia • those with short limbs and trunk: diastrophic dysplasia • those with epiphyseal dysplasias: multiple epiphyseal dysplasia • those with a short trunk but in whom the limbs are less affected; spondyloepiphyseal and spondylometaphyseal disorders • metaphyseal disorders: metabolic disease • abnormal bone density: osteogenesis imperfecta

Other relevant investigations for skeletal dysplasia Other relevant investigations for skeletal dysplasia include: a metabolic screen, if a metaphyseal disorder is suspected • • MRI of the brain with the cervical and lower spine, if there are neurological signs or there is evolving hydrocephalus • molecular analysis (e.g. FGFR3 in achondroplasia and hypochondroplasia) • cytogenetic screen for X-​chromosome deletions

Prognosis of skeletal dysplasia, and how to estimate it In skeletal dysplasia, severe conditions can present in utero, and many are lethal because of reduced lung capacity or evolving hydrops. Prognosis in terms of eventual height and complications is condition specific.

Treatment of skeletal dysplasia, and its effectiveness As treatment for skeletal dysplasia, surgical management of deformities to improve function and, occasionally, operations to lengthen

limbs may be suggested. Growth hormone treatment is of no benefit to the majority of children. Exercise can be helpful, to maintain range of movement and build strength. A referral for mobility aid assessment can be considered.

under 10  years old. About 10% of cases will have asymptomatic mitral valve prolapse, and 24% of affected males (but only 4% of affected females) have non-​progressive aortic dilatation.

Osteogenesis imperfecta

When diagnosing osteogenesis imperfecta, take a three-​generation family history of fracturing, deformity, and the associated features. It is generally possible to diagnose the type on history and examination findings alone.

Most patients with osteogenesis imperfecta have mutations in COL1A1 or COL1A2. Abnormal collagen production gives a more open meshwork to the early bone model, and this eventually leads to reduced mineralization. There are four main types of osteogenesis imperfecta (see ‘Natural history of osteogenesis imperfecta, and complications of the disease’); osteogenesis imperfecta types I and IV are dominantly inherited, type II is generally caused by a de novo dominant mutation, and type III is mostly dominant, although some recessive families have been described.

Typical symptoms of osteogenesis imperfecta, and less common symptoms The typical presentation of osteogenesis imperfecta is with multiple fractures, sometimes prenatally. There may be associated short stature, bone deformity, dentogenesis imperfecta, blue sclera, and hearing loss. This is a collagen disease, and patients can have the soft skin, lax joints, scoliosis, and mitral valve prolapse seen in other conditions affecting collagen. Spinal deformity can cause neurological and respiratory compromise.

Demographics of osteogenesis imperfecta The most common form of osteogenesis imperfecta, osteogenesis imperfecta type 1, has a frequency of 2–​5/​100 000.

Natural history of osteogenesis imperfecta, and complications of the disease

Other diagnoses that should be considered aside from osteogenesis imperfecta Recurrent childhood fractures require sensitive questioning, given the possible confusion with non-​accidental injury. Juvenile and premature osteoporosis can lead to fractures, as can hypophosphatasia. Bruck syndrome is a recessive condition linking blue sclera, Wormian bones, and congenital contractures of large joints.

‘Gold-​standard’ diagnostic test for osteogenesis imperfecta The following are gold-​standard diagnostic tests for osteogenesis imperfecta: • skin biopsy for examination of fibroblast collagens via electron microscopy • COL1A1, COL1A2 and rarer gene mutation testing

Acceptable diagnostic alternatives to the gold-​standard for osteogenesis imperfecta Wormian bones on a skull X-​ray are often seen in osteogenesis imperfecta type I  but bone density generally can be variable and often normal. For more severe forms of osteogenesis imperfecta, a full skeletal survey will be helpful. Offer hearing tests throughout life, and an initial biochemistry screen to exclude metabolic bone disease.

The natural history of osteogenesis imperfecta is linked to the severity of the condition, but also the degree of osteoporosis in later life. The clinical classification of osteogenesis imperfecta (called the Sillence classification) is useful in predicting severity and outcome. The main types are:

Other relevant investigations for osteogenesis imperfecta

• type I: • mild • non-​deforming • mild short stature • blue sclera • normal teeth • type II: • perinatally lethal due to respiratory compromise • multiple rib and long-​ bone fractures present at birth, with deformity and dark sclera • low bone density • separated into types IIA, IIB, and IIC, depending on the radiographic appearance • type III: • severe • deforming • very short stature • scoliosis • multiple fractures • patient must often use a wheelchair • grey sclera • dentogenesis imperfecta • triangular facies • type IV: • moderately deforming • moderate short stature • patient may have scoliosis • grey/​white sclera • dentogenesis imperfecta

Prognosis of osteogenesis imperfecta, and how to estimate it

Hearing loss is common, being found in ~50% of cases by 30 years of age, and 95% of cases in later life, but is not usually seen in those

Marfan syndrome is a connective tissue disease with a pattern of symptoms related to the presence of fibrillin in tissues. Typically

Another investigation that is relevant in osteogenesis imperfecta is echocardiography, to assess for valve involvement.

The prognosis of osteogenesis imperfecta will be related to the severity of the bone disease, but also the site of fractures (e.g. if they affect the joints). Often, children with osteogenesis imperfecta fracture recurrently until puberty, when the condition improves. Multiple fractures in childhood may predict later osteoporosis, and bone density scanning in adult life is indicated.

CHAPTER 276  Genetic bone and joint disease

Aetiology of osteogenesis imperfecta

Approach to diagnosing osteogenesis imperfecta

Treatment of osteogenesis imperfecta, and its effectiveness Treatment of osteogenesis imperfecta requires prompt, specialist, orthopaedic management of fractures, with full physiotherapy and rehabilitation support. The use of bisphosphonates is under assessment; these drugs can reduce osteoclast bone reabsorption. However, they are used in specialist centres only, and for severer types of the disease.

Marfan syndrome Aetiology of Marfan syndrome Between 66% and 91% of individuals with Marfan syndrome have a mutation in fibrillin 1 (FBN1; locus: 15q21). Some families have mutations in TGFBR1 or TGFBR2. Marfan syndrome is a dominantly inherited condition, but up to a third of cases are caused by a spontaneous mutation.

Typical symptoms of Marfan syndrome, and less common symptoms

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affected individuals are of tall, thin stature, with long fingers and toes (arachnodactyly), a pectus deformity, and scoliosis. They may have a high palate with dental crowding; lax joints; excessive striae; and a history of recurrent herniae or pneumothoraces.

Demographics of Marfan syndrome

An acceptable diagnostic alternative to fibrillin 1 mutation testing is an assessment of family history and the application of Ghent criteria.

The estimated prevalence of Marfan syndrome is 1/​3000 to 1/​5000.

Other relevant investigations for Marfan syndrome

Natural history of Marfan syndrome, and complications of the disease

Relevant investigations for Marfan syndrome include monitoring the ratio of the aortic diameter to the body surface area, as this can be used to assess the progression of aortic dilatation over time. In addition, an X-​ray of the hip or spinal MRI may be relevant if these features would alter assessment using the Ghent criteria.

In Marfan syndrome, joint hypermobility can give chronic pain and early arthritis. There may be bilateral ectopia lentis (in ~50% of cases), myopia (in 30% of cases), and, rarely, retinal detachment. However, the most serious complication is aortic dilatation, and an annual echocardiogram is requested for affected individuals. Particular care is needed in pregnancy.

Approach to diagnosing Marfan syndrome

CHAPTER 276  Genetic bone and joint disease

Acceptable diagnostic alternatives to the gold-​standard test for Marfan syndrome

When diagnosing Marfan syndrome, take a three-​generation family history detailing symptoms of Marfan syndrome. Measure height, weight, arm span, and lower segment length. A standard examination scoring system for assessing individuals with suspected Marfan syndrome is used. This is referred to as the Ghent criteria and has been shown to detect about 86% of individuals carrying a fibrillin 1 mutation (see Table 276.1); however, this system is less reliable in children. The system scores common features in the skeleton, eyes, heart, lungs, and skin, and notes the presence or absence of dural ectasia or a family history. There are major and minor criteria; in the absence of a family history, two of the major criteria and one of the minor criteria must be present to confirm a clinical diagnosis. An echocardiogram (to measure the aortic root diameter at the level of the sinuses of Valsalva and screen for mitral prolapse) and eye examination (to look for refractive error and lens instability) will be requested. Mutation detection can be undertaken where resources allow, and can be useful for defining screening in large families.

Other diagnoses that should be considered aside from Marfan syndrome Other diagnoses that should be considered aside from Marfan syndrome are summarized in Table 276.1. If there is learning difficulty, homocystinuria should be excluded. Mild Ehlers–​Danlos syndrome can give similar joint hypermobility.

‘Gold-​standard’ diagnostic test for Marfan syndrome The gold-​standard diagnostic test for Marfan syndrome is fibrillin 1 mutation testing.

Prognosis of Marfan syndrome, and how to estimate it Untreated, unscreened people with Marfan syndrome have a 40% reduced life expectance from aortic complications, predominantly dissection. Plotting the aortic root diameter over time helps to plan if aortic replacement is indicated.

Treatment of Marfan syndrome, and its effectiveness The major complication of Marfan syndrome is aortic root dilatation, which predisposes to aortic dissection. Regular surveillance of the aortic root by echocardiography, the use of beta blockers and angiotensin-​receptor blockers to retard dilatation, and aortic root repair when the diameter reaches 5.0 cm improve the prognosis. Contact sports and sports causing high cardiovascular stress should be avoided. Regular ophthalmic review is suggested until adolescence.

Ehlers–​Danlos syndrome Aetiology of the disease Classical Ehlers–​ Danlos syndrome (types I  and II) is caused by dominant mutations in COL5A1 and COL5A2. Hypermobility (Ehlers–​Danlos syndrome type III) is dominantly inherited and molecularly undefined. Vascular Ehlers–​Danlos syndrome (type IV) can be dominantly or recessively inherited with mutations in COL3A1. Kyphoscoliosis (Ehlers–​Danlos syndrome type VI) is a recessive condition caused by mutations in PLOD1. Arthrochalasia (Ehlers–​Danlos syndrome types VIIA and B) is linked to dominant exonic deletions in COL1A1 and COL1A2. Dermatosporaxis (Ehlers–​Danlos syndrome type VIIC) is caused by recessive mutations in a collagen N-​peptidase (ADAMTS2).

Table 276.1  Differential diagnosis of Marfan syndrome Differential diagnosis

Gene

Discriminating features

Loeys–​Dietz syndrome (LDS)

TGFBR1/​2

Bifid uvula/​cleft palate, arterial tortuosity, hypertelorism, diffuse aortic and arterial aneurysms, craniosynostosis, clubfoot, cervical spine instability, thin and velvety skin, easy bruising

Shprintzen–​Goldberg syndrome (SGS)

FBN1 and other

Craniosynostosis, mental retardation

Congenital contractural arachnodactyly (CCA)

FBN2

Crumpled ears, contractures

Weill–​Marchesani syndrome (WMS)

FBN1 and ADAMTS10

Microspherophakia, brachydactyly, joint stiffness

Ectopia lentis syndrome (ELS)

FBN1 LTBP2 ADAMTSL4

Lack of aortic root dilatation

Homocystinuria

CBS

Thrombosis, mental retardation

Familial thoracic aortic aneurysm syndrome (FTAA)

TGFBR1/​2, ACTA2

Lack of Marfanoid skeletal features, levido reticularis, iris flocculi

FTAA with bicuspid aortic valve (BAV) FTAA with patent ductus arteriosus (PDA)

MYH11

Arterial tortuosity syndrome (ATS)

SLC2A10

Generalised arterial tortuosity, arterial stenosis, facial dysmorphism

Ehlers–​Danlos syndromes (vascular, valvular, kyphoscoliotic type)

COL3A1, COL1A2, PLOD1

Middle sized artery aneurysm, severe valvular insufficiency, translucent skin, dystrophic scars, facial characteristics

Reproduced from Journal of Medical Genetics, Loeys et al., The revised Ghent nosology for the Marfan syndrome, volume 47, issue 7, pp. 476–​485, copyright © 2010 with permission from BMJ Publishing Group Ltd.

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Typical symptoms of Ehlers–​Danlos syndrome, and less common symptoms

Other diagnoses that should be considered aside from Ehlers–​Danlos syndrome

All forms of Ehlers–​Danlos syndrome present with variable thinning and fragility of skin, leading to easy bruising and poor scar formation. There is skin and joint laxity. In severe forms, blood vessels and internal organs are affected.

Other diagnoses that should be considered aside from Ehlers–​Danlos syndrome include cutis laxa and Marfan syndrome, which share some features, and benign hypermobility, which is common.

The incidence of Ehlers–​Danlos syndrome (as a group) is about 1 in 5000.

Natural history of Ehlers–​Danlos syndrome, and complications of the disease In Ehlers–​ Danlos syndrome, the degree of hypermobility can decrease with age and move to more stiffness related to arthritis. Vascular Ehlers–​Danlos syndrome causes increasing complications with age.

Approach to diagnosing Ehlers–​Danlos syndrome When diagnosing Ehlers–​Danlos syndrome, take a three-​generation family history of joint dislocation/​early arthritis and abnormal scarring. Examine all joints for range of mobility to give a Beighton score, which is calculated as follows: • passive extension of little finger beyond 90°:  score 1 for each hand • passive opposition of thumb to the flexor surface of forearm: score 1 for each hand • hyperextension of elbow beyond 10°: score 1 for each elbow • hyperextension of knee beyond 10°: score 1 for each knee • flex the spine; if the patient’s hands are flat on the floor, score 1 Therefore, the total Beighton score could be at most 9. Assess the skin for softness, elasticity, and atrophy. The Villefranche classification is used to describe the various patterns of Ehlers–​Danlos syndrome. A  shortened summary of main types is as follows: • classical Ehlers–​Danlos syndrome (types I and II): • soft hyperextensible skin • lax joints • easy bruising • thin scars • varicose veins • risk of prematurity in affected fetuses • hypermobility (Ehlers–​Danlos syndrome type III): • merges into the general population • use if Beighton score >5/​9 • vascular (Ehlers–​Danlos syndrome type IV): • more serious condition • patients tend to look aged, with deep-​set eyes and thin skin • little joint laxity, but high risk for rupture of blood vessels, bladder, bowel, or uterus • kyphoscoliosis (Ehlers–​Danlos syndrome type VI): • soft skin • joint hypermobility • muscle hypotonia • scoliosis • rupture of the optic globe • arthrochalasia (Ehlers–​Danlos syndrome types VIIA and B): • normal scars • severe joint problems, including hip dislocation • dermatosporaxis (Ehlers–​Danlos syndrome type VIIC): • affects the skin which is sagging, redundant, and fragile

‘Gold-​standard’ diagnostic test for Ehlers–​Danlos syndrome The gold-​standard diagnostic tests for Ehlers–​Danlos syndrome are a skin biopsy, to provide a fibroblast culture for electron microscope analysis of collagen fibres, and targeted collagen mutation testing, particularly when Ehlers–​ Danlos syndrome vascular type is being considered.

Acceptable diagnostic alternatives to the gold-​standard tests for Ehlers–​Danlos syndrome An acceptable diagnostic alternative to the gold-​standard tests for Ehlers–​Danlos syndrome is clinical classification.

Other relevant investigations for Ehlers–​Danlos syndrome Other relevant investigations for Ehlers–​Danlos syndrome are an echocardiogram, to look for aortic diameter and mitral valve prolapse in classical, hypermobile, and kyphoscoliotic Ehlers–​ Danlos syndrome, and MRI of major vessels in vascular Ehlers–​Danlos syndrome, although it is still unclear if aneurysm repair is indicated, given the extreme tissue fragility.

Prognosis of Ehlers–​Danlos syndrome, and how to estimate it The majority of individuals with Ehlers–​Danlos syndrome are primarily affected by morbidity from skin and joint problems. Only the vascular type is associated with high mortality. About 25% of affected individuals will have serious complications by 20  years of age, and 50% by 40  years of age. The median life expectancy is around 48  years, with most dying of arterial rupture. Pregnancies are very high risk.

Treatment of Ehlers–​Danlos syndrome, and its effectiveness The management of Ehlers–​Danlos syndrome is largely supportive, with surgical treatment of dislocation and careful management of wounds. Celiprolol has been shown (in one randomized controlled trial) to reduce the risk of complications in vascular Ehlers–​Danlos syndrome.

CHAPTER 276  Genetic bone and joint disease

Demographics of Ehlers–​Danlos syndrome

Further Reading Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010; 47: 476–​85. Malfait F. The 2017 International Classification of Ehlers danlos Syndromes. Am J Med Genet C Semin Genet. 2017; Mar: 175(1) 8–​26. Murphy-​Ryan M, Psychogios A, and Lindor NM. Hereditary disorders of connective tissue: A guide to the emerging differential diagnosis. Genet Med 2010: 12: 344–​54. Radke RM and Baumgartner H. Diagnosis and treatment of Marfan syndrome: An update. Heart 2014; 100: 1382–​91. The Brittle Bone Society (http://​www.brittlebone.org) The Restricted Growth Association (www.restrictedgrowth.co.uk)

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PART 13 Haematological disorders

277 

Normal blood function

Chris Bunch

Introduction

Table 277.2  Common abnormalities of red-​cell morphology

Haematology concerns blood, its formation, function, and disorders. It holds a special position in clinical medicine, as many diseases affect the blood at some stage of their course, and disorders of the blood itself often have effects on one or more of the other organ systems. The accessibility of blood and its cells has allowed the pathophysiology of many haematological disorders to be unravelled in detail, before that of many other diseases, at both the cellular and the molecular level. Indeed, many of the analytical techniques now widely used in molecular biology and genetics were developed for, and first applied to, the study of the blood.

Abnormality

Meaning

Associations

Anisocytosis

Variation in cell size (usually red cells)

Iron deficiency Thalassaemia

Poikilocytosis

Variation in cell shape (usually red cells)

Often associated with Anisocytosis Myelosclerosis

Hypochromia

Pale red cells

Reduced haemoglobin content Iron deficiency Thalassaemia

Microcytosis

Small red cells

Reduced haemoglobin content Iron deficiency Thalassaemia

The composition and function of blood Blood consists of cells of three main types, suspended in a nutrient fluid called plasma. The cellular component comprises about 40%–​50 % of the total volume, and consists of red cells (erythrocytes), white cells (leucocytes), and platelets (see Table 277.1).

Macrocytosis

Large red cells

Various

Spherocytes

Red cells and haemoglobin

Spherical rather than biconcave red cells

Membrane defect leading to loss of surface area

Schistocytes

Fragmented red cells

Microangiopathy Disseminated intravascular coagulation

The red cell is a biconcave disc about 7 μM in diameter. It lacks a nucleus and contains a concentrated solution of haemoglobin —​ an iron-​containing protein responsible for oxygen transport from the lungs to the tissues—​together with a few enzymes necessary to maintain the function and integrity of the haemoglobin and the cell membrane. The biconcave shape maximizes the cell’s surface area in relation to volume—​important for gas exchange—​and contributes to the cell’s flexibility and deformability, allowing it to pass easily through narrow capillaries. In a normal stained blood film, the red cells appear reasonably similar in size, shape, and colour. Abnormal appearances are seen in a variety of conditions (see Table 277.2).

Table 277.1  Indicative reference ranges for haematological values in normal adults

Reticulocytes are young red cells (less than 2–​3 or less days old) recently released from the marrow. They contain residual traces of globin mRNA, which gives the cells a bluish tinge (polychromasia) that contrasts with the normal red colour in a stained blood film. The reticular RNA strands can be demonstrated directly with suitable stains, facilitating estimation of the reticulocyte percentage.

Structure of haemoglobin The haemoglobins are a family of molecules with a basically similar structure consisting of two pairs of globin chains, each associated with a haem moiety. Normal adult haemoglobin (Hb A) is formed from two alpha (α) and two beta (β) globin chains (α2β2). Interaction between the amino acid side chains leads to complex folding of the globin molecule to give a quaternary structure, with the haem molecules tucked inside the folds of the chains (see Figure 277.1).

Parameter (unit) Haemoglobin (g/​dl)

Men: 14–​18 Women: 12–​16

Haematocrit (packed cell volume)

Men: 0.40–​0.52 Women: 10.35–​0.47

Red-​cell count (× 1012/​l)

Men: 4.5–​6.0 Women: 13.8–​5.2

Mean red-​cell volume (fl)

80–​100

Mean red-​cell haemoglobin (pg)

27–​33

Mean cell haemoglobin concentration (g/​dl)

31.5–​36.5

White cells (leucocytes) (× 109/​l) • neutrophils • lymphocytes • monocytes • eosinophils • basophils

4.00–​10.00 2.00–​7.00 (40%–​80%) 1.00–​3.00 (20%–​40%) 0.20–​1.00 (2%–​10%) 0.04–​0.40 (1%–​6%) 0.00–​0.10 (0%–​2%)

Platelets (× 109/​l)

150–​450

Note: These values are typical, but may vary between laboratories; results marginally outside these ranges are not necessarily abnormal, and should be evaluated in the clinical context.

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Hemoglobin Molecule heme group

iron

β chain

α chain

red blood cell β chain

α chain helical shape of the polypeptide molecule

Figure 277.1  A haemoglobin molecule, showing the position of one of the haem molecules in a cleft formed by the globin chain. http://​www.mhhe.com/​biosci/​genbio/​maderinquiry/​234329.html.

4.5 vol. % Oxygen content (vol. %)

15

P50 = 26.5

10

3.3 vol.% P50 = 34.0

5

Venous 0

0

20

40 60 PO2 (mmHg)

Arterial 80

100

Figure 277.2  Oxygen dissociation curves for a normal patient (black line) and an anaemic patient (blue line), showing enhancement of oxygen loading by decreased red-​cell oxygen affinity in the latter: the anaemic patient, with a 50% reduction in haemoglobin concentration, has only a 27% reduction in oxygen unloading, compared to a normal patient; P50, partial pressure of oxygen in the blood at which the haemoglobin is 50% saturated; PO2, partial pressure of oxygen in the blood. Reproduced with permission from Weatherall &Hatton, Anaemia: pathophysiology, classification, and clinical features, in Oxford Textbook of Medicine, Fifth Edition Oxford University Press, Oxford, UK, Copyright © 2010. Reprinted from Chest, volume 62, issue 5, Robert A. Klocke, Oxygen Transport and 2, 3-​Diphosphoglycerate (DPG), pp. 79S-​85S, Copyright (1972), with permission from Elsevier.

Haem consists of a porphyrin ring, with an iron atom at its centre. It has a certain affinity for oxygen, which is sensitive to the surrounding pH and CO2 concentration: as blood passes through the lungs, the pH is relatively high and the CO2 concentration is relatively low, so oxygen readily binds to haem. In the tissues, the reverse is true: oxygen dissociates from haem and becomes available to the surrounding milieu. This can be illustrated by an oxygen-​ dissociation curve, which has a characteristic sigmoid shape (see Figure 277.2). The affinity of haem for oxygen, and the position of the dissociation curve, are also profoundly affected by intracellular levels of 2,3-​bisphosphoglycerate (2,3-​BPG, previously known as 2,3-​diphosphoglycerate or 2,3-​DPG).

Adaptation to anaemia The amount of oxygen extracted from the blood by the tissues depends primarily on:

progressively as the level falls further, and may reach four to five times the normal output • increased blood flow: this is partly due to a rise in cardiac output, but is facilitated by the reduced blood viscosity and a decrease in peripheral vascular resistance; there is a redistribution of blood flow in favour of tissues such as the brain and the myocardium, for which oxygen delivery is especially critical • reduced red-​cell oxygen affinity: this is reflected in a right shift in the haemoglobin oxygen dissociation curve and is mainly due to an increase in the levels of red-​cell 2,3-​BPG, which interacts with the haemoglobin molecule to reduce its affinity for oxygen, allowing greater oxygen release at similar oxygen tensions

Developmental changes in haemoglobin production Other normal human haemoglobins consist of α or the α-​like ζ chain, combined with one of the β-​like chains, ε or γ. The first haemoglobins to appear in the embryo are haemoglobin Gower 1 (ζ2ε2), haemoglobin Portland (ζ2γ2), and haemoglobin Gower 2 (α2ε2). These are replaced in the fetus by fetal haemoglobin (Hb F; α2γ2). Shortly before birth. production switches to HbA, which largely replaces Hb F by the end of the first year of life. In postnatal life, a minor adult haemoglobin, HbA2 (α2δ2), accounts for less than 2.5 % of total haemoglobin. The switch from fetal to adult haemoglobin is affected by some of the molecular lesions responsible for the thalassaemias, and may lead to continued or increased production of HbF, with some amelioration of the expression of the disease.

Genetic control of haemoglobin synthesis The genes for the α chains are found on chromosome 16, together with the embryonic ζ chain gene. The α gene is duplicated on each haploid chromosome, making four in all. The non-​α genes are clustered on Chromosome 11, closely linked and in order of developmental expression: 3′-​ε-​γG-​γA-​δ-​β-​5′. These genes are sequentially activated and then repressed during fetal development to ensure the appropriate developmental changes in haemoglobin production. In addition, α-​chain synthesis and non-​α-​chain synthesis are synchronized, with haem being incorporated into each chain by a separate pathway before they are combined to form the complete haemoglobin molecule. The genetic control of haemoglobin production has several important consequences. First, abnormalities affecting individual globin genes may be inherited from one or both parents (heterozygosity and homozygosity, respectively). Second, different abnormalities can be inherited from each parent (double heterozygosity). Third, abnormalities affecting the β chain will not become apparent until after the first 3–​6  months of life, when β-​chain synthesis supersedes γ-​chain production. On the other hand, disorders affecting α-​chain production may become apparent during fetal life, although duplication of the α-​chain gene affords protection from limited abnormalities.

White cells (leucocytes)

the circulating haemoglobin level • • blood flow • the difference in oxygen tension between the red cell and the tissues • the affinity of the haemoglobin for oxygen

The white cells are a group of cells whose principal collective function is defence against infection. This role is principally played out in the tissues, and the white cells’ presence in the blood is largely transitory. There are three main groups of white cells:

Under resting conditions, the tissues require about 250 ml of oxygen per minute. Normal blood carries 20 ml of oxygen per 100 ml (1.34 ml of oxygen per gram of haemoglobin). Thus, at a resting cardiac output of 5 l per minute, about 1 l of oxygen per minute would be available to the tissues. As blood flows through the capillaries, the lower oxygen tension in the tissues promotes the release of oxygen from haemoglobin. Extraction of 250 ml of oxygen is associated with a reduction in the red-​cell oxygen tension from 100 mm Hg (13.5 kPa) at the arterial end of the capillary to 40 mm Hg (5.5 kPa) at the venous end. In anaemia, the extraction of the same amount of oxygen from a reduced amount of haemoglobin would involve a greater degree of oxygen desaturation and would eventually lead to tissue hypoxia if a number of compensatory mechanisms did not come into play. These include:

• polymorphonuclear cells (polymorphs) or granulocytes, which have multilobed, condensed nuclei and contain prominent cytoplasmic granules; they are classified according to the staining characteristics of the main granule type as neutrophils, eosinophils, or basophils • lymphocytes, which are the cells of the immune system • monocytes, which are the precursors of tissue macrophages.

• increased cardiac output: this becomes evident once the haemoglobin level has fallen to around 7–​8 g/​dl. The output then rises

CHAPTER 277  Normal blood function

20

Neutrophils are the predominant granulocytes and are phagocytic cells primarily concerned with defence against bacterial invasion. They spend just a few hours in the bloodstream before migrating into the tissues, where they become attracted to sites of infection and inflammation, by a process of chemotaxis along a gradient of soluble mediators released by other inflammatory cells at the affected site. A reduction in the concentration of neutrophils in the blood is termed neutropenia; an increase is a neutrophil leucocytosis,

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Box 277.1  Quantitative alterations in circulating neutrophil and eosinophils

Increased neutrophils: Neutrophilia infection • • inflammation • stress/​exercise • corticosteroids • malignancy • tissue damage/​infarction

Decreased neutrophils: Neutropenia marrow failure • • severe infection • endotoxin • hypersplenism • immune destruction

Increased eosinophils: Eosinophilia

parasitic infestations • • allergies: asthma, drugs, hay fever, polyarteritis nodosa • skin disorders:  eczema, urticaria, pemphigus, dermatitis herpetiformis • sarcoidosis • malignancy: carcinoma, lymphoma • hypereosinophilic syndrome

CHAPTER 277  Normal blood function

Reduced eosinophils: Eosinopenia

hypercortisolaemia: Cushing’s disease, steroids, stress • • adrenaline • congenital (very rare)

or neutrophilia. Causes of neutropenia and neutrophilia are shown in Box 277.1. Eosinophils have granules that stain deep red with eosin and represent 2% or less of total leucocytes. They are phagocytic but less so than neutrophils. They are important in the defence against certain parasitic infestations, and in modulating hypersensitivity reactions. Common causes of an increase in circulating eosinophils (eosinophilia) are given in Box 277.1. Basophils are the least numerous of the leucocytes. They have deeply basophilic granules containing a variety of substances including histamine, heparin, a factor chemotactic for eosinophils, and one that promotes platelet aggregation and degranulation. They are probably related to tissue mast cells. They have membrane receptors for the Fc portion of IgE, and participate in immediate hypersensitivity reactions.

Platelets The platelets are small discoid bodies that are primarily concerned with haemostasis. Their morphology, function, and disorders are described in Chapter 281.

Plasma Plasma is the liquid phase of blood and normally makes up around 55% of blood volume. It consists of a variety of proteins and salts suspended in water. The predominant proteins are albumin (35–​45 g/​dl), immunoglobulins (IgG, IgA, IgM), coagulation factors, and a number of transport proteins such as caeruloplasmin and transferrin. Serum is that part of plasma that remains after blood (or plasma) has clotted: the principal difference is the absence of fibrinogen in serum.

The formation of blood cells: Haemopoiesis Blood cells are formed from progenitor cells in the bone marrow by haemopoiesis, which is a process of proliferation and differentiation. This process is carefully regulated throughout life to ensure both the steady replacement of ageing blood cells, and to provide a brisk increase in production when required. Given the central role

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that erythrocytes, leucocytes, and platelets have in sustaining life and maintaining the body’s integrity, it is not surprising that failure of marrow function can have serious consequences.

Normal haemopoiesis All peripheral blood cells arise from progenitor cells known as stem cells (see Figure 277.3). Stem cells have the responsibility for providing all the blood cells required in a lifetime:  to do this, they must maintain their own numbers by proliferation, as well as regularly ‘committing’ some to differentiate down the pathways that lead to mature cells. The number of stem cells is very small: differentiation and proliferation go hand in hand at first, so that each stem cell eventually gives rise to a large number of mature, non-​dividing cells.

Regulation of haemopoiesis Growth and differentiation of haemopoietic progenitors is to a large extent governed by a series of glycoprotein hormones, or growth factors. These react with specific cell-​surface receptors to stimulate proliferation and differentiation, and some also enhance granulocyte function. Growth factors are produced by cells that are in a good position to ‘sense’ the need for increased haemopoietic activity. For example, specialized cells in the juxtaglomerular region of the kidney (an organ with very high oxygen demand) sense reduced oxygen delivery and release erythropoietin, a hormone which stimulates erythropoiesis. Analogous granulocytic growth factors are produced by a wide range of connective tissue cells, macrophages, and activated T-​cells, which are all cells that are affected by tissue injury or infection. Most of the haemopoietic growth factors have been isolated and their genes molecularly cloned. This has enabled several factors to be synthesized and made available for clinical use, via recombinant DNA techniques.

Erythropoietin Erythropoietin is secreted by the kidney in response to reduced oxygen delivery. It acts both to expand the committed erythroid progenitor pool and to stimulate differentiation, increasing the output of red cells. Reduced erythropoietin production leads to reduced red-​cell production. This is largely responsible for the anaemia of renal failure and contributes to the anaemia of infection and chronic inflammatory disorders. On the other hand, increased erythropoietin production leads to erythrocytosis or polycythaemia. Recombinant human erythropoietin is now widely used to treat the anaemia of chronic renal failure, and clinical studies are currently under way in the anaemia of chronic disorders and in myelodysplasia.

Granulocyte colony-​stimulating factor Granulocyte colony-​stimulating factor (G-​CSF) is produced by macrophages and stimulates granulocyte production and release from the marrow. Recombinant human G-​CSF accelerates granulocyte recovery after chemotherapy for malignant disease and bone marrow transplantation, and reduces the risks of infection after these treatments.

Granulocyte–​macrophage colony-​stimulating factor Granulocyte–​ macrophage colony-​ stimulating factor (GM-​ CSF) is also produced by macrophages, but has a wider spectrum of action than G-​CSF does, stimulating the production of monocytes as well as granulocytes. Recombinant GM-​CSF has also been used to stimulate granulocyte recovery after chemotherapy for malignancy, but has more pronounced side effects of fever, fluid retention, bone pain, pruritus, and possibly thrombosis.

Interleukin-​3 Interleukin-​3 has an even broader spectrum of action than G-​CSF and GM-​CSF do. It acts on a more primitive cell, and is able to stimulate erythroid and megakaryocytic as well as granulocytic activity. It is currently undergoing clinical trials in a range of marrow failure states.

Other factors affecting haemopoiesis Proliferating cells require both vitamin B12 and folate for DNA synthesis. Lack of either results in megaloblastic haemopoiesis (see Chapter 279).

CHAPTER 277  Normal blood function Figure 277.3  Major cytokine sources and actions and transcription factor requirements for haemopoietic cells. Cells of the bone-​marrow micro-​environment, such as macrophages, endothelial cells, and reticular fibroblastoid cells, produce macrophage-​colony-​stimulating factor (M-​CSF), granulocyte–​macrophage-​colony-​stimulating factor (GM-​CSF), granulocyte-​colony-​stimulating factor (G-​CSF), interleukin 6 (IL-​6), and probably stem cell factor after induction with endotoxins (macrophages) or interleukin 1 (IL-​1)/​tumour necrosis factor (TNF; endothelial cells and fibroblasts). T-​cells produce interleukin 3 (IL-​3), GM-​CSF, and interleukin 5 (IL-​5) in response to antigenic and IL-​1 stimulation. These cytokines have overlapping actions during haematopoietic differentiation, as indicated and, for all lineages, optimal development requires a combination of early acting and late-​acting factors. Transcription factors important for survival or self-​renewal of stem cells are shown at the top, and stages of haemopoiesis blocked after the depletion of indicated transcription factors are shown for multipotent and committed progenitors; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; EPO, erythropoietin; GMP, granulocyte–​macrophage progenitor; LTR-​HSC, long-​term repopulating haematopoietic stem cell; MEP, megakaryocyte–​erythrocyte progenitor; NK, natural killer; SF, scatter factor; STR-​HSC, short-​term repopulating haematopoietic stem cells; TNF, tumour necrosis factor; Tpo, thrombopoietin. Reproduced with permission from Sieff, Stem cells and haemopoiesis, in Oxford Textbook of Medicine, Fifth Edition Oxford University Press, Oxford, UK, Copyright © 2010.

A further important regulatory factor for erythropoiesis is the iron supply. Developing erythroblasts acquire iron for haemoglobin synthesis directly from adjacent marrow macrophages. Iron availability is reduced not only in iron deficiency (see Chapter 279), but also in inflammation and infection, when macrophages retain iron and the serum iron falls. Why this happens is a matter of some controversy, but sequestration of body iron may disadvantage bacteria, which depend on iron for their growth.

primary disorders affecting haemopoietic progenitors themselves are discussed here. Megaloblastic haemopoiesis and anaemia is covered in Chapter 279, and disorders of red-​cell production due to abnormal haemoglobin synthesis in Chapter 280. The majority of primary haemopoietic disorders are acquired and arise from a single defective progenitor. Congenital disorders are rare and often associated with other congenital abnormalities (see Box 277.2).

Disorders of haemopoiesis

The concept of clonality

Disorders of haemopoiesis may involve over-​or underproduction of one or more cell types by the marrow (see Box 277.2). Intrinsic or

One of the central concepts in cell biology is that every individual differentiated cell originates from a single progenitor, or stem cell and,

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Box 277.2  Disorders of haemopoiesis

Box 277.4  Causes of aplastic anaemia

Clonal disorders originating in pluripotent stem cells and so affecting all three cell lines

• drugs: • antibiotics (chloramphenicol, penicillin, cephalosporins, sulfonamides) • anti-​ inflammatory agents (phenylbutazone, indomethacin, penicillamine, gold) • hypoglycaemics (chlorpropamide, tolbutamide) • antithyroid drugs • phenothiazines • antimalarials • antiepileptics • chemicals and toxins: • pesticides • benzine derivatives and related solvent compounds • dyes • radiation • infections: • hepatitis • EBV • CMV • rubella • pregnancy

• myeloproliferative disorders:  chronic granulocytic leukaemia, polycythaemia rubra vera, thrombocythaemia, myelofibrosis • paroxysmal nocturnal haemoglobinuria • acute myeloid leukaemia (some) • myelodysplastic syndromes • congenital cyclical neutropenia (rare)

Clonal disorders affecting committed progenitors acute myeloid leukaemia (some) • • myelodysplasia (some) • acute lymphoblastic leukaemia • chronic lymphocytic leukaemia • myeloma • lymphomas

Non-​clonal disorders affecting all cell lines

• aplastic anaemia (some cases may have underlying clonal abnormality) • megaloblastic haemopoiesis

CHAPTER 277  Normal blood function

Non-​clonal disorders affecting primarily a single cell line selective cytopenias (autoimmune or drug induced) • • thalassaemias • iron-​deficiency anaemia • congenital dyserythropoietic anaemia • pure red-​cell aplasia • parvovirus infection (erythroid progenitors)

conversely, that each stem cell gives rise to a family (or ‘clone’) of differentiated daughter cells. Once a pluripotent haemopoietic stem cell becomes committed to differentiation, it ultimately produces a number of red cells, granulocytes, platelets, and lymphoid cells, which thus belong to the same clone. Similarly, each committed granulocyte progenitor (for example) gives rise to a single clone of granulocytes, which is therefore a subclone of the parent pluripotent stem cell.

Box 277.3  Some drugs and other toxic agents causing bone marrow failure

Predictable (dose related) radiation • • cytotoxic drugs • chloramphenicol

Idiosyncratic (not dose related) Agents causing granulocytosis • antithyroid drugs • dapsone • amidopyrine • NSAIDs • co-​trimoxazole • chlorpromazine

Agents causing thrombocytopenia heparin • • quinine • quinidine • gold • NSAIDs • co-​trimoxazole

Agents causing aplastic anaemia

chloramphenicol • • phenylbutazone and other NSAIDs • benzene and derivatives • gold • penicillamine • pesticides

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From time to time, an individual progenitor sustains genetic damage which alters its potential for growth and differentiation. This may give the cell and its progeny a growth advantage over normal cells, allowing clonal expansion of the affected line. The consequences of this will depend upon the nature of the mutant cell, the nature of the damage, and its effect on growth and differentiation. Uncontrolled clonal expansion of this sort is the basis of virtually every malignant neoplastic disorder. Clonal disorders of haemopoiesis include frank haematological malignancies such as leukaemia and lymphoma, as well as less obviously malignant myelo-​and lymphoproliferative disorders (see Box 277.2).

Bone marrow failure Failure of haemopoiesis usually results from damage to proliferating marrow cells by cytotoxic drugs or radiation, haemopoietic malignancy, or a combination of the two. Much less commonly, damage to one or more cell lines can occur in patients taking other medication, due to immune mechanisms, certain viral infections, or for unknown reasons (see Box 277.3). Marrow replacement by metastatic malignancy may also result in marrow failure. The result is a varying degree of anaemia, neutropenia, and thrombocytopenia; reduction in all three cell types is known as pancytopenia. The term aplastic anaemia is reserved for primary marrow failure with pancytopenia that is not obviously due to cytotoxic drugs or radiation.

Anaemia Cessation of erythropoiesis leads to anaemia (see Chapter  279). The normal erythrocyte life span is 120  days, so interruption of production will lead to a fall in haemoglobin of about 1% per day (1 g/​dl per week). Infection and bleeding, secondary to neutropenia and thrombocytopenia, are therefore often earlier and more serious manifestations of marrow failure. Anaemia can be corrected by red-​cell transfusions. In general, the aim is to maintain a haemoglobin level compatible with good health, normally above 9 g/​dl. Below this level, there is a significant risk of optic fundal haemorrhage, which may occur in any form of anaemia but which can be particularly troublesome if infection and thrombocytopenia are also present. Transfusion should be with packed red cells or red-​cell concentrates, given slowly, and with diuretics if necessary, to avoid circulatory overload.

Neutropenia Unlike red cells and platelets, neutrophil granulocytes have a predominantly extravascular role, and circulate in the blood for only a few hours, before passing into the tissues. The generation of mature

Thrombocytopenia Platelets survive in the circulation for an average of 9–​10 days, but are consumed more rapidly in the presence of bleeding, infection, or fever. The likelihood of abnormal bleeding depends upon the platelet count and the nature of the injury: spontaneous haemorrhage is uncommon unless the count falls below 20 ×109/​l. At levels below this, petechial haemorrhages occur in the skin and mucous membranes, and in the internal organs. Bleeding is aggravated by minor trauma and is most noticeable in dependent areas (because of hydrostatic pressure) and in pressure areas. The most serious risk from thrombocytopenia is cerebral haemorrhage. Bleeding can be treated and prevented by transfusion of platelet concentrates. In an average adult, a transfusion of 5–​6 units of

platelet concentrate will raise the platelet count by 10–​30 × 109/​l. Transfused platelets have a slightly shorter life span than normal, and 2–​3 transfusions weekly may be required—​increasing to daily in the presence of active bleeding or infection, both of which increase platelet consumption. The major problem with repeated platelet transfusions is sensitization to foreign human leucocyte antigens (HLA) and platelet-​ specific antigens, which may lead to rapid platelet destruction, and ineffectiveness of transfusions from random donors. In this situation, good responses may be obtained by using platelets from HLA-​ matched donors, often as single-​donor transfusions (collected on a cell separator), from the outset of thrombocytopenia to reduce the subsequent risk of sensitization. Since the responsible HLAs are most strongly expressed on leucocytes, an alternative approach is to use high-​efficiency in-​line filters at the time of transfusion to remove any leucocytes. Despite such measures, however, sensitization to platelet-​specific antigens may still occur.

Drug-​induced cytopenias A variety of drugs may damage the marrow (see Box 277.3). Myelo­ toxicity is a well-​recognized (and often intended) dose-​dependent effect of the cytotoxic drugs used to treat malignant disease or as immunosuppressants. Other drugs may, on rare occasions, produce a severe reduction in the production of one or more cell types, in a non-​dose-​dependent or idiosyncratic fashion. Prompt recovery usually follows withdrawal of the offending drug, provided this is rapidly identified. Prognosis is good except in patients who present with severe infection, and in whom mortality is high. Full supportive measures should be given as outlined in ‘Neutropenia’.

Aplastic anaemia Aplastic anaemia is a rare form of marrow failure leading to pancytopenia with a hypocellular or acellular bone marrow. In the majority of cases, no specific cause can be found, although various factors may be implicated in a minority (see Box 277.4). Most cytotoxic drugs can produce severe pancytopenia, but this is usually recoverable, as the pluripotent stem cell population is relatively resistant to permanent damage. However, the alkylating agent busulphan, when used carelessly, can lead to prolonged or permanent aplasia, as can high doses of whole-​body irradiation. Several drugs and chemicals have been associated with severe aplastic anaemia, presumably through an idiosyncratic and possibly immune-​ mediated mechanism. The diagnosis of aplastic anaemia requires demonstration of the severely hypocellular marrow, preferably on two separate trephine examinations. Aplastic anaemia is said to be severe when, over a period of at least 3–​4 weeks, the following findings are observed:

CHAPTER 277  Normal blood function

neutrophils from pluripotent stem cells takes 10–​14  days, although the last few days in the marrow are spent in a non-​mitotic maturation compartment which can be mobilized into the circulation rapidly in response to infection. Neutrophil lifespan in the tissues is only 2–​3 days, so neutropenia is usually the earliest and most pronounced feature of marrow failure, reaching a nadir 7–​10 days after haemopoiesis has been arrested. The principal function of the neutrophil is bacterial phagocytosis and, in the steady state, most neutrophils scavenge for normal commensal gut organisms and other organisms which gain access to the body through breaks in the skin or gut mucosa. Bacterial infection is thus the major consequence of neutropenia, and will occur in around one-​half of patients with peripheral blood neutrophil counts less than 0.5 × 109/​l, and virtually all those with less than 0.2 × 109/​l, lasting more than 10–​14 days. Gram-​negative organisms of bowel origin are most commonly involved but, in hospitalized patients, the normal gut flora is often supplemented by resistant pathogens, such as Klebsiella spp. and Pseudomonas spp. Gram-​positive organisms, such as Staphylococcus epidermidis, are commonly associated with the use of implanted central venous catheters for vascular access. The earliest and often only manifestation of serious infection is fever. Local inflammatory signs are impaired, and focal signs may be minimal. Pulmonary, soft tissue, and urinary infections may occur. Septicaemia is common, although positive blood cultures are obtained in less than one-​third of patients with a temperature higher than 38°C. Suspected infection must be treated promptly, as delay may prove rapidly fatal. If a temperature >38°C develops, blood and urine cultures should be taken, and a chest radiograph performed. IV broad-​spectrum antibiotics should be started immediately, following local protocols which should reflect the local pattern of organisms. Antibiotic therapy may be subsequently modified by the results of cultures. Modern antimicrobials are capable of curing the majority of bacterial infections in neutropenic patients. Problems occur when neutropenia is particularly prolonged, especially in association with aggressive cytotoxic therapy, which may damage mucosal barriers and impair macrophage, as well as neutrophil production. Deep-​ seated fungal infections may develop in this situation and are often difficult to diagnose in vivo. Empirical IV antifungal therapy (e.g. with amphotericin) is advisable when fever or signs of infection persist, despite broad-​spectrum antibiotic cover. Infection may be prevented in severely neutropenic patients by strict isolation in a sterile environment, together with rigorous decontamination of skin and gut with disinfectants and antibiotics. In general, however, such measures do not improve the overall outcome, and their expense and poor patient acceptability has led most centres to abandon such regimes. Certain oral antibiotics, such as co-​ trimoxazole, ciprofloxacin, and norfloxacin may reduce the incidence of systemic infection and are often recommended in prolonged neutropenia, although there is potential risk of antibiotic resistance. Recombinant growth factors (e.g. G-​CSF) can reduce the period and severity of neutropenia after cytotoxic therapy, and thereby the morbidity and mortality from infection. Alternatively, by reducing myelotoxicity, they may permit the safe use of higher, and thus perhaps more effective, doses of cytotoxic therapy for malignant disease.

the neutrophil count remains less than 0.5 × 109/​l • • platelets are less than 20 × 109/​l • the absolute reticulocyte count (red blood cell count × per cent reticulocytes) is less than 20 × 1012/​l Untreated, severe aplastic anaemia is almost always ultimately fatal, although spontaneous recovery may occur occasionally. Management involves supportive care, but with particular attention to the risk of sensitization to HLAs by transfusion, as this may impair platelet support and increase the risk of graft rejection if bone marrow transplantation (BMT) is undertaken. BMT is the treatment of choice in patients who are under the age of 50 and who have an HLA-​compatible sibling donor. Two-​thirds of transplanted patients will be cured permanently; the major problem is graft-​vs-​host disease, which tends to be less severe in younger patients. An alternative to BMT is antithymocyte globulin (ATG). This was initially used as an immunosuppressant in the early days of BMT, but apparent early success of BMT in some patients was shown to be due to autologous recovery of the patient’s own marrow, following failure of engraftment. Infusion of ATG over 5 days produces a response in about one-​half of patients; the response is complete in about one-​quarter and is sustained in over two-​thirds. Age is not a factor influencing response, and ATG therapy is the treatment of choice over the age of 50, and in younger patients without a marrow donor. The success of ATG therapy suggests a possible immune basis for aplasia in those who respond, although other non-​myelotoxic

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immunosuppressive agents, such as corticosteroids and cyclosporin A, have only occasionally produced a response.

Pure red-​cell aplasia Rare causes of severe anaemia occur in which the marrow shows complete absence of erythroid activity, but normal white-​cell and platelet production. A congenital form, Diamond–​Blackfan anaemia, is apparent at or shortly after birth and is associated with a variety of other, mainly skeletal, deformities in about one-​third. There is a reduction in erythroid progenitors, which are also relatively insensitive to erythropoietin. Acquired red-​cell aplasia is thought to be autoimmune, with cytotoxic immune reactions directed against developing erythroblasts or, rarely, autoantibodies to erythropoietin. There is an association with thymoma, and it is worth doing a CT scan of the chest in affected patients, as removal of a thymoma may reverse the red-​cell aplasia. Treatment is otherwise with corticosteroids. It is also occasionally seen in patients with chronic lymphocytic leukaemia (see Chapter 287). Transient erythroblastopenia of childhood is an uncommon condition in which sudden onset of anaemia is associated with the erythropoiesis being temporarily suppressed.

CHAPTER 277  Normal blood function

Leukaemia

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Leukaemias are clonal malignant proliferations of leukocytes and/​or their precursors. Acute leukaemias (see Chapter 286) are characterized by uncontrolled growth of immature haemopoietic progenitor cells, at the expense of normal marrow function, and most of the clinical features are therefore those of marrow failure. They are of either myeloid (more common in adults) or lymphoblastic (more common in childhood) origin, and are rapidly fatal if untreated, but potentially curable with appropriate treatment.

Chronic leukaemias are clonal proliferations of haemopoietic cells that have not completely lost the ability to differentiate. Chronic myeloid (granulocytic) leukaemia has features in common with myeloproliferative disorders, while chronic lymphocytic leukaemia is best considered as a form of low-​grade non-​Hodgkin lymphoma.

Myeloproliferative disorders The myeloproliferative disorders are a group of clonal disorders arising in haemopoietic or pluripotent stem cells characterized by uncontrolled growth but relatively normal differentiation—​predominantly (but not always exclusively) down one of the three main haemopoietic pathways. The result is a significant expansion of red cells, granulocytes, or platelets and their precursors, alone or in combination. Clinically, the myeloproliferative disorders may be classified according to the predominant cell type: polycythaemia rubra vera: red cells • • essential thrombocythaemia: platelets • myelofibrosis: fibroblasts proliferating in response to growth factors, produced by an immature haemopoietic clone • chronic granulocytic leukaemia: granulocytes

Further Reading Boxer LA. How to approach neutropenia. Hematology 2012; 2012: 174–​82. Carson JL Triulzi DJ, and Ness PM. Indications for and Adverse Effects of Red-Cell Transfusion. N Engl J Med 2017; 399: 1261–​72. Koury MJ and Rhodes M. How to approach chronic anemia. Hematology 2012; 2012: 183–​90. Stasi R. How to approach thrombocytopenia. Hematology 2012; 2012: 191–​7.

278 

Diagnosis and investigation in haematology Chris Bunch

The full blood count A routine full blood count performed by the haematology laboratory will include the following parameters (some of these are measured directly, while others are derived by calculation; typical reference ranges are given in Table 278.1): • haemoglobin (Hb): the concentration of haemoglobin in whole blood (expressed as grams per decilitre) • red-​cell count (RCC): • the concentration of red cells (× 1012/​l) • changes in the RCC tend to parallel changes in the haemoglobin and haematocrit • a decrease in the RCC is called anaemia • an increase in the RCC is called erythrocytosis or polycythaemia • mean corpuscular volume (MCV): • the average volume of individual red cells (expressed in femtoliters) • a low MCV indicates microcytosis • a high MCV indicates macrocytosis • haematocrit, or packed cell volume: • the proportion of red cells in a unit volume of blood, usually expressed as a ratio (e.g. 0.45) or a percentage • derived from MCV × RCC • mean cell haemoglobin (MCH): • the average amount of haemoglobin per cell (expressed in picograms) • derived from Hb/​RCC • mean cell haemoglobin concentration (MCHC): • the mean concentration of haemoglobin per cell (expressed as grams per decilitre of red cells) • derived from Hb/​(MCV × RCC) Table 278.1  Normal values for full blood count Variable

Normal range

Hemoglobin

Male: 13.5–​17.5 g/​dl Female: 12.0–​16.0 g/​dl

Hematocrit

Male: 41–​53% Female: 36–​46%

Mean corpuscular volume (MCV)

80–​100 fl

Red cell distribution width (RDW)

11.5–​14.5%

Reticulocyte count

0.5–​2.5% red cells

White blood cell count Neutrophils Lymphocytes Monocytes Eosinophils Basophils

4.5–​11.0 ∙ 109/​L 40–​70% 22–​44% 4–​11% 0–​8% 0–​3%

Platelet count

150–​350 ∙ 109/​L

Reproduced from David C. Sprigings, John B. Chambers, Acute Medicine: A Practical Guide to the Management of Medical Emergencies, 4th Edition, Chambers, Wiley-​Blackwell, UK, Copyright © 2007. Data from Kratz et al., Laboratory reference values, New England Journal of Medicine, volume 351, pp. 1548–​63. Copyright 2004.

• the MCHC tends to remain fairly constant but may be reduced in severe iron deficiency or thalassaemia • pale (hypochromic) red cells on a blood smear may indicate small red cells (low MCV and MCH) but is more striking when MCHC is also reduced • white-​cell (leucocyte) count: • the total concentration of leucocytes (× 109/​l) • an increase is called a leucocytosis • a decrease is leucopenia • differential leucocyte count: • either the absolute concentration (× 109/​l) or the percentage of each type of white cell • this may be derived manually by examination of a stained blood smear or by automated counters which differentiate cells by size, staining, or other characteristics • automated counters are potentially more accurate numerically (especially with low counts), but may misclassify some abnormal leucocytes • platelet count: the concentration of platelets (× 109/​l)

The blood film or smear Examination of a stained blood film is one of the key investigations in haematology, as alterations in the appearances of red cells, white cells, and platelets may give clues to the cause of any blood count abnormality, while the presence of abnormal cells, for example immature leucocytes in leukaemia, may be diagnostic (see Tables 278.2–​6 and Box 278.1). Unfortunately, the automation of blood counts has led to blood film examination becoming less routine in many laboratories, but a film should always be requested if a blood count abnormality cannot readily be explained by the clinical context.

The reticulocyte count The reticulocyte count can give valuable information about the dynamics of erythropoiesis. In the normal, steady state, 1%–​2% of red cells are reticulocytes. A normal marrow will respond to anaemia by increasing red-​cell production and, thereby, the proportion of reticulocytes. This effect is most marked when red-​cell lifespan is also reduced, as in haemolysis. Because anaemia implies a reduction in the absolute RCC, a small increase in reticulocyte percentage does not necessarily indicate a healthy marrow response to anaemia, and calculation of the absolute reticulocyte count (% reticulocytes × RCC: normally 25 × 109/​l to 85 × 109/​l) is a more accurate guide.

The erythrocyte sedimentation rate, and plasma viscosity When anticoagulated whole blood is left to stand, the red cells, white cells, and platelets sediment over time. The rate of red-​ cell sedimentation is directly proportional to the concentration of macromolecules such as fibrinogen and immunoglobulins in the plasma; so, any condition that increases these will increase the erythrocyte sedimentation rate (ESR). In practice, the ESR is measured by timing the extent of red-​cell sedimentation

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Table 278.2  Clues from the blood film Finding

Interpretation/​causes

CHAPTER 278  Diagnosis and investigation in haematology

Red cells Microcytes

Iron deficiency Anaemia of chronic disease Thalassemia Sideroblastic anaemia

Macrocytes

Drug induced Vitamin B12/​folate deficiency Haemolysis Primary bone disorder Alcohol Hypothyroidism Chronic liver disease

Red cell aggregation

Rouleaux, seen in: high polyclonal immunoglobulin • monoclonal immunoglobulin (paraprotein, e.g. myeloma) • high fibrinogen • Agglutination, reflecting the presence of cold agglutinin, seen in: mycoplasma infection • infectious mononucleosis • lymphoproliferative disorder • idiopathic •

Fragmented red cells (schistocytes)

Microangiopathic haemolytic anaemia, seen in: disseminated intravascular coagulation • thrombotic thrombocytopenic purpura/​haemolytic • uremic syndrome disseminated cancer • pre-​eclampsia/​eclampsia with HELPP syndrome • malignant phase hypertension • Prosthetic heart valve Severe burn

‘Bite cells’ (keratocytes)

Acute haemolysis induced by oxidant damage (e.g. in glucose-​6-​phosphate dehydrogenase deficiency)

Target cells

Iron deficiency Thalassemia Liver disease Postsplenectomy

Nucleated red cells

Marrow replacement, due to: carcinoma (most commonly of breast or prostate origin) • myelofibrosis • myeloma • tuberculosis •

White cells Blast cells

Leukemias Lymphomas Marrow replacement

Platelets Platelet clumps

EDTA-​induced platelet clumping may cause spurious thrombocytopenia

Other findings Abnormal cells

Lymphoma cells Myeloma cells

Data from Bain, B.J. Diagnosis from the blood smear. N Engl J Med 2005; 353: 498–​507; and Tefferi, A. et al. How to interpret and pursue an abnormal complete blood cell count in adults. Mayo Clinic Proc 2005;80: 923–​36.

after 1 hour in a standardized calibrated tube, and the result is expressed in millimetres per hour. The upper limit of normal is age-​and sex-​dependent, ranging from 17 mm/​h in men aged 17–​50, and 30  mm/​h in men over 70, with acceptable values being 5–​10 mm/​h higher in women.

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The ESR is most commonly raised in infections and inflammation, reflecting predominantly increased levels of fibrinogen, an ‘acute phase reactant’. In this respect, it gives information similar to that provided by C-​reactive protein (CRP) levels. However, it is a very non-​specific test and may be raised in a range of underlying disorders, including malignancy. It will usually be higher than normal with significant anaemia (reflecting the reduced haematocrit). The ESR can be significantly elevated when immunoglobulin levels are high, as in polyclonal hypergammaglobulinaemia (suggestive of chronic infection or inflammation), or monoclonal paraproteinaemia due to myeloma. Very high ESR levels (>100 mm/​h) are highly suggestive of myeloma, Waldenstrom’s macroglobulinaemia, tuberculosis, or vasculitic conditions, such as polymyalgia rheumatica or giant cell arteritis. The CRP level can sometimes help differentiation, as it is elevated in ‘acute phase’ conditions (inflammation or infection) but is usually unaffected by monoclonal paraproteinaemia. The ESR is simply an indirect measure of plasma viscosity, which is increased by the same macromolecules, and some laboratories offer plasma viscosity measurements by preference. The information obtained is the same, and just as non-​specific.

Iron, vitamin B12, and folate studies Iron-​deficient erythropoiesis occurs when the iron supply to developing erythroblasts is reduced, typically due to iron deficiency or the anaemia of chronic disorders (ACD) and results in anaemia with a reduced MCV (microcytosis). Serum iron estimation alone is insufficient, as it is reduced in both cases, and proper evaluation requires serum ferritin and transferrin levels and/​or transferrin saturation as well. In iron deficiency, ferritin is low and transferrin high; in ACD, transferrin is normal or low, and ferritin normal or raised (ferritin is also an ‘acute phase reactant’). Serum vitamin B12 and folate levels are required to determine the cause of megaloblastic anaemia and to elucidate macrocytic anaemia generally. Low folate levels in dietary folate deficiency can be rapidly reversed by refeeding, and the diagnosis missed. If this is suspected, then red-​cell folate estimation may be helpful, as low levels recover much more slowly. Vitamin B12 levels are often requested in the investigation of dementia, but the interpretation of low levels in the absence of anaemia or typical neurology is a matter of some debate. Low levels may be associated with increased risk of falls in the elderly. High vitamin B12 levels are seen in patients receiving intramuscular vitamin B12 replacement, and in some myeloproliferative disorders, but are not diagnostic.

Radioisotopic studies Radiation protection regulations have severely limited the availability of radioisotopes for haematological investigation. Traditional uses include blood volume estimations (red cells labelled with 51Cr; plasma with 125I), red-​cell survival (51Cr-​labelled red cells), and the Schilling test for pernicious anaemia (absorption of 57Co-​ or 58Co-​labelled cobalamins, with and without bound intrinsic factor).

Bone marrow examination Although the nature of many haematological disorders can be determined from the blood count and film, examination of the bone marrow is essential to the proper evaluation and diagnosis of many disorders (see Box 278.2). The simplest form of marrow examination involves needle aspiration of marrow cells from the posterior iliac crest, after infiltrating the skin and periosteum with local anaesthetic. Smears are made and stained in the same way as a blood film and allow quantitative and qualitative assessment of the developing blood cells. Marrow can also be biopsied for histological examination, by using a special trephine biopsy needle. This can be performed at the same time as marrow aspiration from the iliac crest. A marrow aspirate is usually sufficient to diagnose qualitative and quantitative defects in blood cell precursors, although it must be recognized that it only provides a ‘snapshot’ of a dynamic process. On occasions, marrow cells cannot be aspirated, and the attempt yields just a ‘dry’ or ‘blood’ tap. This may occur in myelofibrosis with a

Table 278.3  Microcytic anaemia (mean corpuscular volume 30% and MCV 100 fl) Cause

Clues from full blood count and film

Other blood results

Drug-​induced

Usually unremarkable

No specific abnormality

Causes/​comment Many drugs, e.g. azathioprine, zidovudine

Vitamin B12/​folate deficiency

Oval macrocytic red cells, hypersegmented neutrophils, pancytopenia

Low serum B12/​red-​cell folate Positive intrinsic factor antibodies in pernicious anaemia

B12 deficiency: pernicious anemia/​ malabsorption Folate deficiency: inadequate dietary intake/​malabsorption

Hemolysis

Hemolytic anemia is usually normocytic, but can be macrocytic if there is marked reticulocytosis

Primary bone marrow disorder

MCV usually >110 fl Other cytopenias Leukocytosis Monocytosis Thrombocytosis Blast cells

No specific abnormality

Alcohol

Alcohol excess may also cause lymphopenia and thrombocytopenia

Abnormal liver function tests, with raised AST (>ALT) and γGT

Hypothyroidism

Usually unremarkable

Raised TSH, low free T4/​free T3

Chronic liver disease

Associated thrombocytopenia may be seen in cirrhosis with portal hypertension and splenomegaly

Abnormal liver function tests/​ prothrombin time

CHAPTER 278  Diagnosis and investigation in haematology

Table 278.4  Normocytic anaemia (mean corpuscular volume 78–​100 fl)

Myelodysplasia, leukemia

Hypothyroidism may also cause normocytic anemia

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; γGT, gamma-glutamyl transferase; MCV, mean corpuscular volume; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone. Reproduced with permission from David C. Sprigings, John B. Chambers, Acute Medicine: A Practical Guide to the Management of Medical Emergencies, 4th Edition, Chambers, Wiley-Blackwell, UK, Copyright © 2007.

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CHAPTER 278  Diagnosis and investigation in haematology

Table 278.6  White blood cell abnormalities Finding

Possible causes

Neutrophilia

Sepsis Metastatic cancer Acidosis Corticosteroid therapy Trauma, surgery, burn Myeloproliferative disorders

Neutropenia

Drugs (e.g. carbimazole) Infections (e.g. viral, severe bacterial, HIV) Vitamin B12 and folate deficiency Systemic lupus erythematosus Felty syndrome Hematological disorders (e.g. leukemia)

Lymphocytosis

Infections (e.g. infectious mononucleosis) Chronic lymphocytic leukemia

Lymphopenia

Infections (e.g. viral, HIV, severe bacterial) Immunosuppressive therapy Systemic lupus erythematosus Alcohol excess Chronic renal failure

Monocytosis

Infections Myeloproliferative disorders (e.g. chronic myelomonocytic leukemia) Metastatic cancer

Eosinophilia

Drug allergy Parasitic infestation Hematological disorders (e.g. lymphoma, leukemia) Churg–​Strauss vasculitis Disorders with eosinophilic involvement of specific organs Adrenal insufficiency Atheroembolism

Reproduced with permission from David C. Sprigings, John B. Chambers, Acute Medicine: A Practical Guide to the Management of Medical Emergencies, 4th Edition, Chambers, Wiley-​Blackwell, UK, Copyright © 2007.

Box 278.1  Causes of pancytopenia Aplastic anemia • Idiopathic • Cytotoxic drugs and radiation • Idiosyncratic drug reaction • Viral infections Acute leukemia Marrow replacement • Cancer • Myelofibrosis • Military tuberculosis Vitamin B12/​folate deficiency Paroxysmal nocturnal hemoglobinuria Myelodysplasia HIV Reproduced with permission from David C. Sprigings, John B. Chambers, Acute Medicine: A Practical Guide to the Management of Medical Emergencies, 4th Edition, Chambers, Wiley-​Blackwell, UK, Copyright © 2007

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Box 278.2  Indications for examination of bone marrow • haematological malignancy, including leukaemia, lymphoma, myeloma, chronic granulocytic leukaemia, and myelodysplasia • pancytopenia, or selective thrombocytopenia or neutropenia, where cause otherwise is not evident • refractory anaemias (those not due to or responding to iron, vitamin B12, folate replacement, or to obvious red-​cell production disorders, such as thalassaemia • unexplained protracted fever; may rarely demonstrate tuberculosis, kala azar, or underlying malignancy • leucoerythroblastic anaemia; to detect metastatic carcinoma, or myelofibrosis • to confirm megaloblastic anaemia (rarely necessary)

hypercellular or ‘packed’ marrow—​as in some cases of leukaemia or other haematological malignancies—​or if the marrow is severely hypocellular. Trephine biopsy is necessary in these circumstances and is also helpful if marrow infiltration with metastatic malignancy is suspected. Where haematological malignancy is suspected or being investigated, a sample for cytogenetics may be taken for karyotyping and/​or molecular studies. Marrow aspirate and biopsy are invasive and unpleasant procedures and should not be undertaken lightly. It is important to consider carefully what information is being sought and to plan the samples and sample handling accordingly. Formal consent should be obtained:  although the risks are low, occasional fatalities have occurred; extensive bleeding may occur in patients with recognized or unrecognized coagulation, or platelet function abnormalities, and inadvertent puncture of internal organs or blood vessels may occur if an unduly long biopsy needle is used. Particular care should be taken in the elderly, who may have a degree of osteopenia.

Further Reading Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005; 353: 498–​507. Boxer LA. How to approach neutropenia. Hematology 2012; 2012: 174–​82. Chabot-Richards DS and Foucar K. Does morphology matter in 2017? An approach to morphologic clues in non-neoplastic blood and bone marrow disorders. Int J Lab Hematol 2017; 39 Suppl 1: 23–​30. Koury MJ and Rhodes M. How to approach chronic anemia. Hematology 2012; 2012: 183–​90. Stasi R. How to approach thrombocytopenia. Hematology 2012; 2012: 191–​7.

279 

Deficiency anaemias

Chris Bunch

Definition Erythropoiesis requires an adequate supply of iron for haem formation, as well as vitamin B12 and folic acid (folate) to support high levels of DNA synthesis, and a lack of any of these will result in anaemia. Iron-​deficient anaemias are typically microcytic, while a deficiency in vitamin B12 or folate results in megaloblastic haemopoiesis and a macrocytic anaemia.

Aetiology Iron deficiency When iron loss exceeds iron intake, the body stores of iron are mobilized for haemoglobin production. As the stores become depleted, the ability to absorb iron from the diet is increased, and serum ferritin falls. As stores are further depleted, the serum iron level falls, and the total iron binding capacity (transferrin) rises. If a negative iron balance continues, the stores become exhausted, and tissue iron deficiency and anaemia will develop. Iron deficiency will result from poor dietary iron intake, poor absorption, increased demands, blood loss, or combinations of these.

Diet The bioavailability of iron in the diet is low for many people worldwide, although poor diet is rarely the sole cause of iron deficiency in Western societies, except in the very poor and the elderly. Even in populations whose diet is largely vegetarian and is poor in available iron, deficiency may only develop at times of increased losses or physiological demands.

Increased physiological demands Increased physiological demands will commonly lead to a degree of iron deficiency in infants (6–​24  months), adolescents (especially at the time of the growth spurt and puberty), and in menstruating women who are also childbearing. The additional requirements during pregnancy, amounting to about 500 mg, include iron supply to the fetus, the expanded maternal red-​cell volume, and blood losses at delivery.

Blood loss Menstruating women form the largest group of people who suffer sufficient blood loss to cause iron deficiency. Losses of up to 80 ml a month may be tolerated by increased absorption, provided the diet is adequate. However, worldwide, this is often not the case and, with the additional stresses of pregnancy, menstruating women are frequently iron deficient. Even in Western societies, where only 5% of women are overtly iron deficient as assessed by haemoglobin measurements, some 30% may respond to iron supplementation with a rise in haemoglobin. Gastrointestinal bleeding accounts for the majority of other cases involving blood loss. The normal insensible loss in the gastrointestinal tract amounts to 1 ml/​day. Since tests for occult bleeding are insensitive below about 20 ml/​day, and bleeding is often intermittent, even moderate intestinal bleeding cannot always be documented. The most important benign causes of gastrointestinal bleeding are: haemorrhoids • • hiatus hernia • NSAID use • diverticulosis • peptic ulceration • angiodysplasia (especially in the elderly)

The possibility of occult bowel malignancy is always a major concern in postmenopausal women and adult males. Such patients should have upper gastrointestinal endoscopy and colonoscopy, or barium studies if these are not available. Hookworm infestation is a major cause of blood loss in developing countries, and should always be considered in recent immigrants.

Malabsorption Malabsorption of iron occurs in coeliac disease, and may be its only manifestation, although there is usually also folate deficiency. Iron deficiency secondary to gastric atrophy is common in association with pernicious anaemia, but simple atrophic gastritis may respond to iron therapy, and thus be a result, rather than a cause, of iron deficiency.

Megaloblastic anaemias Megaloblastic haemopoiesis produces a macrocytic anaemia with a slow and pernicious onset. This allows time for compensatory mechanisms to develop, and symptoms may not be apparent until the haemoglobin is very low, often below 6 g/​dl. The principal complaint is therefore of progressive lassitude, with shortness of breath. Angina pectoris may occur in patients with coexistent impairment of myocardial function or coronary blood flow. Increased bilirubin production, associated with ineffective erythropoiesis and a shortened red-​cell survival, may give rise to mild jaundice which, combined with extreme pallor, gives rise to a ‘lemon-​yellow’ appearance.

Anaemia due to vitamin B12 deficiency Vitamin B12 is synthesized only by microorganisms, and is obtained in man by ingestion of other animal products, or from bacterially contaminated vegetable matter. Pure dietary deficiency is therefore rare, and seen only in strict vegans. Dietary vitamin B12 binds to R factor in saliva and gastric juices. In the duodenum, it dissociates from R factor, and binds to intrinsic factor (IF) in the presence of pancreatic enzymes. The IF–​B12 complex is taken up by receptors (cubilin) in the terminal ileum and then released into plasma, bound to transcobalamins TC I, II, or III. Vitamin B12 enters cells by receptor-​mediated endocytosis and is metabolized into two coenzymes:  adenosylcobalamin and methylcobalamin. The usual cause of severe vitamin B12 deficiency in Western countries is an autoimmune atrophic gastritis, in which there is a loss of gastric parietal cell numbers and an absence of intrinsic factor production, which effectively prevents vitamin B12 absorption. This is the classical pernicious anaemia, and it is often seen in association with other autoimmune disorders, such as myxoedema (hypothyroidism), Addison’s disease (hypoadrenalism), and vitiligo. Vitamin B12 deficiency may result from infestation with the fish tapeworm Diphyllobothrium latum. More rarely, it may result from total gastrectomy; surgery or disease (e.g. Crohn’s) affecting the terminal ileum, or congenital deficiencies of intrinsic factor, cubilin (the IF–​B12 receptor), or transcobalamins.

Anaemia due to folate deficiency Folate deficiency may result from a poor diet, from malabsorption, or when demand for folate is increased, for example during pregnancy or with increased haemopoiesis in haemolytic anaemias or myeloproliferative disorders. Dietary sources of folate are varied, with high amounts in liver, kidney, green vegetables, yeast, nuts, and fruit. Cooking at high temperatures and in large volumes of water largely destroys it. Alcoholics

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whose caloric intake is in large part derived from ethanol are particularly prone to folate deficiency. Folate malabsorption occurs in gluten-​sensitive enteropathy (coeliac disease), and most untreated patients will have low serum and red-​ cell folate levels. Clinical anaemia is more often due to combined iron and folate depletion, but folate deficiency may be sufficiently severe to lead to pure megaloblastic anaemia. Dermatitis herpetiformis may also be associated with folate malabsorption. Less common causes are jejunal resection; partial gastrectomy; extensive Crohn’s disease involving the small bowel; lymphoma; and severe systemic infection. Tropical sprue is an important cause on a worldwide basis.

CHAPTER 279  Deficiency anaemias

Typical symptoms of the disease, and less common symptoms The symptoms and signs of anaemia due to deficiency in iron, vitamin B12, or folate are principally those of any associated anaemia—​tiredness, fatigue, pallor—​and may occasionally presage the development of anaemia. Deficiency of iron or folate is associated with slowed growth and impaired cognitive development in infants and young children, and with premature birth and low birthweight in pregnancy. In addition, folate deficiency is linked to neural tube defects. Severe iron deficiency may also be associated with pica (an abnormal appetite for non-​nutritional substances such as clay, or for food ingredients such as raw meat or vegetables), mucous membrane inflammation affecting the tongue (glossitis) and sometimes the pharynx and oesophagus (Plummer–​Vinson/​Paterson–​Brown–​Kelly syndrome), brittle, ridged nails (koilonychia), or hair loss. Severe vitamin B12 deficiency may be complicated by a symmetrical peripheral neuropathy, with predominant signs in the lower limbs. A  classical and often irreversible complication of vitamin B12 deficiency is subacute combined degeneration of the spinal cord. Psychiatric disturbance and optic atrophy may also occur. Recently, low blood levels of vitamin B12 have been linked to postural hypotension and falls in the elderly in the absence of anaemia. The biochemical basis of these neurological complications is unclear. Low vitamin B12 and folate levels have also been linked to depression. Folate in the 5-​methyltetrahydrofolic acid form is a cosubstrate for methionine synthase in the conversion of homocysteine to methionine; consequently, homocysteine accumulates in folate deficiency and is strongly associated with atherosclerotic vascular disease such as coronary artery disease and stroke.

Demographics of the disease Demographics of iron deficiency Iron deficiency is a worldwide problem, reflecting the heavy physiological demands for iron and its limited bioavailability in many diets. Overall, more than 500  million people are thought to be affected. Even in ‘advanced’ Western societies, around 10% of infants, adolescents, and menstruating women are iron deficient, with anaemia evident in around a quarter of these. Both chronic blood loss and poor diet play a part.

Demographics of folate deficiency Like iron deficiency, folate deficiency is a worldwide problem associated with inadequate nutrition. Dietary lack may be aggravated by previous gastric or abdominal surgery, gastrointestinal disorders such as chronic tropical sprue, and chronic inflammatory conditions, such as rheumatoid arthritis and chronic infections, which appear to inhibit absorption. Pure dietary deficiency may also occur in infants fed goats’ milk (which is very low in folate) as a substitute for mother’s or cows’ milk. Since 1998, food fortification with folic acid has been compulsory in the US, and this has been accompanied by a reduction in the prevalence of low serum folate levels from 16% to 0.5%

Demographics of vitamin B12 deficiency Nutritional vitamin B12 deficiency is much less common than iron or folate deficiency, reflecting the widespread availability of vitamin B12 in all but the strictest vegan diets. However, the risk of developing vitamin

956

B12 deficiency increases with age for a number of reasons, including cognitive dysfunction, social isolation, mobility limitations, and poverty. Pernicious anaemia, which is vitamin B12 malabsorption due to a lack of gastric intrinsic factor, is the commonest form of vitamin B12 deficiency. It is most common in Caucasians of Northern European descent, affecting up to 3% of individuals over 60.

Natural history and complications of the disease Deficiency anaemias are progressive until the deficiency is corrected. As the onset is usually slow, adaptive mechanisms can mitigate the symptoms of anaemia, which in extreme cases may only become symptomatic at very low haemoglobin levels (2–​4 g/​dl). However, anaemia is likely to aggravate coexisting coronary or cerebrovascular disease.

Approach to diagnosing the disease Iron deficiency should be considered in any anaemia that is microcytic, and vitamin B12 or folate deficiency in any anaemia that is macrocytic. The aim of investigation is to establish whether or not a deficiency exists, as well as the underlying cause. The former can usually be achieved by laboratory tests. The latter depends on the clinical picture, so a full clinical history, covering diet as well as bleeding history, together with a full clinical examination (including neurology) is important and will dictate subsequent investigation.

Other diagnoses that should be considered Causes of red-​cell microcytosis and macrocytosis are given in Table 279.1.

‘Gold-​standard’ diagnostic test The diagnosis of deficiency anaemias is made on the basis of the clinical and haematological picture, together with measurement of serum levels of iron, ferritin, and transferrin (iron deficiency); serum and red-​cell folate levels (folate deficiency); and serum vitamin B12 levels (vitamin B12 deficiency). A bone marrow aspirate stained for iron has long been considered the gold-​standard test for iron deficiency, but it is invasive, painful, and rarely justified for this purpose alone. On the other hand, while the blood film may reveal features of megaloblastic anaemia (e.g. macrocytosis, circulating megaloblasts, hypersegmented neutrophils), a bone marrow aspirate may occasionally be necessary to confirm the presence of megaloblastic haemopoiesis in vitamin B12 or folate deficiency, if these features are not unequivocally present.

Acceptable diagnostic alternatives to the gold standard Acceptable diagnostic alternatives to the gold-​standard test for iron deficiency A low serum iron and ferritin, with a raised serum transferrin, is virtually diagnostic of iron deficiency. In practice, the ferritin level is more useful than iron or transferrin levels, although it is an acute phase Table 279.1  Causes of red-​cell microcytosis and macrocytosis Microcytic

Macrocytic

Iron deficiency Anaemia of chronic disease Thalassaemias (alpha and beta) Abnormal haemoglobins (haemoglobin C, S/​C, or E)

Alcohol Pregnancy Reticulocytosis Liver disease Hypothyroidism Liver disease Myeloma Myelodysplasia Cytotoxic drugs Vitamin B12 deficiency Folate deficiency

Acceptable diagnostic alternatives to the gold-​standard test for folate deficiency Folate status is normally assessed by measurement of serum and red-​cell folate concentrations. A normal serum folate more or less excludes significant folate deficiency, but a reduced level does not in itself make a diagnosis of deficiency. This is because serum folate levels reflect recent folate intake and may be depressed after a short period of inadequate intake, while red-​cell folate reflects folate status over the previous 2–​3 months, and a low level is a more reliable indicator of tissue folate depletion. As a single meal can improve a low serum folate level within a few hours, red-​cell folate should be measured in patients who have been admitted to (and fed in) hospital. Low folate levels reflect poor dietary intake or absorption, while high levels may be associated with blind loop syndrome (bacterial production), active liver disease (release of stored folate), or folate supplementation.

Acceptable diagnostic alternatives to the gold-​standard test for vitamin B12 deficiency Serum vitamin B12 levels in megaloblastic anaemia due to vitamin B12 deficiency are usually significantly reduced, and the diagnosis is then straightforward. More difficult to interpret are marginally reduced vitamin B12 levels in the absence of significant anaemia or macrocytosis. This is a fairly common situation in the elderly, who are also prone to falls, a condition which is thought by many to be a consequence of mild, subclinical deficiency. A diagnosis of pernicious anaemia (vitamin B12 malabsorption due to gastric atrophy and intrinsic factor deficiency) as the cause of anaemia due to vitamin B12 deficiency normally rests on the demonstration of a reduced absorption of radioactive vitamin B12 administered orally, and increased absorption when the dose is combined with intrinsic factor—​the Schilling test. However, tougher regulation of medical radioisotope use has all but completely eliminated the availability of this test, and the diagnosis rests on probabilities. The presence of other autoimmune conditions such as thyroid disease and adrenal insufficiency (Addison’s disease), as well as the presence of gastric parietal cell antibodies or intrinsic factor antibodies, are strong pointers to pernicious anaemia being the cause.

Other relevant investigations Less commonly available investigations that may be helpful in diagnosing the presence of deficiency anaemias include: • circulating transferrin receptor levels, which parallel tissue receptor levels and are increased in iron deficiency • serum or urinary hepcidin levels, which are low in iron deficiency but raised in anaemia of chronic disease • methylmalonic acid and homocysteine levels, which may be useful in the evaluation of slightly reduced or low-​normal vitamin B12 or folate levels; a raised methylmalonic acid and/​or homocysteine level gives some support to the diagnosis of vitamin B12 and folate deficiency

Prognosis Deficiency anaemias are usually easily correctable by replacement of the missing substance, so the main determinant of prognosis is the underlying cause.

Treatment and its effectiveness Treatment for iron deficiency In most cases, iron deficiency responds well to oral replacement: ferrous sulfate 200 mg or ferrous fumarate 300 mg daily, raising to twice, and then three times daily if tolerated. In uncomplicated iron deficiency, a rise in haemoglobin of 1 g/​dl per week may be expected. Treatment should continue for 6  months after the anaemia is corrected, in order to replenish iron stores. If this is not done, the risk of recurrence is high. Response to iron therapy may be suboptimal in the presence of infection, inflammation, renal impairment, cancer, or continuing blood loss. Oral iron commonly causes gastrointestinal symptoms such as nausea, epigastric pain, and diarrhoea; in addition, iron supplementation turns the stools black, so that they are commonly mistaken for melaena. Ideally, for maximal absorption, iron should be taken between meals, although side effects are likely to be worse. Concomitant administration of vitamin C improves absorption of a given dose. Alternative oral preparations (liquid, slow release) may cause fewer side effects but are less effective because they contain less iron and/​o r release most of it beyond the duodenum and upper jejunum, where iron is absorbed. In rare cases of complete intolerance or refusal to take oral iron, it may be given intravenously. Earlier IV iron preparations were high-​ molecular-​weight carbohydrate complexes (e.g. iron dextran) and were associated with serious (and sometimes fatal) side effects. Newer preparations such as iron sucrose appear to be more effective and safer.

Treatment of folate deficiency Folate is easily replaced orally in a dose of 5–​15 mg of folic acid daily, with no side effects. IV replacement is necessary, only in patients receiving total parenteral nutrition.

Treatment of vitamin B12 deficiency Vitamin B12 is usually replaced by regular intramuscular injection of hydroxocobalamin, which is available in 1 mg ampoules. This is about 1000 times the normal daily requirement, but this is not a problem as the vitamin is inexpensive and safe, and most of it is excreted in the urine. For this reason, initial treatment should be 1 mg on alternate days for a fortnight and then monthly thereafter.

Indications for blood transfusion There is sometimes a temptation to perform a blood transfusion on a patient with severe or even moderate anaemia that is clearly due to a deficiency in iron, vitamin B12, or folate. This temptation should be resisted in most instances, and is usually only justified if there is ongoing bleeding, when iron replacement may be insufficient to correct the anaemia. Indeed, transfusion may be dangerous:  deficiency anaemias usually develop gradually over weeks or months, giving plenty of time for adaptive mechanisms to develop. Such red cells, that are circulating, are actually highly attuned to optimal oxygen delivery. Transfused red cells are the opposite:  they have been refrigerated, are metabolically inert, and have lost much of their 2,3-​diphosphoglycerate, shifting the oxygen-​dissociation curve in favour of retaining rather than delivering oxygen.

CHAPTER 279  Deficiency anaemias

reactant and is raised in the presence of infection or inflammation. In the presence of microcytic anaemia, a ferritin of 100 μg/​l virtually excludes it. Acute or chronic inflammation, infection, or malignancy can confuse the picture, as these may cause a mild-​to-​moderate anaemia that is normocytic to microcytic with a reduced serum iron but, typically, a raised ferritin and normal or low transferrin—​the anaemia of chronic disease. For this reason, a trial of oral iron therapy should be considered in anaemic patients with a serum ferritin of 50

Major surgery

Variable recommendations >50 to >80

Surgery on the eye or brain

>100

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CHAPTER 282  Platelet disorders 974

DIC

Further Reading

DIC is a clinicopathological diagnosis that requires evidence of a disease process that is known to predispose to DIC, and laboratory tests to support this diagnosis. Treatment for patients who are bleeding involves treating the underlying disease, and transfusing fresh frozen plasma, platelets, and cryoprecipitate as necessary.

Harrison P, Mackie I, Mumford A, et  al. Guidelines for the laboratory investigation of heritable disorders of platelet function. Brit J Haematol 2011; 155: 30–​44. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med 2014; 370: 847–​59.

283 

Normal haemostatic function

Raza Alikhan

Introduction Humans have evolved an intricate system that maintains blood in a fluid state. This relies on an intact vascular endothelium modulating vascular tone and forming a barrier between blood components and reactive subendothelial components. It also involves the production of inhibitors of both blood coagulation and platelet aggregation. In addition, haemostatic systems are primed to convert blood from its fluid state to a solid state, to allow the formation of a haemostatic plug, following vessel injury, to stem the flow of blood from or within a blood vessel. It is convenient to divide these haemostatic processes into: • primary haemostasis: • vasoconstriction • platelet activation and aggregation at the site of vessel injury • secondary haemostasis: • stimulation of protein serine enzyme coagulation pathways, resulting in thrombin generation, and formation of a fibrin clot at the site of vessel injury • fibrinolysis: • a process whereby the size of the fibrin clot is initially limited to the site of injury, by plasmin, and is then broken down once vessel wall healing has occurred It is important to remember that these processes often occur simultaneously, rather than in a stepwise manner. These haemostatic systems exist in a dynamic state of equilibrium in the majority of people, but disturbances in this balance may result in bleeding disorders (see Chapter 284) or thrombotic disorders (see Chapter 285).

Endothelium The normal vascular endothelium maintains blood fluidity by producing inhibitors to platelet aggregation and blood coagulation, by promoting fibrinolysis, and by regulating vascular tone. The endothelium inhibits platelet aggregation by releasing: prostaglandin I2 (PGI2, or prostacyclin) • • nitric oxide (NO) The endothelium inhibits blood coagulation by synthesizing and secreting: thrombomodulin • • heparin sulphate The endothelium promotes fibrinolysis by synthesizing and secreting: tissue plasminogen activator • • urokinase plasminogen activator • plasminogen activator inhibitor In addition to their effects on platelet aggregation, both PGI2 and NO (also known as endothelium-​derived relaxing factor) exert vasodilatory effects on smooth muscle cells in the vessel wall, to modulate vascular tone and help to maintain blood flow.

Platelets Following injury to the blood vessel wall, platelets become activated and begin to aggregate, forming a haemostatic plug to stem the flow of blood. In addition, the platelet phospholipid membrane provides a surface for the assembly of the procoagulant complexes tenase and prothrombinase, which are central to the production of thrombin

and the fibrin clot. Chapter 281 describes normal platelet synthesis and function, including their roles in haemostasis (see Figure 283.1).

Coagulation Historically, the coagulation system has been divided into an extrinsic pathway (tissue factor–​factor VIIa complex) and an intrinsic pathway (contact factors). However, such a division does not occur in vivo. There are essentially two linked phases of coagulation: an initiation phase and a propagation phase (see Figure 283.2). Initiation of clotting arises when tissue factor, expressed on damaged endothelium or activated monocytes, comes into contact with the active form of the vitamin K-​dependent factor VII, factor VIIa. Approximately 1%–​2% of factor VII circulates in the active form. The tissue factor–​factor VIIa complex converts two other vitamin K-​dependent factors, factor IX and factor X, to factor IXa and factor Xa, respectively. Factor Xa cleaves prothrombin and generates a small amount of thrombin, which activates factors V, VIII, and XI. These activated factors are crucial to the development of the tenase and prothrombinase complexes and the propagation phase of coagulation.

Tenase complex Once factor VIIIa is formed, factor IXa, generated by the tissue factor–​factor VIIa complex, combines with factor VIIIa on the platelet phospholipid membrane, in the presence of calcium, to form ‘factor Xase’. This ‘tenase’ complex is the major activator of factor X.

Prothrombinase complex Factor Xa binds to factor Va (which is generated by the small amount of thrombin during the initiation phase). In the presence of calcium and membrane-​bound phospholipids, the ‘prothrombinase’ complex is formed. This prothrombinase complex is 300 000-​fold more active than factor Xa alone in catalysing the conversion of prothrombin and results in a ‘thrombin burst’ that is responsible for more than 95% of the thrombin activity generated. Thrombin has a number of roles in haemostasis. The primary role of thrombin is to cleave fibrinogen to form a fibrin clot. This clot is further stabilized by cross linkage in the presence of factor XIII, which is activated by thrombin. Thrombin activation of factors V, VIII, and XI allow formation of the tenase and prothrombinase complexes.

Inhibition of coagulation The presence of natural anticoagulants regulates and localizes the formation of the haemostatic plug to the site of endothelial damage. Antithrombin (AT), also known as heparin cofactor I, is a serine protease inhibitor (or serpin) that inactivates the serine proteases thrombin (factor IIa) and factors IXa, Xa, and XIa. AT binds irreversibly, via an arginine residue in its active site, to the active serine site of the serine proteases. In the presence of heparin or vessel wall heparan sulphate, a conformational change of AT results in potentiation of its inhibition of thrombin. Congenital deficiency of AT results in a significantly increased risk of venous thromboembolism (VTE; see Chapter 285). Heparin cofactor II, another serpin, can also be activated by heparin or dermatan sulphate and selectively inhibits thrombin (but not factor Xa). Protein Z, a vitamin K-​dependent protein, is a cofactor for the inhibition of factor Xa by Z protease inhibitor.

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VESSEL INJURY

A D H E S I O N

1. Vessel injury leads to exposure of the subendothelial matrix (i.e. collagen).

Initial binding allows the platelet to slow down

3. Now the platelet is moving more slowly, it can bind using other receptors; i.e. GPIV binds to collagen. 4. This causes a conformational change to the receptors GPIIb/IIIa & GPIa/IIa. The platelet adheres strongly.

CHAPTER 283  Normal haemostatic function

2. The platelet binds to vWF using the GPIb receptor. vWF binds to the collagen. These bonds are weak, but slow the platelet down in the vessel.

A C T I V A T I O N

5. The platelet can then bind to vWF and collagen using GPIIb/IIIa and GPIa/IIa respectively. These bonds are much stronger.

Agonists Intracellular changes cause activation of the platelet

6. Platelet agonists such as ADP, thrombin, and TxA2, which are in the surrounding plasma, lead to activation of the platelets.

7. The platelet then undergoes a shape change and ‘spreading’ along the vessel wall, as well as release of its alpha and dense granule contents.

Granule release

A G G R E G A T I O N

8. These reactions lead to recruitment of more platelets, increased generation of thrombin and fibrin, and the formation of a stable clot.

Key platelet collagen vWF GPIb

GPVI GPIIb/IIIa GPIa/IIa fibrinogen

Figure 283.1  The role of the platelet; ADP, adenosine diphosphate; GPIa, glycoprotein Ia; GPIb, glycoprotein Ib; GPIIa, glycoprotein IIa; GPIIb, glycoprotein IIb; GPIIIa, glycoprotein IIIa; GPIV, glycoprotein IV; TXA2, thromboxane A2; vWF, von Willebrand factor.

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Tissue Factor (TF)

FXI FIX

FX FVIIa

FXIa TF-FVIIa

Prothrombin

TENASE FIXa

FVIIIa PROTHROMBINASE FVa

Thrombin

FXIIIa Fibrinogen

Fibrin

Fibrin (cross-linked)

Figure 283.2  Haemostasis pathway; FVa, factor Va; FVIIa, factor VIIa; FVIIIa, factor VIIIa; FIX, factor IX; FIXa, factor IXa; FX, factor X; FXa, factor Xa; FXI, factor XI; FXIa, factor XIa; FXIIIa, factor XIIIa; TF-​FVIIa, tissue factor–​factor VIIa complex.

t-PA, u-PA

PAI-1 & 2

CHAPTER 283  Normal haemostatic function

FXa

Plasminogen activation

Plasminogen

Cross-linked fibrin

Plasmin

α2-Antiplasmin, TAFI

Fibrinogen/fibrin degradation products

t-PA –tissue plasminogen activator, u-PA –urokinase plasminogen activator, PAI –plasminogen activator inhibitor, TAFI –thrombin activatable fibrinolysis inhibitor Figure 283.3 The fibrinolysis pathway; PAI, plasminogen activator inhibitor; TAFI, thrombin- activatable brinolysis inhibitor; t- PA, tissue plasminogen activator; u-PA, urokinase plasminogen activator.

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CHAPTER 283  Normal haemostatic function

Thrombomodulin forms a complex with thrombin and enhances thrombin’s activation of protein C. Protein C, a vitamin K-​dependent protein, is activated by thrombomodulin to activated protein C (APC) and inhibits factors Va and VIIIa. Hereditary resistance to APC (factor V Leiden) arises due to a mutation in factor V, which prevents APC from inactivating factor Va. This results in a procoagulant state and is associated with an increased risk of VTE (see Chapter 285). Protein S, a vitamin K-​dependent protein, is a cofactor for activated protein C.  Protein S deficiency is also associated with an increased risk of VTE (see Chapter 285). Tissue factor pathway inhibitor (TFPI) inhibits both the tissue factor–​factor VIIa complex and the conversion of factor X to factor Xa. TFPI may serve a potentially crucial role in maintaining the endothelium in a thromboresistant state. However, unlike the case with the other natural anticoagulants, an inherited deficiency of TFPI with an increased risk of VTE has not yet been described. Alpha-​2 antiplasmin is the primary inhibitor of plasmin. It limits the fibrinolytic response and allows the haemostatic plug to remain intact until healing has occurred. Deficiency of alpha-​2-​antiplasmin results in dissolution of the haemostatic plug before healing is complete and results in a haemorrhagic disorder. Alpha-​ 2-​ macroglobulin is a secondary or backup inhibitor for plasmin and thrombin. No clinical disorder of alpha-​2-​macroglobulin deficiency has yet been described.

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The fibrinolytic system The fibrinolytic system contributes to the localization of the haemostatic plug to the site of vessel injury and ensures that the clot is removed once healing has occurred.

During the initial period of haemostatic plug formation, platelets and endothelial cells release plasminogen activator inhibitors 1 and 2, alpha-​2 antiplasmin, alpha-​2 macroglobulin, and thrombin activatable fibrinolysis inhibitor, which facilitate fibrin formation by inhibiting both the conversion of plasminogen and the action of plasmin (see Figure 283.3). By a poorly understood but timely orchestrated process, tissue plasminogen activator and, to a much lesser extent, urokinase plasminogen activator convert plasminogen to the serine protease active form, plasmin, by cleavage of a single peptide bond. Both fibrinogen and fibrin are substrates for plasmin, leading to the production of specific fragments collectively known as fibrinogen/​fibrin degradation products. Cleavage of fibrinogen produces transient X fragments, which degrade into D and E fragments. Cleavage of fibrin leads to a different pattern of fragments, because of the cross linkage of fibrin by factor XIIIa. These fragments, DY, YY, and DD (D-​dimer), are characteristic of fibrin breakdown. The measurement of D-​dimer levels has been incorporated into clinical decision models for the diagnosis of VTE. Normal D-​dimer levels in a patient with a low clinical probability of VTE can be used to exclude the presence of deep vein thrombosis or pulmonary embolism, without the need for further investigation.

Further Reading Mackie I, Cooper P, Lawrie A, et  al. Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis. Int J Lab Hem 2013; 35: 1–​13 Versteeg HH, Heemskerk JWM, Levi M, et al. New fundamentals in hemostasis. Physiol Rev 2013; 93: 327–​58. Wahad A. Coagulation: the bare essentials. http://hemepathreview. com/Heme-Review/Chap26-Coagulation.pdf

284 

Bleeding disorders

Raza Alikhan

Introduction From the rabbinical writings in the second century AD, to the spread of haemophilia within the royal families of Europe, there have been reports of bleeding disorders throughout history. The most common inherited bleeding disorders are haemophilia and von Willebrand’s disease. There are also a number of rarer inherited bleeding disorders, which are summarized in Table 284.1.

Haemophilia Definition of haemophilia Haemophilia, from the Greek haima (‘blood’), and philia (‘friend’), is the most common of the severe bleeding disorders. Haemophilia A and B arise as a result of deficiencies of factors VIII and IX, respectively, and are inherited in an X-​linked recessive fashion.

Aetiology of haemophilia The factor VIII gene, F8, is located on the long arm of the X chromosome (Xq28). It is a large gene, spanning 186 000 base pairs of DNA, and is comprised of 26 exons. This accounts for its greater risk of mutation, compared with the gene for factor IX, F9, which is also

located on the long arm of the X chromosome (Xq27), but is only 34 000 base pairs long. A number of mutations have been described in F8. The most common is the Intron 22 inversion mutation, which occurs in 20% of haemophilia A patients, and always produces severe disease, accounting for up to 50% of cases of severe haemophilia A.

Typical symptoms of haemophilia, and less common symptoms Affected haemophiliac males suffer from joint and muscle bleeds, as well as easy bruising, the severity of which is closely related to the concentration or level of activity of the affected coagulation factor (see Table 284.2). Haemophilia A and B have an identical presentation, and can only be distinguished by measuring the specific factor levels. Although factor VIII or IX deficiency is present at birth, spontaneous bleeding during the neonatal period is uncommon. Children with severe haemophilia tend to present this within the first year of life. In contrast, those suffering with mild or moderate haemophilia may not present with symptoms until adolescence or adulthood. The most common presenting symptoms are oral bleeding, either when teeth begin to erupt at age 6–​9 months, or associated with a bitten tongue or lip. Bleeding from the frenulum of the upper or lower lip is

Table 284.1  Rare coagulation disorders Deficiency

Diagnosis

Treatment

Prevalence

Genetics

Factor I (fibrinogen)

↑ PT ↑ APTT ↑ TT ↓ Fibrinogen

Fibrinogen concentrate Cryoprecipitate

1 in 1 000 000

Autosomal recessive Chromosome 4

Factor II (prothrombin)

↑ PT ↑ APTT ↓ Factor II

Prothrombin complex

1 in 2 000 000

Autosomal recessive Chromosome 11

Factor V

↑ PT ↑ APTT Normal TT ↓ Factor V

Fresh frozen plasma

1 in 1 000 000

Autosomal recessive Chromosome 1

Combined Factor V + Factor VIII

↑ PT ↑ APTT ↓ Factor V ↓ Factor VIII

Fresh frozen plasma + Factor VIII concentrate

1 in 1 000 000

Autosomal recessive Chromosome 18

Factor VII

↑ PT Normal APTT ↓ Factor VII

Recombinant Factor VIIa (Novoseven)

1 in 500 000

Autosomal recessive Chromosome 13

Factor X

↑ PT ↑ APTT Normal TT ↓ Factor X

Prothrombin complex

1 in 1 000 000

Autosomal recessive Chromosome 13

Factor XI

Normal PT ↑ APTT Normal TT ↓ Factor XI

Factor XI concentrate

1 in 1 000 000

Autosomal recessive Chromosome 4

Factor XIII

Normal PT Normal APTT ↓ Factor XIII

Factor XIII concentrate

1 in 1 000 000

Autosomal recessive Chromosome 6

Abbreviations: APTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time.

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CHAPTER 284  Bleeding disorders

Table 284.2  Presentations of haemophilia Severity of haemophilia

Activity of coagulation factor

Presentation

Severe

5 to 1%) suffer from significantly less spontaneous bleeds; the aim of prophylactic treatment is to maintain trough factor levels above 1 IU/​dl Once bleeding has started, it is important to raise factor VIII or factor IX to a haemostatic level, with the appropriate factor replacement concentrate, to arrest bleeding and prevent complications. Factors VIII and IX are currently available as both plasma-​derived and recombinant factor concentrates. For patients presenting with a joint bleed, the aim of treatment is to raise the level of factor VIII or factor IX to above 50 IU/​dl; for a major bleed, such as ICH, the aim is to raise factor levels above 100 IU/​dl. In addition to factor replacement, the ‘PRICE regime’ is recommended following an acute bleed: • P (protection):  reduced weight bearing on the affected joint or muscle for the first 24–​48 hours • R (rest): the affected area should initially be rested completely; this allows swelling to settle and prevents further bleeding • I  (ice):  helps to reduce swelling, prevents further bleeding, and eases pain • C (compression):  due to increased volumes of fluid, the more swollen an affected area, the more painful it becomes; compression reduces swelling and eases pain • E (elevation): this also helps to reduce swelling and reduces blood flow to the affected area

von Willebrand’s disease Definition of von Willebrand’s disease von Willebrand’s disease is a bleeding disorder caused by inherited defects in the concentration, structure, or function of vWF. vWF has two essential functions: • primary haemostasis: vWF enables platelets to adhere to injured vascular endothelium, and then to form platelet aggregates

• secondary haemostasis: vWF binds to and stabilizes factor VIII; in the presence of vWF, the half-​life of factor VIII is 8–​12 hours; in its absence, it is 15 minutes • oral cavity bleeding, such as gingival bleeding, bleeding with tooth eruption, or bites to lips and tongue, that requires medical attention • heavy, prolonged, or recurrent bleeding after dental extraction, tonsillectomy, or adenoidectomy • menorrhagia not associated with structural lesions of the uterus Preliminary investigations include: • full blood count:  the platelet count should always be performed when investigating a suspected bleeding disorder; patients with type 2B von Willebrand’s disease may have a moderate thrombocytopenia • APTT:  this is often prolonged in von Willebrand’s disease; however, a normal APTT does not exclude a diagnosis of von Willebrand’s disease • prothrombin time, thrombin time, and fibrinogen are all normal in von Willebrand’s disease • PFA-​100: this allows a rapid and simple determination of platelet-​ vWF function; it simulates primary haemostasis in the high sheer stress environment that occurs after small vessel injury

Other diagnoses that should be considered aside from von Willebrand’s disease Platelet-​type (pseudo-​) von Willebrand’s disease is a rare disorder resulting from mutations that affect the platelet glycoprotein Ib/​glycoprotein IX receptor complex and causes increased binding between vWF and platelets (i.e. the defect is in the platelets rather than in vWF). Laboratory findings are similar to those found for type 2B von Willebrand’s disease (thrombocytopenia, increased ristocetin-​ induced platelet aggregation (RIPA), and decreased HMW multimers). Therefore, to differentiate type 2B von Willebrand’s disease from pseudo-​von Willebrand’s disease, cryoprecipitate (containing normal vWF) is added to the patient’s plasma; it will result in aggregation of platelets in pseudo-​von Willebrand’s disease, but not in type 2B von Willebrand’s disease.

‘Gold-​standard’ diagnostic test for von Willebrand’s disease There is no single diagnostic test for von Willebrand’s disease; it requires a series of tests to be performed and interpreted in a stepwise manner, as described in Figure 284.3. • Factor VIII functional assay: factor VIII is frequently reduced in von Willebrand’s disease, as the half-​life of this factor is regulated by vWF

CHAPTER 284  Bleeding disorders

Plasma vWF Ag

Normal/Reduced vWF Ag

Undetectable vWF Ag

FVIII:C and vWF RiCof and/or vWF CBA

Type 3 vWD

vWF CBA : vWF Ag vWF RiCOf : vWF Ag > 0.6 Confirm diagnosis by FVIII:vWF binding assay

Type 2N vWD

< 0.6

Type 1 vWD

Type 2 vWD

Measure RIPA & vWF multimers Multimers

Increase sensitivity to RIPA Absent HMW Multimers

Type 2B vWD

Type 2M vWD

Type 2A vWD

vWF: von Willebrand factor, FVIII: factor VIII, RiCof: risctoceitin cofactor; CBA: collagen binding activity; RIPA: ristocetin induced platelet aggregation Figure 284.3  Sequence of tests in the diagnosis of von Willebrand’s disease subtypes; Ag, antigen; CBA, collagen-​binding activity; FVIII, factor VIII; FVIII:C, factor VIII antigen; HMW, high molecular weight; RiCof, risctoceitin cofactor; RIPA, ristocetin-​induced platelet aggregation; vWD, von Willebrand’s disease; vWF, von Willebrand factor.

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Treatment of von Willebrand’s disease, and its effectiveness Desmopressin (1-​deamino-​8-​d-​arginine vasopressin; Desmopressin) is a synthetic analogue of vasopressin. It causes vWF to be released from endothelial stores, and increases factor VIII and vWF levels to 3–​5 times their baseline level, 30–​60 minutes after IV or subcutaneous administration. Side effects include headache, facial flushing, hypotension, and hyponatraemia. It should be avoided in patients with cardiovascular disease, as it has been associated with myocardial infarction and stroke. Desmopressin (0.3 μg/​kg) is most effective in patients with type 1 von Willebrand’s disease, where increasing levels by three-​to fivefold is sufficient for haemostasis. It is of no use in type 3 von Willebrand’s disease. Patients with type 2 von Willebrand’s disease have a variable response, and a trial of Desmopressin should be considered in type 2A and 2M von Willebrand’s disease. Desmopressin is usually avoided in patients with type 2B von Willebrand’s disease, because it appears to exacerbate thrombocytopenia. Tranexamic acid is an antifibrinolytic agent that binds to the lysine-​ binding sites of plasminogen and therefore inhibits the binding of

plasminogen to fibrin. Like desmopressin, it is useful for the management of epistaxis and menorrhagia and following dental extraction. It can be given orally (15–​25 mg/​kg three times per day), intravenously (10 mg/​kg three times per day), or as a mouthwash (10 ml of a 5% solution four times per day). Patients unresponsive to desmopressin require transfusion with vWF/​factor VIII concentrates derived from plasma, as there is no recombinant vWF currently available. There are a number of vWF/​f actor VIII concentrates available: Haemate P, Alphanate, and Fanhdi. The aim of treatment is to raise the vWF:RiCof and factor VIII levels to above 100 IU/​dl for a major surgical procedure, or to treat a significant bleed. The vWF:RiCof and factor VIII levels are then maintained above 50 IU/​dl until wound healing has occurred.

Rare inherited bleeding disorders Rare coagulation disorders are outlined in Table 284.1.

Further Reading Berntorp E and Shapiro AD. Modern haemophilia care. Lancet 2012; 379: 1447–​56. GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA 2nd edition Prepared by the Treatment Guidelines Working Group, on behalf of the World Federation of Hemophilia (WFH) http:// www1.wfh.org/publications/files/pdf-1472.pdf Laffan MA, Lester W, O’Donnell JS, et al. The diagnosis and management of von Willebrand disease: A United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Brit J Haematol 2014; 167: 453–​65. Leebeek FW and Eikenboom JC. Von Willebrand’s Disease. N Engl J Med 2016; 375: 2067–​80. Mumford AD, Ackroyd S, Alikhan R, et al. Guideline for the diagnosis and management of the rare coagulation disorders: A United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology. Brit J Haematol 2014; 167: 304–​26. Peyvandi F, Garagiola I, Young G. et al. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016; 388: 187–​97.

CHAPTER 284  Bleeding disorders

• vWF antigen (vWF:Ag):  vWF antigen levels are measured by immunological methods, such as ELISA assays • vWF ristocetin cofactor activity (vWF:RiCof ): addition of the antibiotic ristocetin promotes the binding of vWF to platelet glycoprotein Ib; this is a functional assay, rather than an antigen assay (like vWF:Ag), which only measures the level of vWF present vWF collagen-​ binding activity:  this is another functional assay RIPA:  in this assay, ristocetin is added at several concentrations (ranging from 0.2 to 1.5 mg/​ml) to platelet-​rich plasma from the patient, to assess the affinity of vWF for platelets by determining the lowest ristocetin concentration that induces agglutination; aggregation at concentrations upper) Pain; no specific characteristics; the location of the pain is not necessarily related to the site of thrombosis; it varies from: aching to cramping • dull to sharp • mild to severe • Swelling Tender Red skin

Homans’ sign: pain in the calf on forced dorsiflexion • Lowenberg’s sign • pain in the calf on inflation of cuff to 180 mm Hg at the thigh • Moses’ sign: pain from compression of calf in a forward/​backward motion is greater • than that from lateral compression Unilateral pitting oedema Tender to palpation Erythema, if associated inflammation

Splanchnic vessels (hepatic, portal, mesenteric veins) Upper abdominal pain: all patients present with a varying degree of this very non-​specific symptom • sudden onset of pain/​post-​prandial abdominal pain is suggestive of • mesenteric artery thrombosis gradual onset of pain is more suggestive of venous thrombosis • Nausea + vomiting Bloody stools

Abdominal pain + hepatomegaly + ascites: need to consider obstruction of the hepatic vein: Budd–​Chiari syndrome • Splenomegaly portal vein thrombosis • portal hypertension •

Headache Lethargy Fits Stroke Coma

Focal neurological signs

Pulmonary embolism Chest pain: often pleuritic in nature, worse on deep inspiration • Dyspnoea: subjective experience of hampered breathing • Haemoptysis Cough

• elevation of the platelet count; if present, consider essential thrombocythaemia, or a cause of reactive thrombocytosis, such as sepsis or malignancy • reduction of the platelet count: this may be a feature of drug-​ induced thrombocytopenia (due to heparin), thrombotic thrombocytopenia purpura (TTP), SLE, or PNH • a blood film; look for red cell fragments, as these may indicate DIC or TTP • the following coagulation tests: • prothrombin time • APTT, using a lupus sensitive reagent; this will provide an initial screen for the presence of a lupus anticoagulant • fibrinogen: to screen for dysfibrinogenaemia The following tests may also be requested, depending on the suspected clinical disorder: • special coagulation tests, such as: • protein C activity (followed by protein C antigen level if the activity is low) • protein S activity (followed by free protein S antigen level if the activity is low; the total protein S antigen level may be helpful if the level of free protein S antigen is low) • AT activity • the APC resistance ratio; if the ratio is abnormal (low), test for the FVL mutation • a test for the prothrombin G20210A mutation • selective special tests, such as: • tests for anticardiolipin and anti-​beta-​2-​glycoprotein 1 antibodies (IgG and IgM), to exclude APS • tests for platelet anti-​ PF4/​ glycosaminoglycan antibodies, to exclude heparin-​induced thrombocytopenia

Circulatory collapse: right ventricular dysfunction • Tachypnoea: objective observation of increased respiratory rate • Hypoxia Tachycardia

• a test for the JAK2 mutation, to exclude myeloproliferative disorder (portal or splanchnic vein thrombosis) • a test for plasma ADAMTS13 activity, to exclude acquired or familial TTP • flow cytometry, to detect PNH

CHAPTER 285  Prothrombotic conditions

Cerebral vein thrombosis

In addition, the following selective general tests may be requested: renal function tests • • liver function tests: • abnormal results occur in the Budd–​Chiari syndrome, which is characterized by ascites, hepatomegaly, and obstruction of the hepatic venous circulation • hypoalbuminaemia occurs in nephrotic syndrome • urinalysis: • protein, to exclude nephrotic syndrome • bilirubin, to exclude PNH In addition, if associated symptoms are suggestive of malignancy, the following tests may be requested: • tests for tumour markers (e.g. prostate-​specific antigen, carcinoembryonic antigen, cancer antigen 125) • imaging: • chest X-​ray • ultrasound of abdomen/​pelvis • CT abdomen/​pelvis

‘Gold-​standard’ diagnostic test The gold-​standard diagnostic test for DVT (upper or lower limb) is venography. The gold-​standard diagnostic test for cerebral and splanchnic vein thrombosis is magnetic resonance angiography. The

987

gold-​standard diagnostic test for pulmonary embolism (PE) is pulmonary angiography. Thrombophilia testing should not be performed during an acute thrombotic episode because interpretation during such an event is difficult, as levels of e.g. protein C or S are affected by the present of thrombosis and anticoagulants. In addition, note that thrombophilia results do not alter the initial treatment.

CHAPTER 285  Prothrombotic conditions

Acceptable diagnostic alternatives to the gold standard

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Table 285.7  Duration of anticoagulation for specific clinical conditions Condition

Duration

Target INR (range) for warfarin

First idiopathic VTE: proximal DVT or PE

>3 months*

2.5 (2.0–​3.0)

First proximal DVT or PE, with precipitating factors (e.g. surgery, trauma, pregnancy)

3 months

2.5 (2.0–​3.0)

First idiopathic calf DVT

3 months

2.5 (2.0–​3.0)

First calf vein DVT, with precipitating factors (e.g. surgery, trauma)

6 weeks to 3 months

2.5 (2.0–​3.0)

Recurrent VTE

Long term

2.5 (2.0–​3.0)

VTE while on warfarin

Long term

3.5 (3.0–​4.0)

Acceptable diagnostic alternatives to the gold-​standard test for DVT are Doppler ultrasound and compression ultrasound. MRI is an acceptable diagnostic alternative to the gold-​standard test for cerebral vein thrombosis. Acceptable diagnostic alternatives to the gold-​ standard test for splanchnic vein thrombosis are Doppler ultrasound and CT. Acceptable diagnostic alternatives to the gold-​standard test for PE are CT pulmonary angiography and ventilation/​perfusion scintigraphy (also known as a V/​Q scan).

Abbreviations: DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; VTE, venous thromboembolism. *Patients with unprovoked DVT or PE should be treated for a minimum of 3 months. After 3 months, all patients should be evaluated for the risk–​benefit ratio of long-​term treatment. Patients with unprovoked VTE and in whom risk factors for bleeding are absent and good anticoagulant monitoring is achievable should receive long-​term treatment.

Treatment and its effectiveness

Further Reading

The initial treatment of VTE should be with a rapidly acting anticoagulant such as:

Connors JM. Thrombophilia testing and venous thrombosis. N Engl J Med 2017; 377: 2298. Martinelli I, De Stefano V, and Mannucci PM. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 2014; 11: 140–​56. Piazza G. Thrombophilia testing, recurrent thrombosis, and women’s health. Circulation 2014; 130: 283–​7. Trousseau A. ‘Phlegmasia alba dolens’, in Clinique Medicale de l'Hotel-​ Dieu de Paris, 1865. JB Balliere et Fils. Watson HG, Keeling DM, Laffan R, et  al. Guideline on aspects of cancer-​ related venous thrombosis. Br J Haematol 2015; 170: 640–​8. Sciascia S, Baldovino S, Schreiber K et  al. Thrombotic risk assessment in antiphospholipid syndrome: the role of new antibody specificities and thrombin generation assay. Clin Mol Allergy 2016; 14: 6.

unfractionated heparin (UFH) • • low-​molecular-​weight heparin (LMWH) • fondaparinux Selected patients with extensive acute proximal DVT but who have a low risk of bleeding, and patients with PE and haemodynamic compromise, should be considered for catheter-​directed or systemic thrombolysis. Vena caval filters should not be used routinely and are only indicated for patients in whom anticoagulation is contraindicated. In addition to UFH, LMWH, or fondaparinux, a vitamin K antagonist (e.g. warfarin) or direct-​acting oral anticoagulant should be started, with duration of treatment as given in Table 285.7.

286 

Acute leukaemia

Graham Collins and Chris Bunch

Definition of the disease Acute leukaemia is a rapidly progressive, clonal haematopoietic stem cell disorder resulting in the accumulation of immature blood cell precursors (known as blasts) in the bone marrow. There are two main types of acute leukaemia: • acute myeloid leukaemia (AML), which is defined by the presence of myeloid lineage markers on the blast cells • acute lymphoblastic leukaemia (ALL), which is defined by the presence of lymphoid markers on the blast cells Occasionally, the blast cells express markers from both lineages. Such cases are referred to as ‘biphenotypic’.

Aetiology of the disease AML is associated with a number of predisposing factors: • other haematological conditions such as myelodysplasia or myeloproliferative conditions can transform into AML • previous chemotherapy agents predispose to AML (e.g. topoisomerase II inhibitors, alkylating agents) • toxins (e.g. benzene) • ionizing radiation • inherited predisposition:  Down’s syndrome is associated with a significantly increased risk of developing a rare subtype of AML called acute megakaryoblastic leukaemia Frequently, however, no etiological factors can be identified. ALL can also arise from chronic myeloid leukaemia and is also associated with Down’s syndrome. In the vast majority of cases, no cause can be identified.

Typical symptoms of the disease, and less common symptoms Acute leukaemia frequently presents with symptoms and signs of bone marrow failure: anaemia: fatigue, shortness of breath, headache, palpitations • • leucopenia: bacterial or fungal infections • thrombocytopenia: purpuric rash, mucosal haemorrhage In children, a very important symptom of ALL is bone pain, which can often be rather vague and simply present as a limp. Less commonly, a very high white-​cell count can cause symptoms of leucostasis: shortness of breath, retinal haemorrhages, confusion, and priapism. In certain forms of leukaemia, disseminated intravascular coagulation can result in catastrophic haemorrhage and, in other forms, tissue infiltration by blast cells can produce gum hypertrophy, skin lesions (called chloromas), organomegaly, and lymphadenopathy.

Demographics of the disease Demographics of ALL ALL is the commonest childhood cancer, although, overall, it is an uncommon disease. ALL accounts for only 20% of adult acute leukaemia. In childhood, there is a clear peak in incidence between 1 and 6 years of age with the highest incidence between ages 2 and 3. In adults, the incidence increases with age. Childhood ALL is 30% more frequent in boys than in girls.

Demographics of AML The incidence of AML peaks between 60 and 70 years of age; 80% of cases are diagnosed in the over-​50 group. It also can occur in children, although it is uncommon in that age group.

Natural history, and complications of the disease Acute leukaemia is a rapidly progressive condition which rapidly causes deterioration and death if left untreated. Progressive bone marrow failure causes worsening anaemia with subsequent organ failure, increased risk of severe haemorrhage, and a high risk of life-​ threatening bacterial and fungal infections. Numerous complications are associated with the treatment of the disease. Potentially curative chemotherapy is intensive and associated with hair loss, fatigue, gastrointestinal disturbances, reduced fertility, and specific organ damage. The most frequent complication encountered is infection. Prolonged episodes of neutropenia result in a high risk of invasive bacterial infections (especially with Pseudomonas and other Gram-​ negative bacteria, although the incidence of Gram-​ positive sepsis is increasing) and fungal infections (especially with Aspergillus). In ALL, high-​dose steroids form an integral part of treatment but frequently result in infections, mood swings, and bony avascular necrosis. In acute leukaemia patients with very high white counts, tumour lysis syndrome (TLS) is a potential complication in which biochemical disturbances caused by rapid cell death, such as hypocalcaemia, hyperkalaemia, hyperuricaemia, and hyperphosphataemia, are seen. Renal failure may ensue unless prompt action is taken. Treatment is focused on prevention by identifying at-​risk patients, initiating IV fluids, and using allopurinol or rasburicase (recombinant urate oxidase). Treatment of established TLS is by correcting clinically important biochemical disturbances and possibly initiating renal dialysis. In some patients, an allogeneic stem cell transplant is offered as part of the treatment strategy. In addition to infection, graft-​vs-​host disease (GvHD) is an important complication of this procedure. Acute GvHD (within 100  days of the transplant) typically causes a rash, diarrhoea, and jaundice. GvHD is also immunosuppressive and is frequently complicated by bacterial, fungal, and/​or viral infections, including reactivation of CMV. Chronic GvHD (after 100 days from the transplant) can result in numerous manifestations such as mouth ulcers, sclerodermatous skin changes, pulmonary involvement, and neuropathies.

Approach to diagnosing the disease Acute leukaemia should be considered in the following clinical situations: • rapidly falling blood counts (more than one lineage involvement should raise suspicion further) • a rapidly rising white-​cell count with blasts seen on the blood film • deterioration of a previously stable haematological condition (e.g. a rapidly enlarging spleen in a patient with chronic myeloid leukaemia or myelofibrosis) • a child who is non-​specifically unwell and has vague bony symptoms or signs (such as a mild limp)

989

Other diagnoses that should be considered A serious underlying infection or solid tumour can cause a reactive blood picture associated with circulating immature blood cell precursors, including blast cells. This is called a ‘leukaemoid reaction’, and care should be taken not to diagnose acute leukaemia in these cases. Acute viral infections such as infectious mononucleosis frequently result in atypical lymphocytes being seen on a blood film. Occasionally, these can be hard to distinguish from blast cells. A bone marrow aspirate in these cases can also be hard to distinguish from acute leukaemia. Clinicians should have a low threshold for performing a monospot test.

‘Gold-​standard’ diagnostic test Acute leukaemia is a disorder of the bone marrow, and accurate diagnosis requires a bone marrow biopsy; an aspirate will often suffice, although a trephine may be helpful in some situations. Morphological examination will give a diagnosis of acute leukaemia but immunophenotyping (by flow cytometry or immunohistochemistry) will allow accurate subtyping.

CHAPTER 286  Acute leukaemia

Acceptable diagnostic alternatives to the gold standard In some cases (particularly when curative treatment is not appropriate), sufficient diagnostic material may be obtained from the peripheral blood. Although superseded by immunophenotyping, cytochemistry is an acceptable alternative to enable accurate subtyping.

Other relevant investigations Other relevant investigations for acute leukaemia include: • a full blood count: to determine the extent of bone marrow failure or leucocytosis; a blood film may or may not show circulating blast cells • a coagulation screen: some acute leukaemias (especially acute promyelocytic leukaemia) may present with disseminated intravascular coagulation • a blood group and antibody screen:  blood transfusion is highly likely due to the disease or its treatment • biochemistry:  patients may be acutely unwell at diagnosis, with renal and/​or liver impairment; renal impairment increases the risk of TLS • serum calcium: may be elevated in a subset of patients • inflammatory markers: may indicate an underlying infection • viral serology including monospot: to exclude acute viral infection in the differential • serum urate: raised levels increase the risk of TLS • cytogenetics (preferably from a bone marrow aspirate): can provide important prognostic information  from  molecular testing which looks for certain genetic mutations and is also important in prognostication and in guiding subsequent disease monitoring and treatment • septic screen, including blood cultures, chest X-​ray, urinalysis • ECG: in preparation for receiving cytotoxic chemotherapy

Prognosis and how to estimate it When acute leukaemia is diagnosed in a patient who is unfit for potentially curative treatment, life expectancy is in the order of a few months to a few years. In younger adults with acute leukaemia, intensive chemotherapy with or without allogeneic stem cell transplantation results in 5-​year survival rates of approximately 40%. In children, intensive treatment of ALL results in long-​term remission rates of 80%. In childhood ALL, a number of parameters indicate prognosis. Factors associated with a worse prognosis include: • male sex

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age 9 years of age • • white-​cell count at diagnosis of >50 × 109/​l • CNS involvement • certain cytogenetic findings (e.g. Philadelphia chromosome, complex karyotype, low hypodiploidy, t(4:11), t(8:14)) • poor response to initial treatment, as assessed by clearance of blasts from the bone marrow, or failure to eliminate the presence of minimal residual disease, as assessed by molecular techniques For AML, poor prognostic factors include: increasing age and comorbidities • • cytogenetic features (e.g. complex karyotype, monosomy 5 or 7, abnormal 3q) • antecedent myelodysplastic syndrome or myeloproliferative disease • specific genetic mutations, such as internal tandem duplications involving the FLT3 gene • poor response to initial chemotherapy

Treatment and its effectiveness Wherever possible, patients with any malignancy should be treated within the context of a clinical trial. This is especially true in acute leukaemia, for which national clinical trials are designed to incorporate the broadest possible spectrum of patients, including childhood ALL, adult ALL, adult AML, and elderly AML.

Treatment of ALL Treatment of ALL typically consists of three main phases: • remission induction:  this uses agents such as corticosteroids (prednisolone or dexamethasone), vincristine, asparaginase, and daunorubicin • intensification:  this involves multidrug chemotherapy regimens, including treatment directed to the CNS; agents used include cyclophosphamide, cytarabine, etoposide, and methotrexate • maintenance: this phase of treatment lasts for 2 years in girls, and 3 years in boys; typical regimens include daily oral mercaptopurine, weekly oral methotrexate, and occasional IV vincristine Approximately 80% of children achieve long-​ term remission, although the figure is much less in adults. Current clinical trials are aimed at using the technique of minimal residual disease (a genetic test which can pick up very small amounts of residual leukaemia) to identify those patients who are responding well to treatment and those that are responding poorly. Poor responders may benefit from intensification of treatment, and good responders may benefit from de-​escalation.

Treatment of AML Potentially curative treatment of AML involves one or two courses of remission induction chemotherapy followed by one or two courses of consolidation chemotherapy. In fit patients with a poor prognosis and with a suitable donor, allogeneic bone marrow transplant may form part of the consolidation. Standard induction chemotherapy generally consists of cytarabine and daunorubicin. Alternative agents include fludarabine and idarubicin. Induction and consolidation chemotherapy is intense and associated with profound myelosuppression. Most patients have a central venous cannula (such as a Hickman line) to avoid repeated venepuncture and peripheral cannula insertion. Most patients achieve an initial remission with standard chemotherapy, although relapse remains a major problem. Allogeneic bone marrow transplantation is the most effective strategy for prevention of relapse, as demonstrated by a number of studies. However, the treatment-​related mortality of these procedures is high and limits their use to relatively young and fit patients and to those with a suitable donor. Conventional allogeneic transplants involve high-​dose chemotherapy, often with total body irradiation. The intensity of the regimen limits its use to those aged under

Further Reading Döhner H, Estey E, Grimwade D et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129: 424–47. Guidelines and management recommendations of the European Leukaemia Net (http://​www.leukemia-​net.org/​content/​physicians/​ recommendations/​index_​eng.html) Guidelines and management recommendations of the American Society of Hematology (http://​www.hematology.org) Terwilliger T and Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J 2017; 7: e577.

CHAPTER 286  Acute leukaemia

45. More recent developments include the use of reduced-​intensity conditioning transplants which utilize conditioning protocols which are better tolerated. The efficacy of these procedures relies on a graft-​vs-​leukaemia effect. In patients unfit for standard chemotherapy, supportive care or low-​dose cytarabine are options. The focus of clinical trials is shifting towards targeting specific types of AML, using small molecule inhibitors of deregulating cellular pathways. Alternatively, monoclonal antibodies are being used to deliver chemotherapy in a more targeted way.

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287 

Chronic leukaemia

Chris Bunch

Definition of the disease Leukaemia is, in broad terms, a ‘cancer of the blood’. However, this is inaccurate, as the malignant process primarily occurs outside of the bloodstream. In acute leukaemias, it occurs in the bone marrow within immature blood-​forming cells. In the two forms of chronic leukaemia, leukaemogenesis occurs in two completely different cell types (and possibly even two different anatomical sites), leading to two very different forms of the disease: chronic myeloid leukaemia (CML) and chronic lymphocytic leukaemia (CLL). CML is best thought of as a myeloproliferative disorder. It is a clonal disorder of the haematopoietic stem cell, leading to overproduction of the myeloid cells: neutrophils and their precursors, basophils and eosinophils. CLL is best thought of as a low-​grade lymphoma. It is a clonal disorder of mature B-​lymphocytes (possibly memory B-​cells). The site of initiation of this disorder is unclear; it could be within lymph nodes or within the bone marrow.

Aetiology of the disease Aetiology of CML A higher incidence of CML is associated with heavy radiation exposure but this applies to the minority of patients. CLL is the only leukaemia that is not associated with radiation exposure and it also shows the strongest degree of familial clustering, although, again, this applies to the minority. Much is understood of the pathobiology of CML. CML was the first malignant disease in which a recurrent chromosomal translocation was described, between Chromosomes 9 and 22. This forms an abnormal derivative chromosome termed the Philadelphia chromosome. At the molecular level, this leads to the juxtaposition of the 3′ end of the c-​ABL proto-​oncogene on Chromosome 9 with the 5′ end of the BCR gene from Chromosome 22. This fusion gene is transcribed and produces a constitutively active tyrosine kinase. This protein then phosphorylates a number of substrates, leading to changes in cell proliferation, differentiation, adhesion, and survival. Interestingly, mouse models indicate that the Philadelphia chromosome is both necessary and sufficient for the development of CML. The result is an inappropriate expansion of the myeloid component of the bone marrow. This leads to an increasing white-​cell count and, often, pronounced splenomegaly.

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Typical symptoms of the disease, and less common symptoms Symptoms of CML CML typically presents with one or more of the following: systemic symptoms: anorexia, weight loss, sweats • • symptoms of splenomegaly:  abdominal bloating, early satiety, haemorrhoids • symptoms of leucostasis: breathlessness, blurred vision, priapism, confusion, seizures Patients are usually symptomatic, although a routine blood test may also pick up the condition. It is most common to present in the chronic phase of the disease, although, occasionally, patients may present in blast crisis. Blast crisis is really a form of acute leukaemia and most commonly presents with symptoms and signs of bone marrow failure (anaemia, infections due to leucopenia, and bleeding/​ bruising due to thrombocytopenia).

Symptoms of CLL CLL is much more commonly picked up incidentally from a blood test taken for an unrelated reason (40%–​50% of cases). In such situations, there is usually a lymphocytosis with a normal haemoglobin and platelet count. Symptomatic patients usually complain of one or more of: systemic symptoms: fevers, weight loss, anorexia, night sweats • • lymphadenopathy (e.g. a lump in the neck, axilla, and/​or inguinal regions) • symptoms of bone marrow failure, especially anaemia; it should be borne in mind that CLL is associated with autoimmune haemolytic anaemia and so anaemia should not be immediately ascribed to bone marrow involvement • symptoms of organomegaly (e.g. abdominal bloating); however, the spleen is rarely as large as that typically seen in CML CLL is also associated with a number of autoimmune conditions and may present with one of these. Most commonly, this would be autoimmune haemolytic anaemia, although idiopathic thrombocytopenic purpura and pure red cell aplasia are also sometimes seen.

Demographics of the disease

Aetiology of CLL

Demographics of CML

The pathobiology of CLL is much less well understood than that for CML. No single chromosomal aberration is found in CLL cells. However, recurrent cytogenetic changes of various types are found in up to 80% of cases, suggesting that the familiar morphology of CLL cells may represent the final state of a number of different acquired genetic anomalies. Some cytogenetic changes define specific clinical groups. For example, deletion of the short arm of 17p (which results in loss of the tumour suppressor gene p53) is associated with a clinically aggressive course and resistance to standard chemotherapy agents. Although CLL is a clonal disorder of B-​cells, the type of B-​cell giving rise to CLL remains a matter of some debate. Genetic analysis of the immunoglobulin genes shows that some cases of CLL have very few mutations affecting these genes, suggesting it has not experienced antigen and traversed the germinal centre. However, other cases show a higher burden of mutations, suggesting a post-​germinal centre origin. These do not represent two clear groups, however, as there is a spectrum of mutational events affecting this gene. Also, gene expression profiling experiments suggest that the closest normal cell is actually a memory B-​cell, leading some to think that this may be the cell of origin.

For CML, the median age at presentation is 50–​60 years of age, and the disease affects men slightly more often than it does women. The incidence is 1–​2 per 100 000 per year.

Demographics of CLL For CLL, incidence increases with age, with the median age at presentation being 60–​70 years of age. Like CML, CLL affects men more than women. The annual incidence of CLL is approximately 10–​20 per 100 000 per year.

Natural history and complications of the disease Natural history and complications of CML CML has defined phases of disease, although the natural history has been significantly altered by improvements in treatment. Most patients present with chronic phase disease, which is characterized clinically by slowly evolving symptoms and in the laboratory by a

neutrophilia and circulating immature granulocytes called myelocytes (but a relatively small number of circulating primitive cells, or blasts). Without treatment using modern tyrosine kinase inhibitors (TKIs), the risk of progressing to the accelerated or blast phase is 10% per year for the first 2 years but this rises to 30% per year thereafter. This means that a typical duration for the chronic phase before the advent of TKIs was 3–​4 years. The onset of the accelerated phase of CML is characterized by the progression of symptoms and haematological abnormalities, despite escalation of treatment. At the molecular level, there is an accumulation of additional genetic alterations and genomic instability. The accelerated phase proceeds to blast crisis, which is the accumulation of primitive cells in the bone marrow, leading to bone marrow failure. The prognosis for blast crisis remains poor.

Other diagnoses that should be considered aside from CLL

Natural history and complications of CLL

‘Gold-​standard’ diagnostic test

Approach to diagnosing the disease Diagnosing CML In diagnosing CML, a clinical history should be taken and the examination and investigations should be performed to exclude other causes of splenomegaly with or without hepatomegaly and to search for solid malignancies, as, in a blood film test, these can sometimes produce a so-​called leukaemoid picture which can be similar to that seen in CML. Specific investigations for CML should then be undertaken.

Diagnosing CLL In diagnosing CLL, a clinical history should be taken and the examination and investigations should be performed to exclude other causes of lymphadenopathy. Specific diagnostic tests should then be performed.

Other diagnoses that should be considered Other diagnoses that should be considered aside from CML Other diagnoses that should be considered aside from CML include: • myelofibrosis (another cause of massive splenomegaly in developed countries) • a solid tumour (which can produce a ‘leukaemoid’ blood film appearance) • essential thrombocythaemia (CML and essential thrombocythaemia can present with isolated thrombocythaemia)

• a solid tumour with regional lymphadenopathy (e.g. head and neck cancer causing cervical nodes) • infections (endocarditis, TB, viral infections): • note that, in children, a raised lymphocyte count is never indicative of CLL, as children have a higher lymphoctye:neutrophil ratio than adults • pertussis is also well known to cause a very elevated lymphocyte count • other lymphoproliferative disorders can present with a lymphocytosis (e.g. follicular lymphoma, mantle cell lymphoma)

Gold-​standard diagnostic test for CML The gold-​standard diagnostic tests for CML are: • PCR for the BCR–​ABL fusion gene on peripheral blood and/​or bone marrow aspirate • fluorescent in situ hybridization (FISH) for t(9;22) on peripheral blood or bone marrow aspirate

Gold-​standard diagnostic test for CLL The gold-​standard diagnostic tests for CLL are: immunophenotyping of peripheral blood lymphocytes • • bone marrow aspirate with immunophenotyping of lymphocytes

Acceptable diagnostic alternatives to the gold standard Acceptable diagnostic alternatives to the gold-​standard test for CML An acceptable diagnostic alternative to the gold-​standard test for CML is conventional karyotyping to identify the Philadelphia chromosome.

Acceptable diagnostic alternatives to the gold-​standard test for CLL An acceptable diagnostic alternative to the gold-​standard test for CML is lymph node excision or core biopsy with immunohistochemistry. This is usually not needed, as blood or bone marrow will usually give the diagnosis. Rarely, only lymph nodes are involved (a condition often called small lymphocytic lymphoma rather than CLL). In these cases, a lymph node biopsy is required.

CHAPTER 287  Chronic leukaemia

CLL has a much less predictable clinical course than CML. Patients who are diagnosed incidentally, at a very early stage, may never progress to the point where they need treatment. However, a proportion will and, despite advances in prognostication, it is not easy to identify those with an indolent course from those with an aggressive course. In those who do progress, treatment is not curative but frequently results in a remission. CLL then becomes a relapsing and remitting illness, although the benefit obtained from treatment tends to become less the higher the number of previous treatment courses used. It is not unusual for patients with CLL to develop extremely high white-​cell counts (>300 × 109/​l). However, leucostasis due to such a high count is extremely uncommon, and treatment is rarely initiated purely due to a high white-​cell count. Other well-​known complications of CLL include haematological autoimmune disorders. Autoimmune haemolytic anaemia is a relatively common occurrence during the course of the disease and its incidence is increased by treatment with fludarabine monotherapy. Immune thrombocytopenic purpura is the second most common autoimmune manifestation, followed by pure red cell aplasia, whereby there is immune attack against red cell precursors, resulting in profound anaemia with low reticulocytes. It is also becoming appreciated that the incidence of solid cancers is increased in CLL, although the mechanism is unclear. Finally, infections are common in CLL, mainly due to hypogammaglobulinaemia (although bone marrow failure and drug-​related immunosuppression also contribute). The most common organism involved is Pneumococcus.

Other diagnoses that should be considered aside from CLL include:

Other relevant investigations Other relevant investigations for CML Other relevant investigations for CML include: • a full blood count and a blood film: • patients will often be anaemic at presentation • blast count, basophil count, and platelet count also give an idea as to the prognosis of the disorder • bone marrow aspirate and cytogenetic evaluation:  in addition to establishing the diagnosis, cytogenetic changes in addition to t(9;22) may give prognostic information • CT chest, abdomen, and/​or pelvis if there is diagnostic doubt, looking for a solid tumour giving rise to a ‘leukaemoid’ reaction • PCR for BCR–​ABL: if not already performed to establish the diagnosis, a baseline is needed in order to monitor response to treatment • biochemistry, including liver function tests: note that the TKIs can cause liver toxicity, so baseline readings are important

Other relevant investigations for CLL Other relevant investigations for CML include the following: • a full blood count and a blood film: • the classic blood film picture shows numerous mature lymphocytes with smear cells; while this is characteristic, it is not pathognomonic and should not be considered diagnostic

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• the film may also show evidence of haemolysis (polychromasia and spherocytes) • a direct Coombe’s test, a bilirubin test, a lactate dehydrogenase test, and a reticulocyte count, to look for the presence of coexisting autoimmune haemolysis • biochemistry, including renal and liver function tests: these measurements are needed to calculate the correct doses of chemotherapy drugs to use and to monitor for side effects • FISH (or, preferably, mutation analysis) for p53:  although not required at diagnosis, it is required before treatment, as p53 deletion or mutation is strongly predictive of resistance to standard chemotherapy agents • immunophenotyping for CD38 and Zap70:  expression of these markers has been associated with a worse prognosis • analysis of the mutational status of immunoglobulin heavy chain genes: mutated cases have a better prognosis than unmutated ones • serum beta 2 microglobulin is raised in more aggressive disease • CT chest, abdomen, and/​or pelvis: may be helpful in cases characterized more by lymph node involvement than blood or marrow involvement (e.g. cases of small lymphocytic lymphoma)

Prognosis, and how to estimate it

CHAPTER 287  Chronic leukaemia

Prognosis for CML For CML, various factors at diagnosis indicate a worse prognosis, although these are less important in the era of TKI therapy. The two most commonly used prognostic scores are the Sokal score and the Hasford score. Poor prognostic factors include advancing age, increasing spleen size, raised platelet count, raised basophil count, and raised blast count. However, the most important factor is the response to treatment. Patients who respond to TKIs have an excellent prognosis. Overall, current estimates are of a 90% 5-​year survival rate for a newly diagnosed patient with CML treated with TKIs. In those who respond well (defined as achieved a stable cytogenetic remission in which the t(9;22) translocation cannot be detected by FISH on bone marrow samples), the 8-​year survival rate is in excess of 95%.

Prognosis for CLL In CLL, the following factors at diagnosis confer a worse prognosis: deletion or mutation of the p53 gene • • an 11p deletion • a rapid lymphocyte doubling time (less than 12 months) • CD38 expression • Zap70 expression • a raised level of beta-​2 microglobulin • an unmutated immunoglobulin heavy chain gene • advanced clinical stage (by the Rai or the Binet staging system) Overall, the average life expectancy of a patient with CLL is in the region of 10–​12 years. However, this is highly variable. A Binet stage A patient with mutated immunoglobulin heavy chains has a life expectancy of 25 years, whereas this falls to 8 years when the heavy chains are unmutated. In cases of p53 mutation or deletion, the average life expectancy is only on the order of 3 years.

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Treatment and its effectiveness Treatment for CML The standard treatment for patients with CML is with TKIs (e.g. imatinib). This is highly effective at inducing haematological remission (normal blood count) and cytogenetic remission (no evidence of t(9;22) by FISH). In some patients, it also produces a molecular remission (no evidence of BCR–​A BL on PCR testing). Drug resistance can be present at diagnosis or can evolve. Depending on the mechanism of resistance, a number of novel TKIs (e.g. dasatinib, nilotinib) remain effective in many of these cases. These drugs have transformed the outlook of CML and are generally well tolerated. Before TKIs, the life expectancy of a patient with CML was 3–​5  years, unless the patient had an allogeneic bone marrow transplant. With TKIs, the 5-​year survival rate is approximately 90%. However, they are not considered curative, as most patients who stop them do relapse, even when they achieved a molecular remission. TKIs also should not be taken in pregnancy; interferon is the drug of choice in this situation. The treatment of blast crisis, however, is poor and consists of high-​d ose chemotherapy followed by an allogeneic stem cell transplant if the patient is young and fit enough to tolerate this approach.

Treatment for CLL Asymptomatic CLL is usually not actively treated. However, the development of symptoms or evidence suggesting critical organ involvement does warrant treatment. Treatment is in the form of chemo-​immunotherapy. In younger patients with a good performance status, fludarabine and cyclophosphamide combined with rituximab is considered to be the gold-​standard treatment, due to clinical trial evidence showing superior survival outcomes. In older patients, drugs such as bendamustine or chlorambucil (again, usually in combination with rituximab) may be more appropriate, due to a more favourable toxicity profile. Treatment of relapsed disease is more difficult, relying mainly on similar chemo-​immunotherapy agents. In younger patients with more aggressive disease, an allogeneic stem cell transplant offers a potential cure but at relatively high risk of morbidity and mortality. In p53 mutated or deleted cases, treatment with the anti-​CD52 antibody alemtuzumab followed by a stem cell transplant is considered optimal therapy. Novel agents which are being trialled include novel monoclonal antibodies (e.g. ofatumumab) and immunomodulatory drugs such as lenalidomide. Chemo-​immunotherapy is not considered curative.

Further Reading Apperley JF. Chronic myeloid leukaemia. Lancet 2014; 385: 1447–​59. Guidelines and management recommendations of the American Society of Hematology (http://​www.hematology.org) Guidelines and management recommendations of the European Leukaemia Net (http://​www.leukemia-​net.org/​content/​physicians/​recommendations/​index_​eng.html) Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol 2017; 92: 946–​65.

288 Myelodysplasia Chris Bunch

Introduction The myelodysplastic syndromes (or myelodysplasias) comprise a spectrum of disorders characterized by dysplastic or ineffective haemopoiesis that leads to variable anaemia, neutropenia, and thrombocytopenia. There is often a degree of red-​cell macrocytosis. The majority are clonal stem cell disorders in which the abnormal clone predominates and expands only slowly over a number of years. Myelodysplasias have a tendency to develop ultimately into acute leukaemia in some patients; for this reason, they are sometimes referred to as ‘preleukaemias’, even though two-​thirds of patients will never develop this complication. Classifications of myelodysplasia have traditionally focused on clinical and pathological features but now take into account other prognostic features, notably cytogenetics (see Box 288.1). Additional risk classifications, including multiple scoring systems, have been used to define prognosis in myelodysplasia and to evaluate its potential for transformation to acute myeloid leukaemia. The International Prognostic Scoring System takes into account specific cytopenias, age, and cytogenetics, in addition to bone marrow morphology. It defines four risk categories, Low, Intermediate-​1, Intermediate-​2, and High, which indicate both survival and evolution to acute myeloid leukaemia.

General features Myelodysplasia is mainly a disease of the elderly, and is becoming more common as the population ages. The median age at diagnosis is 70–​75, and comorbidities are common and have a significant effect on prognosis. Most cases arise de novo, but myelodysplasia develops occasionally in patients who have been treated with radiation and/​or cytotoxic chemotherapy for some other condition. These secondary cases occur mostly 5–​10 years after the original therapy and, again, are more frequent in older patients. The condition usually presents as a mild symptomatic, refractory anaemia or comes to light following a routine blood count. This may be normocytic but typically shows a mild macrocytosis (mean corpuscular volume, 95–​110 fl) with frequent red-​cell abnormalities on the blood film. There may also be mild-​to-​moderate thrombocytopenia and/​or neutropenia. Platelets and neutrophils may also be morphologically abnormal with giant platelets and neutrophil hypogranularity with reduced nuclear lobulation. Bleeding and infection may occur in severe cases. The marrow is usually hypercellular and shows abnormal cellular and nuclear maturation with evidence of ineffective haemopoiesis and intra-​medullary cell death (i.e. dysplasia). Thus, despite apparent increased cellular activity, output of blood cells is reduced. In around 10% of cases, the marrow is hypocellular; here, there is overlap with aplastic anaemia. An abnormal karyotype is found in at least one-​ half of primary cases and 85%–​90% of secondary cases and generally has an adverse effect on prognosis. Over 600 different cytogenetic abnormalities have been described, although only a few occur commonly.

Box 288.1  The World Health Organization classification of myelodysplasia (2008) Refractory cytopenia with unilineage dysplasia (RCUD) Refractory anemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with excess blasts-​1 (RAEB-​1) (75%

0.48 in women) or raised platelet count (≥450 × 109/​l) is the current gold standard for diagnosis of primary polycythaemia and essential thrombocythaemia respectively. It ET and MF which are negative for Jak2, mutations in the MPL gene and Calreticulin gene can also confirm the diagnosis. For myelofibrosis, the result of a bone marrow biopsy is more crucial in the diagnosis. Findings of megakaryocytic proliferation and/​or atypia plus increased marrow fibrosis in conjunction with an activating JAK2 mutation or other clonal marker is diagnostic of myelofibrosis.

For cases of primary polycythaemia and essential thrombocythaemia at diagnosis, the prognosis is excellent, although thrombotic risk is significantly raised. Life expectancy is roughly equivalent to the normal population. In the rare cases which transform to myelofibrosis or acute myeloid leukaemia, however, the prognosis is much worse. Transformation risk is increased by certain agents such as busulphan and 32P. Hydroxycarbamide may be associated with a small increased risk of acute myeloid leukaemia, although this remains controversial. The platelet-​lowering agent anagrelide is associated with a slightly increased risk of myelofibrosis. In myelofibrosis, the prognosis is highly variable. Lower-​ risk patients have a median survival of around 12 years, whereas high-​risk patients have a median survival of 2–​3 years. A worse prognosis is associated with:

Secondary causes of a raised platelet count Secondary causes of a raised platelet count include: infections: especially occult abscess, TB • • inflammatory conditions (e.g. lupus, rheumatoid arthritis) • underlying malignancy • iron deficiency

Acceptable diagnostic alternatives to the gold standard Diagnostic criteria for primary polycythaemia and essential thrombocythaemia where the JAK2 mutations is either negative or unavailable are published. For primary polycythaemia, the first step is to prove that the raised haematocrit is due to an absolute erythrocytosis (as opposed to a relative erythrocytosis). A haematocrit of ≥0.60 in a man and ≥0.56 in a woman cannot be due to plasma volume depletion and is diagnostic of an absolute erythrocytosis. In patients with raised values less than these levels, a red-​cell mass analysis has to be performed which must show a mass of >25% above predicted. Secondary causes must then be excluded and, if these patients also have a palpable spleen or a cytogenetic abnormality on bone marrow aspirate, then the diagnosis is secure. If neither of these last two conditions is met, other supportive criteria are needed, such as a raised platelet count, a raised neutrophil count, or radiological evidence of splenomegaly.

CHAPTER 291  Myeloproliferative disorders

Other diagnoses that should be considered

age > 60 • • abnormal karyotype of cytogenetic analysis • presence of constitutional symptoms • elevated white-​cell count • increased circulating immature precursors • circulating blast cells

Treatment and its effectiveness Treatment of primary polycythaemia Reduction of the haematocrit is achieved by repeated venesections. In cases of primary polycythaemia, the target haematocrit is 38.3°C) or hypothermia (temperature 90/​min or more than two standard deviations above the normal value for age) is common, and the pulse may be hyperdynamic. Assess for the presence of arterial hypotension (systolic blood pressure 10% immature forms Plasma C-​reactive protein >2 S.D. normal parameters Hyperlactatemia (>3 mmol/​l) and acidosis

Organ dysfunction parameters Arterial hypotension (systolic blood pressure of >90mmHg, mean arterial pressure  60 s) Thrombocytopenia (platelet count 65), impaired immune system function (due to AIDS, neutropenia, splenectomy, neoplasm, renal or hepatic failure, diabetes, alcohol dependence, or malnutrition), IV drug use, and prolonged use of intravascular and indwelling urinary catheters. A  comprehensive list of pathogens causing sepsis is beyond the scope of this chapter; however, some of the most common infections and microbes responsible for causing sepsis in the community and hospitalized patients are shown in Table 309.1.

Natural history, and complications of the disease The clinical spectrum usually begins with infection (bacteraemia) that leads to sepsis, organ dysfunction, and septic shock. Complications develop as a result of organ damage, and their clinical presentation usually is superimposed on the signs and symptoms of the systemic response. Findings indicative of organ dysfunction may be the first symptoms noticed by clinicians when assessing the patient. Common complications of sepsis include toxic metabolic encephalopathy; acute respiratory distress syndrome; myocardial dysfunction and decreased ejection fraction; renal failure; impaired gut mobility; elevation in the levels of transaminases; hyperbillirubinaemia; disseminated intravascular coagulation; pancytopenia; a rise creatinine kinase levels, together with critical illness myopathy; and adrenal haemorrhage resulting in Addison’s disease.

Approach to diagnosis The cornerstone of the management of sepsis is early recognition and prompt initiation of supportive therapy  combined with antimicrobial therapy. Emergency management should be focused on simultaneous evaluation and resuscitation. The evaluation of the patient should begin with a carefully taken history focused on the assessment of any underlying or predisposing disorder such as an impaired immune system, recent surgery, chemotherapy, transplantation, trauma, or any treatment given. Special attention should be devoted to any history of previous infections and antimicrobial treatment, along with any microbiological data that may be available from previous studies. In addition, an accurate travel history, a recreational drugs history, and history of exposure to infectious agents, whether from contacts or in the environment, can be valuable to the clinician in the identification of an infectious process. A comprehensive physical examination should be undertaken looking for clues to the source of infection. For instance, cutaneous manifestations of Gram-​positive or Gram-​negative infections, such as cellulitis, erythroderma, bullae, ecthyma, petechia, or splinter haemorrhages, can provide an opportunity for early diagnosis and initiation of specific antimicrobial therapy.

Other diagnosis that should be considered Non-​infectious etiologies of SIRS to be considered include pancreatitis; trauma; burns; pulmonary embolism; anaphylaxis; drug overdose; dissecting or rupture aortic aneurysm; occult haemorrhage; myocardial infarction; and adrenal insufficiency.

Suspected focus of infection

Most likely organism

Possible empiric therapy*

Unknown

Gram-​negative bacteria Gram-​positive bacteria Anaerobe species

Community acquired: third-​generation cephalosporin + metronidazole; consider aminoglycoside Hospital acquired: piperacillin–​tazobactam + aminoglycoside; add vancomycin if MRSA colonized or suspected

Community-​acquired pneumonia

Streptococcus pneumoniae Haemophilus influenzae Chlamydophila pneumoniae Mycoplasma pneumoniae

Third-​generation cephalosporin + clarithromycin or doxycycline

Hospital-​acquired pneumonia

Klebsiella spp. Staphylococcus aureus Pseudomonas aeruginosa Enterobacteriaceae Anaerobes

Piperacillin–​tazobactam; add vancomycin if MRSA colonized or suspected; add metronidazole or clindamycin if aspiration pneumonia

Urinary tract infection

Escherichia coli Enterobacteriaceae Enterococci

Co-​amoxiclav + aminoglycoside or third-​generation cephalosporin

Intra-​abdominal sepsis

Escherichia coli Bacteroides fragilis Peptostreptococcus ssp. Clostridium spp.

Piperacillin–​tazobactam + metronidazole + consider aminoglycoside

Septic arthritis

Staphylococcus aureus Streptococci Aerobic Gram-​negative bacilli

Third-​generation cephalosporin; add vancomycin if MRSA suspected

Biliary sepsis (cholangitis)

Escherichia coli Klebsiella pneumoniae Pseudomonas spp. Enterococcus faecalis

Piperacillin–​tazobactam + aminoglycoside; add metronidazole if severe pancreatitis is present

Skin and soft tissue

Staphylococcus aureus Streptococcus pyogenes Coagulase-​negative staphylococci Clostridium spp. in necrotizing infections

Flucloxacillin; add vancomycin if MRSA suspected If necrotizing fasciitis is present, third-​generation cephalosporin + clindamycin + aminoglycoside

Meningitis and encephalitis

Neisseria meningitides Streptococcus pneumoniae Haemophilus influenzae

Third-​generation cephalosporin + vancomycin in areas with resistant pneumococci

AIDS

Pneumocystis jiroveci Streptococcus pneumoniae Salmonella spp. Pseudomonas spp.

Co-​trimoxazole for pneumocystis pneumonia Third-​generation cephalosporin + metronidazole or clindamycin

Neutropenic sepsis

Gram-​positive bacteria (Staphylococcus aureus, coagulase-​negative staphylococci, enterococci) Gram-​negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa)

Piperacillin–​tazobactam + aminoglycoside

CHAPTER 309 Sepsis

Table 309.1  Common organisms

*Local guidelines will differ according to local organisms and variations in practice.

‘Gold-​standard’ diagnostic test There is no specific test that confirms the diagnosis of sepsis syndrome or severe sepsis. However, the combination of physical, clinical, and laboratory parameters should prompt the clinician to conclude that a patient is ‘septic’. The selection of laboratory studies should be based on the physical findings and the overall clinical presentation. Definitive etiologic diagnosis requires isolation of the microorganism from blood or a local site of infection. An attempt should be made to obtain infected secretions or body fluids or to aspirate an area that is suspicious for infection. Blood cultures are essential, and a minimum of two sets of blood cultures (10 ml each) taken at different venous sites are strongly recommended.

Other relevant investigations In order to aid the diagnosis and assess the severity of the disease, all patients with suspected sepsis syndrome should be considered for the following investigations:

a full blood count • • urinalysis • coagulation profile • liver function tests • electrolytes • blood glucose • urea • creatinine • arterial blood gas • plasma C-​reactive protein • ECG • chest X ray • HIV test Base excess and blood lactate can be useful as prognostic markers of severity in sepsis and should be included in the initial laboratory screening. Based on the clinical presentation, other investigations may be appropriate; for instance, CSF testing for glucose, protein, cell count, and culture, if meningitis is suspected.

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Prognosis Twenty to thirty-​five per cent of patients with severe sepsis, and 50%–​75% of patients with septic shock, die within 30  days. Poor prognostic factors are advanced age, impaired host immune status, infection with a resistant organism, poor prior functional status, and an APACHE II score ≥25. Although 50% of patients with severe sepsis have bacteraemia at the time of infection, the presence or absence of positive blood cultures does not appear to influence the outcome. Similarly, case fatality rates are similar for culture-​positive and culture-​negative severe sepsis.

Treatment Initial resuscitation Establishing vascular access and initiating resuscitation are the first priorities when managing patients with severe sepsis or septic shock. Early resuscitation should be initiated as soon as tissue hypoperfusion is recognized and should not be delayed pending ICU admission. There is evidence from randomized control trials that early, goal-​ directed resuscitation improves survival for patients presenting to emergency with Septic shock. Early resuscitation comprises: fluid therapy • • support of respiratory function

CHAPTER 309 Sepsis

Fluid therapy Large volumes of IV fluids are indicated to correct the relative vascular hypovolaemia typical of sepsis. IV fluids should be administered in rapid infused boluses. Clinical trials have found no consistent difference between colloids and crystalloid in the treatment of septic shock. IV fluid challenges can be repeated until tissue perfusion is acceptable but, in patients at risk of pulmonary oedema, must be done with caution. Target a central venous pressure of ≥8 mm Hg, a mean arterial pressure of ≥65 mm Hg, and a urine output of ≥0.5 ml/​kg per hour. The rate of fluid administration should be reduced if cardiac filling pressures increase without concomitant hemodynamic improvement.

Support of respiratory function Assessment of airway intubation for high-​risk patients, as well as oxygen supplementation to all patients with sepsis, is indicated. Oxygenation should be monitored continuously with pulse oximetry.

Antimicrobial treatment Antimicrobial treatment should be initiated as soon as possible, ideally after cultures have been obtained. The choice of antibiotics would depend on the patient’s history, the most likely source of infection, the clinical context (hospital or community acquired) and local resistance patterns (see Table 309.1). Reassessment of antibiotic regime is important to optimize efficacy and minimize toxicity.

Other therapies Corticosteroids Corticosteroids do not prevent the development of shock, reverse shock, or improve mortality at 14  days. Therefore, high doses of

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corticosteroids should not be used in patients with severe sepsis unless the patient’s endocrine or corticosteroid history warrants it. In the presence of severe refractory sepsis shock (unresponsive to fluid resuscitation and vasopressors), corticosteroid therapy may be beneficial.

Recombinant human activated protein C Recombinant human activated protein C (rhAPC) was a drug therapy proposed for the treatment of sepsis. The first evidence concerning the use of a form of rhAPC, drotrecogin alfa, in adults was based on two randomized control trials that suggested early administration was associated with better outcomes. In those studies, drotrecogin alfa was of greater benefit in the most acutely ill patients (APACHE II score >25). However, a later Cochrane review found that using drotrecogin alfa did not improve survival rates and, instead, increased the risk of bleeding (Martí-​Carvajal et  al., 2012). The drug was withdrawn from the market in 2011 (Kylat and Ohlsson, 2012).

Control of the sepsis focus Identification of the site of infection should be achieved as soon as possible. Prompt drainage of abscesses, debridement of infected necrotic tissue, and removal of potentially infected devices are usually in the best interest of the patient  but clinical judgement is required to balance risks of source control with those of procedures.

Further Reading Angus DC and van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369: 840–​51. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Critical Care Med 2008; 36: 296–​327. Kaukonen K-​M, Bailey M, Pilcher D, et  al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015; 372: 1629–​38. Kylat RI and Ohlsson A. Recombinant human activated protein C for severe sepsis in neonates. Cochrane Database Syst Rev 2012; 12: CD005385. Long B and Koyfman A. An emergency medicine-focused review of sepsis mimics. J Emerg Med 2017; 52: 34–42. Martí-​Carvajal AJ, Solà I, Gluud C, et  al. Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev 2012; 12: CD004388. National Institute for Health and Clinical Excellence, NICE Guidelines: Sepsis: recognition, assessment and early management. 2016. Available at https://www.nice.org.uk/guidance/ng51/ evidence/full-guideline-2551523297. Vincent JL, Mira JP, and Antonelli M, Sepsis: older and newer concepts. Lancet Respir Med 2016; 4: 237–​40.

310 

Bacterial infection

Tony Bentley

Staphylococci Staphylococci are Gram-​ positive cocci which grow in clusters. Staphylococcus aureus, which can be distinguished from Staphylococcus epidermidis and other less pathogenic species by a positive coagulase test, is capable of producing numerous toxins that act as virulence factors. Toxins and other pathogenic molecules produced by Staphylococcus aureus include: • teichoic acid: an adhesin responsible for binding the organisms to fibronectin present on epithelial cell membranes • fibronectin-​, fibrinogen-​, and collagen-​binding proteins: thought to explain Staphylococcus aureus’s predilection for diseased tissue • protein A: binds to the Fc component of immunoglobulin, resulting in resistance to phagocytosis • catalase: a peroxidase enzyme that helps the organism survive the host’s oxygen-​dependent bactericidal system • coagulase: causes a fibrinous capsule to form around the localized infection • hyaluronidase: causes local tissue destruction • DNAse: causes nucleic acid damage • haemolysins: cause red-​cell damage • Panton–​ Valentine leucocidin (PVL):  a pore-​ forming toxin that results in leakage of leucocyte contents • enterotoxins A–​E: cytotoxins that stimulate receptors in the gastrointestinal tract, interfering with peristalsis and leading to emesis and diarrhoea • pyrogenic exotoxin: causes fever, intense inflammation, and rash • exfoliative toxin:  causes superficial splitting of the granular layer (scalded skin syndrome in children) • toxic shock syndrome toxins: act as superantigens Staphylococcus aureus is well adapted to the human body and colonizes the nasopharynx of approximately 30% of the normal population. It may also colonize the skin, the perineum, the vagina, and the gastrointestinal tract. It is capable of person-​to-​person spread and causes pyogenic, septicaemic, and superficial cutaneous disease. It is able to survive intracellularly. Some staphylococcal infections are toxin mediated (e.g. food poisoning (vomiting induced by ingestion of preformed toxin), scalded skin syndrome (extensive skin disease following localized staphylococcal infection), and toxic shock syndrome (systemic symptoms following localiaed infection)). In other situations, the severity of the infection may be increased due to toxin production by organisms growing in a pyogenic focus (e.g. extensive necrotic skin infection, or pneumonia associated with PVL-​positive strains). Staphylococcus aureus is a major cause of healthcare-​associated and true community-​ acquired bacteraemia. True community-​ acquired bacteraemia affects younger people, is less frequently associated with a primary focus of infection, is more commonly associated with a secondary focus of infection (such as endocarditis and osteomyelitis), and has a higher mortality. The majority of Staphylococcus aureus bacteraemias are healthcare associated. In modern healthcare, however, the majority of these develop in patients living outside hospital. The most common healthcare-​associated sources of Staphylococcus aureus bacteraemia are vascular catheters and wound, skin, and soft tissue infections. Staphylococcus epidermidis and other coagulase-​negative staphylococci are organisms of much lower virulence but are common causes of infection of intravascular devices and prosthetic joints. They are associated with the production of biofilm, which makes their eradication by antibiotic either difficult or impossible. Staphylococcus

saprophyticus is a recognized cause of urinary tract infection in young women. Staphylococcus aureus infection is most commonly treated with flucloxacillin or co-​amoxiclav. Culture and sensitivity testing should be undertaken to confirm any empirical choice. Success relies on the strain being reported by the laboratory as meticillin sensitive. Alternative agents for meticillin-​sensitive strains include erythromycin and tetracyclines. MRSA is detected in less than 1% of the overall population but in about 7% of those recognized as being at higher risk (e.g. individuals having multiple comorbidities, individuals having had multiple hospital admissions, and those from residential and nursing homes). Many meticillin-​resistant strains are also erythromycin resistant; for these strains, alternative agents include tetracyclines, the glycopeptides vancomycin and teicoplanin, and linezolid. Combination therapy with oral rifampicin and fusidic acid is also commonly used.

Streptococci Streptococci are Gram-​positive cocci that grow in chains. They are catalase negative. When grown on blood agar, streptococci may produce a green-​coloured zone (alpha haemolysis) or a clear zone (beta haemolysis), or be non-​haemolytic. Streptococci may also be classified according to their Lancefield group antigen. In addition, each strain may be given a species name. This complexity of nomenclature can lead to some confusion. Most alpha-​haemolytic or ‘viridans’ streptococci are normal inhabitants of the mouth. Common species include Streptococcus mutans, Streptococcus mitis, Streptococcus sanguis, and Streptococcus salivarius. Streptococcus mutans is the bacterial cause of dental caries. All are potential causes of infective endocarditis, which, when caused by these organisms, is usually subacute in onset. Streptococcus pneumoniae is a particular alpha-​haemolytic streptococcus recognized in the laboratory by its capsulate appearance, bile solubility, and sensitivity to optochin. The pneumococcus causes many types of infection in addition to pneumonia. These include primary bacteraemia, meningitis, brain abscess, acute sinusitis, otitis media, septic arthritis, septic osteomyelitis, peritonitis, and pericarditis. The capsule, of which over 90 different serotypes have been characterized, is the most important virulence factor. Eight to ten capsular types cause about 60% of the serious infections in adults, and 80% of the invasive infections in children. The pneumococcal polysaccharide vaccine contains purified capsular polysaccharide from 23 capsular types and is thought to be 50%–​70% effective in preventing pneumococcal bacteraemia but ineffective against non-​ bacteraemic disease. It is ineffective in children under 2 years of age. It is recommended for adults over 65 years of age in at-​risk groups (e.g., those with splenic absence or dysfunction; chronic respiratory, heart, liver, or renal disease; diabetes; or immunosuppression). The pneumococcal conjugate vaccine, however, is immunogenic in children over 2 months of age. It was first introduced into the childhood immunization programme in the UK in 2006 and originally contained polysaccharide from seven capsular types conjugated to a protein molecule. This has recently been replaced by a new conjugate vaccine covering a further six pneumococcal serotypes and which is indicated for active immunization for the prevention of invasive pneumococcal disease in adults aged 50 years and over and for the prevention of invasive disease, pneumonia, and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 5 years of age. Streptococcus milleri is the name commonly applied to a group of three closely related alpha-​ haemolytic streptococci (Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius).

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CHAPTER 310  Bacterial infection 1072

These organisms are seen as causes of abscess formation in the brain, liver, and other sites. The most important beta-​haemolytic streptococcus is Lancefield Group A or Streptococcus pyogenes. This organism is responsible for a wide range of infections, including localized skin infections (impetigo, cellulitis, and erysipelas), more extensive skin infections (e.g. necrotizing fasciitis), tonsillitis, and associated abscess formation (quinsy), puerpueral sepsis, wound infection, and, more rarely, overwhelming sepsis. Streptococcus pyogenes can be further classified by the serological characteristics of the surface M proteins (which may prevent opsonization) and T antigens (pili used for bacterial attachment). Streptococcal pyrogenic exotoxins A and C are superantigens secreted by many strains of Streptococcus pyogenes that are responsible for the rash of scarlet fever and many of the symptoms of streptococcal toxic shock syndrome. Serological evidence of Streptococcus pyogenes infection can be sought by detection of anti-​streptolysin O and anti-​DNAse antibodies. The combination of tests is more sensitive than either alone, and interpretation of single test results, particularly in children, should be undertaken with care due to high background levels in some populations. Streptococcus pyogenes can also cause postinfectious, autoimmune-​mediated complications such as rheumatic fever and glomerulonephritis. Group B beta-​ haemolytic streptococcus or Streptococcus agalactiae, originally recognized as a vetinary pathogen causing bovine mastitis, has been reported with increasing frequency as a cause of sepsis in adult patients. In particular, it has been found in those with diabetes and liver disease, as a cause of bone and joint infections and spontaneous bacterial peritonitis. It is a commensal organism of the gastrointestinal tract and vagina and a cause of neonatal sepsis, causing both bacteraemias and meningitis. The commonest non-​ haemolytic streptococci are the enterococci (i.e. Enterococcus faecalis and Enterococcus faecium). Associated diseases include urinary tract infection and, less commonly, endocarditis. Unlike other streptococci, enterococci are resistant to cephalosporins.

Neisseria species Neisseria are Gram-​negative cocci that have a characteristic paired arrangement that resembles coffee beans. Numerous species exist of which two are important human pathogens: Neisseria meningitidis and Neisseria gonorrhoeae. Antibiotic culture media for the recovery of Neisseria meningitidis and Neisseria gonorrhoeae are made selective by the use of an antibiotic cocktail to aid recovery from mixed throat and genital tract flora. The organisms are then identified by Gram stain, a positive oxidase test, and by at least two of the following modes of identification: utilization of sugars, detection of specific preformed enzymes, or immunological tests. Gonorrhoea is a sexually transmitted infection primarily of the mucous membranes of the urethra, the endocervix, the rectum, the pharynx, and the conjunctiva. Common symptoms include urethral and/​or cervical discharge and dysuria, but infection may be asymptomatic in up to 50% of cases. Complications include epididymitis, pelvic inflammatory disease, and haematogenous spread. In addition to routine microscopy and culture methods, molecular amplification techniques are increasingly being used for the detection of Neisseria gonorrhoeae. However, only culture enables sensitivity tests to be performed. As resistance profiles continue to change over time, these are a key part of the management of both the individual patient and his or her contacts, and the maintenance of up-​to-​date local and national treatment guidelines. Meningococcal infection most commonly presents as either meningitis or septicaemia or a combination of both. Haematogenous spread can result in arthritis, pneumonia, and cardiac infection. Localized infection of mucous membranes can occur. Disease usually occurs from 2 to 7 days after acquisition of the organism in the nasopharynx. However, approximately 10% of adults, and a higher proportion of adolescents, carry meningococci without developing disease. When disease occurs, there may be a prodrome, but the disease is often acute with symptoms that include pyrexia, malaise, headache, neck stiffness, photophobia, and vomiting. A  petechial or purpuric non-​blanching rash may accompany meningococcal

septicaemia. In developed countries, overall mortality remains at around 10% with a further 10%–​20% developing permanent sequelae. Meningococci remain fully sensitive to penicillin. Treatment should be initiated promptly upon suspicion with either IV benzyl penicillin given in high and frequent doses such as 2.4 g 4 hourly or with one of the long-​acting cephalosporins such as ceftriaxone 2 g 12 hourly or cefotaxime 2 g 6 hourly. Secondary cases of meningococcal disease are known to occur. The local consultant in communicable disease control should be informed immediately on clinical suspicion of meningococcal disease. The consultant in communicable disease control will make arrangements for all recent close family and other contacts to receive antibiotic prophylaxis aimed at eradicating Neisseria meningitidis from the nasopharynx. The most common agents used in adults are rifampicin 600 mg orally 12 hourly for 2  days, single-​dose ciprofloxacin 500 mg orally, or cefotaxime 500 mg intramuscularly. Of the 13 distinct serogroups of meningococci, the most common in the UK are B and C, while A, Y, and W135 occur less frequently. The decline in the number of cases of serogroup C disease seen since the introduction of the MenC conjugate vaccine in 2000–​2 should be regarded as a major achievement of the UK immunization programme. Group B strains now account for 80% of laboratory confirmed isolates in the UK. Group A  strains are seen predominantly in sub-​Saharan African. In the countries of this ‘meningitis belt’, the disease is seasonal occurring in sudden, severe epidemics at the end of the dry season.

Haemophilus influenzae Haemophilus influenzae is a pleomorphic, Gram-​negative bacillus that is fastidious in its cultural requirements, needing the cofactors haemin and NAD for growth. These are provided in routine culture media by the heating of horse blood to 56°C—​a process that changes the pigmentation from red to brown, producing so-​called chocolate agar. Capsulate strains (typed as a–​f ) are more virulent than non-​capsulate ones, the capsular polysaccharide of serotype b Haemophilus influenzae being recognized as a major virulence factor in relation to invasive disease such as bacteraemia, meningitis, pneumonia, and epiglottitis. Non-​capsulate strains of Haemophilus influenzae are a commonly recognized cause of both pneumonia and acute exacerbations of chronic obstructive pulmonary disease. The Haemophilus influenzae type b vaccine (Hib vaccine) was introduced to the UK in late 1992. The Hib vaccine was the first where the capsular polysaccharide, extracted from Hib cultures, was conjugated to a carrier protein molecule to increase the immunogenicity particularly in young children. In the previous 3  years, there had been approximately 900 cases reported of invasive Hib disease in England and Wales. By 1995, this had been reduced to fewer than 100. Due to the production of beta-​lactamase by many strains of Haemophilus influenzae, antibiotic therapy is usually with co-​amoxiclav or a cephalosporin.

Bacterial enteric pathogens Acute infectious diarrhoea may be caused by any one of a number of bacterial pathogens. Each one requires a somewhat different culture technique to recover it from a faecal sample, making the routine microbiological investigation of this common syndrome both complex and expensive. Nevertheless, the importance of understanding the cause of acute infectious diarrhoea both for the patient and for epidemiological purposes justifies routine investigation. The commonly sought bacterial causes are Campylobacter spp., Salmonella spp., Shigella spp., and enterohaemorrhagic (verocytotoxin-​producing) E. coli O157. Additionally, laboratories will attempt culture of Vibrio spp., provided appropriate clinical details are made available, and will test for Clostridium difficile toxins in hospital patients and those with a history of recent antibiotic use. In order for laboratories to comprehensively yet cost-​effectively search for relevant bacterial, viral, and protozoal pathogens, faecal samples must be accompanied by appropriate clinical detail, including the patient’s age

Uropathogens Urinary tract infection accounts for 1%–​3% of GP consultations in the UK and affects half of all women at some time during their life. Sexually active women aged 20–​50, pregnant women, the elderly, diabetics, and young girls are particularly susceptible to urinary tract infections. Prostatic enlargement in older men may cause obstruction of the urinary tract, thereby increasing the risk of infection. Urinary tract infections are most commonly caused by coliforms, including E. coli and Proteus spp. (which, together, cause about 83% of urinary tract infections); Enterococcus spp. and Group B beta-​haemolytic

streptococci (which cause about 10% of urinary tract infections); Staphylococcus epidermidis and Staphylococcus saprophyticus (which cause about 4% of urinary tract infections); and Pseudomonas aeruginosa. Urinary tract infection is confirmed by a combination of microscopy and semi-​quantitative culture. Laboratory microscopy is now frequently undertaken by an automated system, either one based on flow cytometry or one based on high-​speed microphotography with image recognition. The key elements reported are white blood cells, red blood cells, epithelial cells, and casts. Some automated systems perform a ‘small particle’ count that may act as a surrogate for an estimate of the number of bacteria present. This will not be reported but, together with the cell counts, may aid the laboratory in determining the chance of bacterial growth being found on culture and, therefore, the utility of performing a full culture. Semi-​quantitative culture usually relies on the use of a calibrated bacteriological loop. If a loop delivers 1 μl on to a CLED or chromogenic agar plate, and more than 100 colonies of the same organism are grown after 18 hours incubation, then the original specimen can be said to have >105 colony-​forming units/​ml. This number is said to represent significant bacteriuria (i.e. lesser numbers than this may be regarded as not significant and dismissed as contaminants). It must be remembered, however, that, with suprapubic aspirates or other surgically obtained urine samples, a pure growth of 104 colony-​forming units/​ml may be clinically significant. It is not necessary to send a urine specimen to the laboratory from every patient. Non-​pregnant women who are between teenage years and menopause and who have urinary tract infection symptoms (e.g. dysuria, frequency, urgency, or nocturia) may instead have an early morning midstream urine specimen tested using a multitest dipstick. The four principal analytes are nitrite (bacteria reduce dietary nitrates to nitrites), leucocyte esterase (an enzyme present in white blood cells), protein, and blood. While these tests have very low sensitivity and specificity individually, the negative predictive value of an overall negative test (i.e. when all four indicators are negative) is very high. In patients with a negative urine dipstick, other causes of the patient’s symptoms should be considered (e.g. candidal vulvovaginitis or chlamydial urethritis). The ability of the multitest dipstick to predict a positive culture result is lower. However, in premenopausal non-​pregnant women with clear symptoms of urinary tract infection, the positive dipstick test can be seen as confirmation of infection and empirical antibiotic therapy can be started. A 3-​day course of either trimethoprim 200 mg twice daily, nitrofurantoin 50–​100 mg four times per day, co-​amoxiclav 625 mg three times per day, or cephalexin 500 mg twice daily can be prescribed. These agents are active in vitro against approximately 70%–​90% of urinary tract infection isolates. Urinary tract infection occurring in pregnant women, children, men, or the elderly, or one that either recurs or ascends to the upper tract, should be considered complicated. Infection of the upper tract produces symptoms such as fever, nausea, malaise, or loin pain. All patients with complicated urinary tract infection should have a midstream urine sample sent for microscopy, culture, and sensitivity, and treatment should be based on the results. In general, treatment of complicated urinary tract infection should be for 7 days. This should be extended to 14  days for acute pyelonephritis, for which nitrofurantoin should not be used but ciprofloxacin 500 mg twice daily may be considered. A midstream urine sample should be sent if symptoms of urinary tract infection occur in a pregnant woman and 7 days of treatment begun with either cephalexin or nitrofurantoin. If cultures remain positive after treatment, or symptoms recur, then prophylaxis may be indicated for the remainder of the pregnancy. Pregnant women who develop a urinary tract infection due to Group B beta-​haemolytic streptococcus (Streptococcus agalactiae) should, in addition to treatment being given at the time of infection, be offered intrapartum antibiotic prophylaxis against neonatal Group B beta-​haemolytic streptococcal infection. In older women, clinical symptoms may be less specific (e.g. fever, anorexia, or confusion). Furthermore, up to 20% of elderly women may have asymptomatic bacteriuria that does not justify treatment. Consequently, the diagnosis requires both bacteriological evidence and careful clinical judgement prior to treatment. Similar care is

CHAPTER 310  Bacterial infection

and location, the duration of the patient’s symptoms, and a travel and antibiotic history. Campylobacter spp. are the most frequently identified cause of acute gastroenteritis. They are curved or spiral Gram-​ negative rods that require a culture medium made selective by antibiotics, an atmosphere of 5%–​10% oxygen (microaerophilic), and incubation at 42°C for 48 hours. The common species that cause human gastrointestinal infection are Campylobacter jejuni and Campylobacter coli. These pathogens cause acute diarrhoea which is often associated with severe abdominal pain and malaise. Campylobacter species do not multiply in food. However, the infective dose is small, and transmission to humans usually occurs from undercooked poultry or unpasteurized milk. There is an unexplained seasonality associated with Campylobacter infection, with a peak incidence in late spring. Salmonella species (other than Salmonella typhi and Salmonella paratyphi) cause gastrointestinal infection via the consumption of contaminated food. As Salmonella bacteria colonize the gastrointestinal tracts of many farm animals, food contamination can occur in uncooked or undercooked meat, poultry, eggs, and unpasteurized milk. In addition, contamination of green vegetables and fruit can occur on the farm, and contamination of shellfish can occur from the contamination of seawater with sewage. Salmonella are sought by examination of faecal samples for non-​lactose fermenting coliforms on selective agar plates. Faecal samples are also enriched by using a specialized broth and then subculture, to ensure any small numbers of Salmonella bacteria present are recovered. Salmonella species are identified using serological tests to confirm the antigenic structure of the capsule and flagellae. The most commonly isolated serospecies are Salmonella enteritidis and Salmonella typhimurium. Many other serospecies are known, often bearing the name of the place where that strain was first identified. Some less common species can be acquired from the gastrointestinal tracts of reptiles kept as pets. Salmonella species are capable of infecting patients of all ages. Infants, the elderly, and the immunosuppressed are at greater risk of more serious infection. The four species of Shigella responsible for bacillary dysentery are Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei. All are non-​lactose fermenting and are sought from faecal samples in much the same way as Salmonella spp. The common clinical feature of infection is bloody diarrhoea. Shigella sonnei accounts for most cases of bacillary dysentery seen in the UK. It produces a more mild disease and is often caught by faecal–​oral spread from household or institutional cases, particularly children. Since the peak of an epidemic seen in the early 1990s, the incidence in the UK has fallen significantly to under 1000 reported cases per annum. The other strains are most commonly seen in the UK as imported cases. Infection with Shigella dysenteriae may be severe and be complicated by haemolytic–​uraemic syndrome, due to the production of Shiga toxin. A toxin closely related to Shiga toxin is produced by some strains of E. coli serotype O157. Infection with these verocytotoxin-​producing organisms is the commonest cause of haemolytic–​uraemic syndrome in the UK. Infection can occur in any age group but is more severe in young children. The inoculum required for infection with these organisms is small compared to that for other enteric pathogens. Infection is associated with contaminated milk, contaminated water, undercooked minced beef, and undercooked beef burgers. Children have acquired E.coli O157 infection by petting small animals at open farms. E.coli O157 are sought using a selective agar and can be recognized by their inability to ferment sorbitol.

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needed when prescribing for catheterized patients, who will almost certainly have bacteriuria; antibiotic therapy will not eradicate this and will select resistant organisms.

Further Reading

CHAPTER 310  Bacterial infection

Barnett R. Typhoid fever. Lancet 2016; 388: 2467. Gotts Jeffrey E and Matthay Michael A. Sepsis: Pathophysiology and clinical management. BMJ 2016; 353 :i1585 McGill F, Heyderman RS, Michael BD et al. The UK joint specialist societies guideline on the diagnosis and management of acute

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meningitis and meningococcal sepsis in immunocompetent adults. J Infect 2016; 72: 405–38. Polat G, Ugan RA, Cadirci E, and Halici Z. Sepsis and Septic Shock: Current Treatment Strategies and New Approaches. Eurasian J Med 2017; 49:53–8. Public Health England. Immunisation Against Infectious Disease. Accessible at https://​www.gov.uk/​government/​collections/​ immunisation- ​ a gainst- ​ i nfectious- ​ d isease- ​ t he- ​ g reen- ​ b ook (accessed 14 Sep 2017). Torok E, Moran E, and Cook F. The Oxford Handbook of Infectious Diseases and Microbiology, 2009. Oxford University Press.

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Mycobacterial infection other than tuberculosis Stephen Aston, Geraint Davies, and Nick Beeching

Introduction Mycobacteria are aerobic bacilli with a lipid-​rich cell wall and are widespread both in the environment and in animals. Many species within the genus cause disease in humans, most notably those of the Mycobacterium tuberculosis complex, which cause tuberculosis, and Mycobacterium leprae, the causative agent of leprosy. Several other species, termed non-​tuberculous mycobacteria, can cause chronic cutaneous, pulmonary, and disseminated infections. This chapter will briefly review infection with non-​tuberculous mycobacteria and Mycobacterium leprae; tuberculosis is the focus of Chapter 130.

Non-​tuberculous mycobacterial infection Definition and aetiology of non-​tuberculous mycobacteria infections Non-​tuberculous mycobacteria (NTM) are resilient microorganisms widely distributed in both soil and water. The number of recognized species is steadily rising, with more than 125 catalogued to date, although most human disease is due to a relatively limited number of species (Table 311.1). NTM infection is rare, with an estimated incidence in industrialized countries of 4.0–6.1 cases per 100 000. Significant under-​reporting is probable, since the condition is not notifiable.

Natural history of NTM infections Infection is acquired from environmental sources via respiratory, gastrointestinal, or cutaneous routes. Human-​to-​human transmission of NTM has traditionally been considered unlikely, although recent studies suggest this may be an important mechanism for acquisition of M. abscessus   by individuals with cystic fibrosis. As for Mycobacterium tuberculosis infection, macrophages are key to an effective host immune response. Resident macrophages phagocytose the invading mycobacteria, but then require stimulation with interferon gamma and other cytokines to activate intracellular killing mechanisms and eradicate the infection. Most infections are asymptomatic and, unlike the case with tuberculosis, latent infection with NTM has not been shown to occur. Many NTM species are of low pathogenic potential and, if identified to be the cause of symptomatic illness, would indicate significantly impaired host immunity.

Typical disease syndromes of NTM infections, and their management NTM lung disease Aetiology and natural history of NTM lung disease Lung disease is the most common clinical manifestation of NTM infection. There is some geographic variation in the predominant causal species, but Mycobacterium avium complex (MAC), Mycobacterium kansasii, Mycobacterium abscessus, and Mycobacterium xenopi are frequently implicated (Table 311.1). Classically, NTM lung disease has been recognized as complicating chronic lung conditions such as COPD and bronchiectasis. More recently, it has been described in individuals without structural lung disease and, in this setting, postmenopausal Caucasian women are predominantly affected.

Typical symptoms of NTM lung disease The clinical features of NTM lung disease are highly variable, influenced by the presence of concurrent lung disease, the immunological status of the individual, and the virulence of the relevant NTM species. Virtually all patients have chronic cough. Sputum production, dyspnoea, haemoptysis, chest pain, and weight loss are variably reported; systemic feature become more prominent as the disease progresses.

Approach to diagnosing NTM lung disease Diagnosis of NTM lung disease requires the demonstration of persistently positive sputum culture results in the presence of compatible clinical and radiological features. Investigation of a patient suspected of having NTM lung disease should include a chest X-​ray, high-​resolution CT of the chest, and examination of three or more sputum specimens. However, the diagnosis of NTM lung disease is frequently challenging. The clinical features may resemble those of concurrent chronic lung disease, and radiological changes may be equally non-​ specific. Environmental contamination of clinical specimens yielding false positive results is common, and even repeatedly positive sputum culture may occur in the absence of progressive clinical or radiological features. The following techniques may be used in the diagnosis: • Radiology: • Two main patterns of pulmonary disease are recognized: nodular/​bronchiectatic disease, characterized by nodules and bronchiectasis predominantly affecting the mid-​and lower lung fields; and fibrocavitary disease that resembles the typical upper zone changes of post-​primary TB.

Table 311.1  Main non-​tuberculous mycobacterial species causing human disease Lung disease

Skin, soft tissue, and bone disease

Disseminated disease

Lymphadenitis

Mycobacterium avium complex Mycobacterium kansasii Mycobacterium xenopi Mycobacterium abscessus Mycobacterium malmoense Mycobacterium fortuitum

Mycobacterium marinum Mycobacterium ulcerans Mycobacterium abscessus Mycobacterium chelonae Mycobacterium avium complex Mycobacterium kansasii Mycobacterium terrae

Mycobacterium avium complex Mycobacterium kansasii Mycobacterium chelonae Mycobacterium abscessus Mycobacterium haemophilum Mycobacterium genavense

Mycobacterium avium complex Mycobacterium malmoense Mycobacterium scrofulaceum Mycobacterium genavense

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CHAPTER 311  Mycobacterial infection other than tuberculosis

• The features of any underlying chronic lung disease will also be evident. • It is not possible reliably to distinguish NTM lung disease from pulmonary TB on the basis of radiological features alone. • Microscopy: • Sputum microscopy may reveal acid-​fast bacilli (AFB); nucleic acid amplification tests can then be employed to rapidly differentiate NTM species from those of the Mycobacterium tuberculosis complex. • In areas of low TB endemicity, AFB seen in sputum are more likely to be NTM. • Culture: • NTM commonly contaminate microbiological samples; therefore, a single positive sputum culture sample in isolation is insufficient to prove a diagnosis of NTM lung disease. • At least three sputum samples should be collected on separate days. • Consistently culture-​positive specimens are predictive of NTM disease, but need to be correlated with clinical and radiological features. • Histology: • Granulomatous  inflammation evident on biopsy provides further supportive evidence of NTM disease in individuals with NTM culture-​positive sputum specimens.

Treatment of NTM lung disease The management of NTM lung disease varies according to the species involved and the clinical presentation of the disease. Generally, medical therapy with combinations of antimicrobial agents is used and continued for at least 12  months after achieving negative sputum cultures. Preferred regimens for disease due to MAC and Mycobacterium kansasii are defined. For MAC pulmonary disease, these are combination regimens which include a macrolide, ethambutol, a rifamycin, and, for patients with cavitary or previously treated disease, an aminoglycoside is added. For other NTM species, treatment regimens are generally extrapolated from those used for MAC. It should be remembered that, for many NTM species, the results of in vitro drug susceptibility tests do not correlate with the clinical response to therapeutic agents. For symptomatic individuals with AFB-​positive sputum and presenting with progressive pulmonary disease, commencement of empirical TB treatment while awaiting the results of sputum culture or nucleic acid amplification testing is often appropriate (see Chapter 130). Conversely, treatment may be deferred for individuals whose sputum cultures are persistently positive for NTM but who have no relevant symptoms or radiological evidence of disease progression. These patients should be observed closely with repeated sputum cultures and appropriate interval lung imaging. For patients with disease predominantly localized to one lung, there is a role for resectional surgery in the circumstances of inadequate response to drug therapy, infection with resistant organisms, or the development of significant local complications (e.g. haemoptysis).

Lymphadenitis due to NTM Lymphadenitis due to NTM is most commonly seen in young children and usually involves the submandibular, cervical, and preauricular lymph nodes. In the absence of HIV infection, it rarely occurs in adults. MAC currently accounts for approximately 80% of culture-​ proven cases of NTM lymphadenitis (Table 311.1). The typical clinical presentation of non-​tender, unilateral lymphadenopathy with minimal systemic symptoms is largely indistinguishable from that of tuberculous lymphadenitis which is the main differential diagnosis. In a low TB endemicity setting such as the UK, tuberculous lymphadenitis accounts for only 10% of mycobacterial lymphadenitis in children, but more than 90% in adults. For both tuberculous and NTM disease, histological examination of lymph node material typically shows caesating granulomata with or without visible AFB. A  definitive diagnosis may be made on mycobacterial culture, but results are delayed by several weeks and, frequently, no organism is cultured. Lack of reactivity to a tuberculin skin test is supportive of disease due to NTM. Complete surgical excision of the affected lymph nodes is the recommended treatment for most localized NTM lymphadenitis. Antimycobacterial chemotherapy is usually reserved for recurrent disease or cases where surgical excision is impossible or incomplete.

Skin and soft tissue NTM disease

Leprosy

Skin and soft tissue NTM disease develops after direct inoculation of mycobacteria into the skin as a result of local trauma. It is most commonly due to Mycobacterium fortuitum, Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium marinum, and Mycobacterium ulcerans (Table 311.1). It typically manifests as a chronic, nodular, ulcerating eruption. Deeper inoculation of mycobacteria may occur through accidental trauma or surgery and may result in tenosynovitis, arthritis, or osteomyelitis. The diagnosis of NTM disease is confirmed by biopsy of the skin or affected tissue, in which AFB and granulomata are usually evident. Recommended antimicrobial treatment regimens vary with the NTM species involved and the extent of disease. Surgical debridement may be indicated for extensive disease, abscess formation, or circumstances where adequate drug therapy is difficult. For small isolated lesions, surgical excision alone may be curative.

Definition and aetiology of leprosy

Disseminated NTM disease Disseminated NTM disease is only seen in severely immunocompromised individuals, most commonly those with advanced HIV

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infection. Prior to the introduction of highly active antiretroviral therapy (HAART), it was noted in 40% of patients with advanced HIV. The widespread use of HAART has led to significant falls in incidence. In non-​HIV patients, disseminated NTM disease has been described in the context of malignancy, chemotherapy, long-​term corticosteroids, and genetic defects of the interferon gamma pathway. More than 90% of cases of disseminated NTM cases are caused by MAC (Table 311.1). Disseminated NTM disease typically presents with fever, night sweats, weight loss, and malaise. Hepatosplenomegaly and lymphadenopathy are often evident on imaging, if not detectable on clinical examination. Laboratory tests reveal non-​ specific abnormalities, including anaemia, leucopaenia, and elevated alkaline phosphatase levels. In more than 90% of cases, blood cultures are positive. For the remaining  cases, disseminated NTM disease may be established by culture of a bone marrow or liver biopsy specimen. The possibility of multiple concurrent infectious pathologies should always be remembered, as the affected patients are usually highly immunocompromised. Disseminated MAC disease is treated with either azithromycin or clarithromycin in combination with ethambutol. Rifabutin may be added for highly immunocompromised or symptomatic patients. For HIV-​infected patients, HAART should be initiated promptly after diagnosis. Following the completion of treatment, secondary prophylaxis with either azithromycin or clarithromycin should be continued until adequate immune reconstitution has occurred. The mortality rate due to disseminated NTM infection is around 30% in both HIV-​ infected and uninfected patients.

Leprosy is a chronic granulomatous infection of the skin and peripheral nerves caused by the intracellular bacillus Mycobacterium leprae. It is characterized by anaesthetic skin lesions and peripheral neuropathy with nerve thickening. Left untreated, affected individuals may develop disfiguring and disabling deformities as a result of repeated trauma and secondary infection of anaesthetic areas.

Demographics of leprosy The WHO reports the global prevalence of leprosy as the number of individuals currently on registered treatment programmes. Following the introduction of multidrug treatment, the global prevalence of leprosy has fallen dramatically from an estimated 12 million registered cases in 1985 to fewer than 200 000 at the start of 2011. However, disease transmission continues to occur at substantial levels in some countries. In recent years over 200 000 new cases of leprosy have been detected each year, with over 80% occurring in four countries—​India, Brazil, Indonesia, and the Democratic Republic

Lepromatous leprosy

Box 311.1  WHO diagnostic criteria for leprosy

The presence of one or more of these features is considered diagnostic of leprosy: One or more hypopigmented or reddish patches with definite loss of sensation Thickened peripheral nerves Acid-​fast bacilli identified in slit-​skin smears or biopsy Reproduced with permission of Public Health England

Unlike tuberculoid leprosy, lepromatous leprosy (the ‘LL’ form in the Ridley–​Jopling classification) occurs when the cell-​mediated immune response is poor. Lesions are generally macular, poorly defined, and widely and symmetrically distributed. Diffuse dermal infiltration and skin thickening may result in a classical ‘leonine facies’ appearance. Histological examination demonstrates diffuse infiltration of the deeper dermis with foamy macrophages laden with bacilli but few granulomata.

of Congo. Persistent disability resulting from nerve damage adds to the global burden of disease and means that leprosy remains a leading cause of neurological disability in developing countries. About ten new cases are currently diagnosed each year in the UK, all imported. The last documented case of transmission within the UK occurred over 50 years ago.

Natural history of leprosy The means of transmission and natural history of Mycobacterium leprae infection are not completely understood. Individuals with lepromatous disease produce minute particles laden with bacilli that are presumed to be the vehicle of airborne person-​to-​person transmission. Only a small minority of exposed individuals develop clinical disease. Bacilli are taken up via the upper respiratory tract mucosa and then demonstrate a specific tropism for Schwann cells and macrophages, to establish a slowly replicating intracellular infection. The emergence of mycobacterial antigens from infected cells induces a specific host immune response, which may result in a chronic inflammatory process affecting the skin and peripheral nerves.

Between these polar extremes, several forms of disease are recognized which have intermediate clinical and histological features (the ‘BT’, ‘BB’, and ‘BL’ forms in the Ridley–​Jopling classification). Moving from tuberculoid towards lepromatous disease, there is a reduction in the cellular immune response and a corresponding increase in the bacillary load and the number of skin lesions present. Histological examination reveals small granulomata that become more diffuse on progression towards lepromatous disease. The skin lesions of intermediate forms are highly variable and may be macular, papulonodular, plaque-​like, or geographic. The term ‘multibacillary disease’ includes lepromatous disease and borderline disease states near the lepromatous end of the disease spectrum (see Table 311.2).

Nerve involvement in leprosy Peripheral nerve involvement in leprosy is extremely common. Sensory nerve dysfunction usually predominates, characterized by anaesthetic skin lesions. Motor and autonomic nerves may also be affected, resulting in weakness and reduced sweating, respectively. Affected nerves are usually thickened and palpable but, occasionally, significant nerve dysfunction occurs in the absence of obvious inflammation. Some patients have purely neural leprosy, without visible skin lesions.

Typical symptoms of leprosy, and less common symptoms

Eye involvement in leprosy

The cardinal diagnostic features of leprosy are summarized in Box 311.1. The nature of the host cell-​mediated immune response determines the clinical manifestations of leprosy. The Ridley–​Jopling classification categorizes leprosy into five types on the basis of clinical and histological features and the bacillary load. This is shown in Table 311.2, together with the simplified WHO case definition, which divides the clinical spectrum into paucibacillary disease (≤5 lesions) and multibacillary disease (≥6 lesions in the skin and/​or the nerves).

Reactional states in leprosy

Cutaneous features of leprosy Tuberculoid leprosy A robust cell-​ mediated immune response results in tuberculoid leprosy (the ‘TT’ form in the Ridley–​Jopling classification), which is characterized by localization of infection within one or few nerves, and/​or a small number of well-​demarcated, hypopigmented, anaesthetic patches; this is also termed paucibacillary disease by the WHO. Histological examination demonstrates well-​formed granulomas with an abundance of CD4+ T-​lymphocytes surrounding dermal nerves, and an absence of visible bacilli.

Blindness is a relatively common complication of leprosy. Motor and sensory damage lead to impaired eye closure and reduced corneal sensation, predisposing to corneal ulceration, repeated trauma, and secondary cataract formation. The immune response in leprosy is dynamic, and spontaneous fluctuations can result in rapid alterations in clinical status. Type 1 (reversal) reactions follow spontaneous increases in T-​cell reactivity and are characterized by inflammation of skin lesions and acute neuritis, often associated with rapid deterioration in nerve function. Inflammation must be rapidly controlled in order to prevent permanent nerve damage. Type 1 reactions occur in one-​ third of individuals with borderline disease and may be evident at presentation. Erythema nodosum leprosum (Type 2) reaction is an acute onset systemic disorder with multiple organ involvement that typically occurs in individuals with multibacillary disease. It arises as a result of extravascular deposition of immune complexes and consequent complement and neutrophil activation. Typical features include fever, painful skin nodules, uveitis, arthritis, and dactylitis.

CHAPTER 311  Mycobacterial infection other than tuberculosis

Borderline forms of leprosy

Table 311.2  Classifications and features of leprosy WHO Classification

Paucibacillary (PB)

Bacteriological Index

0

Type of leprosy

Polar tuberculoid

Multibacillary (MB) 0–​1+

1–​3+

3–​5+

Borderline

Ridley–​Jopling Classification

TT

Skin lesions

Increasing number of skin lesions

BT

BB

Nerve lesions

Increasing number of enlarged nerves & nerve involvement

Stability

Stable

5–​6+ Polar lepromatous

BL

Unstable—​may develop reactions and new nerve damage

LL

Stable

Reproduced with permission of Public Health England.

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Table 311.3  WHO-​recommended multidrug therapy regimens Type of leprosy

Drug treatment

Minimum duration of treatment (months)

Monthly supervised

Daily, self-​administered

Paucibacillary

Rifampicin 600 mg

Dapsone 100 mg

 6

Multibacillary

Rifampicin 600 mg Clofazimine 300 mg

Clofazimine 50 mg Dapsone 100 mg

12 12

CHAPTER 311  Mycobacterial infection other than tuberculosis

Reproduced with permission of Public Health England.

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Approach to diagnosing leprosy

Management of reactional states in leprosy

In an endemic area, leprosy should be considered in any patient presenting with peripheral neuropathy or persistent skin lesions. In the UK, leprosy is frequently missed and should be considered in any patient who has ever lived abroad and who presents with peripheral anaesthesia and nerve thickening (which should always be sought in immigrants with supposed diabetic neuropathy), unusual skin lesions, or unexplained acute rheumatological presentations. All suspected patients should be referred to a national specialist in leprosy (see https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/334363/ Memorandum_on_leprosy_2012.pdf for a list of UK consultant advisers in leprosy). Histological diagnosis is the gold-​standard test, with the presence of neural inflammation distinguishing leprosy from other granulomatous disorders. Microscopy of slit-​skin smears for bacilli is useful for identifying infectious patients and to monitor the response to treatment, but is of little value in diagnosis since it is negative in many patients with leprosy. The bacillary load is measured by counting the average number of bacilli seen in 6–​8 slit-​skin smear preparations, yielding a ‘bacterial index’ (BI). In this semi-​quantitative logarithmic scale, a BI of 1+ indicates at least 1 bacillus per 100 microscopic fields, and the maximum possible BI of 6+ found in polar lepromatous leprosy indicates 1000 or more bacilli per field (Table 311.2).

Reactional states require urgent assessment and treatment in order to prevent permanent nerve dysfunction. Type 1 reactions are treated with oral corticosteroids, which are gradually tapered over 3–​5 months. Decompressive surgery is occasionally used to relieve mechanical obstruction caused by nerve oedema if nerve dysfunction persists despite medical treatment. Similarly, high-​dose corticosteroids are initially used to treat erythema nodosum leprosum reactions but alternative agents such as thalidomide may be required to achieve sustained control. Reactions may continue to occur for years after successful antimicrobial therapy, and patients must be educated about the possibility and nature of reactions and the need to contact their physician immediately if symptoms arise.

Other diagnoses that should be considered aside from leprosy The varied manifestations of leprosy lead to a broad differential diagnosis including sarcoidosis, cutaneous leishmaniasis, post-​kala-​azar dermal leishmaniasis, cutaneous TB, syphilis, granuloma annulare, vitiligo, post-​ inflammatory hypopigmentation, pityriasis versicolor, dermatophyte infection, and hereditary neuropathies associated with nerve thickening.

Treatment of leprosy, and its effectiveness Antimicrobial therapy for leprosy All patients diagnosed with leprosy should receive multidrug combination treatment. WHO recommends two first-​line regimens corresponding to its simplified classification system (Table 311.3). Prior to the adoption of current treatment guidelines, 24 months of antimicrobial therapy was recommended for multibacillary disease but this has been reduced to 12 months for field use in endemic settings. Reported relapse rates following directly observed multidrug therapy are very low. All treatment should be managed in conjunction with a leprosy specialist. Contact details for designated consultant advisers in leprosy in the UK are available at https://www. gov.uk/government/uploads/system/uploads/attachment_data/ file/334363/Memorandum_on_leprosy_2012.pdf.

Prevention of disability in leprosy Rapidly identifying nerve dysfunction and early institution of steroid therapy are essential in preventing disability. Hence, a detailed neurological assessment should be performed at each clinical encounter. If neuropathy occurs, prevention of secondary tissue damage is the primary objective. Patients should be educated to avoid activities that put neuropathic areas at risk, provided with appropriate orthotics, and advised to undertake regular self-​examination. Secondarily infected tissues require prompt antibiotic treatment and possibly surgical debridement to minimize tissue damage.

Further Reading Alvarez-​Uria G. Lung disease caused by nontuberculous mycobacteria. Curr Opin Pulm Med 2010; 16: 251–​6. Griffith DE, Aksamit T, Brown-​Elliott BA, et al. An official ATS/​IDSA statement:  Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175: 367–​416. Haworth CS, Banks J, Capstick T et al. British Thoracic Society guidelines for the the management of non-tuberculous mycobacterial pulmonary disease. Thorax 2017; 72: ii1–ii64. Johnson MM and Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis 2014; 6: 210–​20. Public Health England. Memorandum on Leprosy. Departments of Health, 2012. https://www.gov.uk/government/uploads/system/ uploads/attachment_data/file/334363/Memorandum_on_leprosy_2012.pdf. Lastória JC and Abreu MA. Leprosy: Review of the epidemiological, clinical, and etiopathogenic aspects—​Part 1. An Bras Dermatol 2014; 89: 205–​18. Rodrigues LC and Lockwood DNJ. Leprosy now:  Epidemiology, progress, challenges, and research gaps. Lancet Infect Dis 2011; 11: 464–​70.

312 

Spirochaetal infection (non-syphilis)

Lucy Cottle and Mike Beadsworth

Introduction Spirochaetes are slender, helical, Gram-​negative rods. The group includes Treponema, Leptospira, and Borrelia, which are further classified as summarized in Table 312.1. This chapter focuses on leptospirosis and Lyme disease; syphilis is covered in Chapter 313. Discussion of the non-​ venereal treponematoses and relapsing fevers is beyond the scope of this text; they are rarely encountered in the UK.

Leptospirosis Definition of leptospirosis Leptospirosis is a zoonotic infection caused by Leptospira interrogans. There are over 250 serovars associated with infection in different animals, for example Leptospira interrogans icterohaemorrhagiae (rats) and Leptospira interrogans hardjo (cattle).

Aetiology of leptospirosis Animals excrete leptospires in their urine. Humans are incidental hosts and acquire infection through contact with animal urine or contaminated fresh water. Transmission occurs across mucous membranes or damaged skin and possibly via ingestion or inhalation of contaminated water.

Typical symptoms of leptospirosis, and less common symptoms Most infections are asymptomatic or only mildly symptomatic and self-​ limiting. The incubation period is usually 7–​12 days (range 2–​30 days). Illness typically follows a biphasic course, with an acute bacteraemic phase, which lasts for approximately 1 week, and then an immune phase. During the bacteraemic phase, patients may present with a flu-​ like illness with headache, fever, and vomiting. Conjunctival suffusion and myalgia, often affecting the calves, are characteristic. Less frequent findings include hepatosplenomegaly, meningism, and a rash. Patients may show signs of recovery before progressing to the immune phase, when fever and rigors recur with clinical deterioration. Aseptic meningitis is common, while Weil’s disease (jaundice, acute renal failure, and haemorrhage) develops in only a minority.

Demographics of leptospirosis Leptospirosis occurs worldwide, with the highest incidence in tropical and subtropical regions. In the UK, infection is associated with Table 312.1  Principal spirochaetes associated with human disease Genus

Species

Clinical disease

Treponema

Treponema pallidum subspecies pallidum

Syphilis

Treponema pallidum subspecies pertenue

Yaws

Treponema pallidum subspecies endemicum

Bejel

Treponema careteum

Pinta

Leptospira

Leptospira interrogans

Leptospirosis

Borrelia

Borrelia burgdorferi

Lyme disease

Borrelia recurrentis

Epidemic relapsing fever

Various Borrelia spp.

Endemic relapsing fever

occupational or recreational activities carrying a risk of exposure, such as farming, fishing, sewer work, canoeing, windsurfing, and freshwater swimming. Imported cases in adventure travellers are increasingly recognized.

Natural history of leptospirosis, and complications of the disease The bacteraemic phase may resolve without treatment, and only a minority develop biphasic disease. The immune phase can last up to 30 days, and recovery may take up to 3 months after severe disease; however, most patients recover within 2–​6 weeks with appropriate treatment. Complications include renal failure, haemorrhage, hepatic dysfunction, myocarditis, rhabdomyolysis, pulmonary haemorrhage, and acute respiratory distress syndrome.

Approach to diagnosing leptospirosis Diagnosis requires a high index of suspicion in a febrile patient with headache, myalgia, conjunctival suffusion, or jaundice, and possible exposure to leptospires.

Other diagnoses that should be considered aside from leptospirosis Depending on the travel history, the differential diagnosis may include influenza, dengue, yellow fever, hantavirus, malaria, typhoid fever, rickettsial disease, viral hepatitis, meningococcal disease, and relapsing fever.

‘Gold-​standard’ diagnostic test for leptospirosis Most cases of leptospirosis are identified through serology. Antibodies to leptospires may be detected 5–​10 days after symptom onset. An IgM ELISA is used to screen all sera, with positive results confirmed by a microscopic agglutination test. At least two serum specimens are required, taken at least 7 days apart.

Acceptable diagnostic alternatives to the gold-​standard test for leptospirosis PCR is used on clinical samples (e.g. blood, urine, CSF, bronchoalveolar lavage, and tissue) taken within 7  days of symptom onset. Leptospira culture can be performed from blood culture and samples of blood, CSF, and tissue. Culture is performed on clinical samples that have tested PCR positive.

Other relevant investigations for leptospirosis Patients may have a leucocytosis or leucopenia, and about half have mild-​to-​moderate elevations in hepatic transaminases and creatine kinase. In Weil’s disease, the bilirubin may be very high, and there is often thrombocytopenia and renal impairment. CSF may show raised white cells and protein, and normal glucose.

Prognosis of leptospirosis, and how to estimate it For leptospirosis, mortality is 5 cells/​mm3). A  negative direct treponemal test (TPPA or TPHA) on CSF (without blood contamination) excludes neurosyphilis in the majority of cases; however, it can be negative in cortical disease. A  positive test has a high sensitivity for CNS infection. It must be noted that CSF TPPA/​TPHA tests are prone to false-​positive results (poor specificity) due to immunoglobulins crossing the blood–​brain barrier.

The mainstay of treatment is parenteral penicillin, given for a sufficiently long period to cover the slow replication time of T. pallidum. Other agents such as cephalosporins and tetracyclines have also been shown to be effective. Treatment duration is based on the stage of clinical infection. National guidelines for the treatment of syphilis exist, and an expert opinion should also be sought prior to initiating treatment.

Prognosis and how to estimate it If treated in the early stages of infection, syphilis has an excellent prognosis and is curable. If treatment is delayed for several years, disabling and life-​threatening complications can result; therefore, individuals at high risk should undergo regular screening.

CHAPTER 313 Syphilis

Table 313.1  Summary of common clinical and serological manifestations of syphilis infection, by stage

Further Reading Kingston M, French P, Higgins S, et  al. UK national guidelines on the management of syphilis 2015. Int J STD & AIDS 2016; 27: 421–​46. Mattei PL, Beachkofsky TM, Gilson RT, et al. Syphilis: A reemerging infection. Am Fam Physician 2012; 86: 433–​40. Singh AE and Romanowski B. Syphilis: Review with emphasis on clinical, epidemiologic, and some biologic features. Clin Microbiol Rev 1999; 12: 187–​209. Timmermans M and Carr J. Neurosyphilis in the modern era. J Neurol Neurosurg Psychiatry 2004; 75: 1727–​30. Unemo M, Bradshaw CS, Hocking JS et al. Sexually transmitted infections: challenges ahead 2017. Lancet Infect Dis 2017; 17: e235–79

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314 

Rickettsial infection

Tom Fletcher and Nick Beeching

Introduction Rickettsial infections are caused by a variety of obligate intracellular, Gram-​negative bacteria from the genera Rickettsia, Orientia, Ehrlichia, and Anaplasma. Rickettsia is further subdivided into the spotted fever group and the typhus group. Bartonella and Coxiella burnetii bacteria are similar to rickettsiae and cause similar diseases. The range of recognized spotted fever group infections is rapidly expanding, complementing long-​recognized examples such as Rocky Mountain spotted fever (Rickettsia rickettsii) in the US, and Australian tick typhus (Rickettsia australis), as well as those in southern Europe and Africa. Animals are the predominant reservoir of infection, and transmission to people is usually through ticks, mites, fleas, or lice, during blood-​feeding or from scarification of faeces deposited on the skin. In this chapter, we will focus on the two of the most relevant infections encountered in UK practice: African tick typhus, and Q fever.

African tick typhus Definition of African tick typhus African tick typhus is a collective name used for two distinct spotted fever group rickettsial infections that occur in Africa: African tick-​bite fever and Mediterranean spotted fever (MSF; also known as ‘fièvre boutonneuse’). There has been considerable overlap historically between the two, but it is now well recognized that they are distinct diseases, with different epidemiology, bacteriology, and disease presentations.

Aetiology of African tick typhus African tick-​bite fever is caused by Rickettsia africae and is transmitted by hard ticks (Amblyomma spp.) that feed on a wide range of domestic and wild animals. MSF is caused by Rickettsia conorii and is transmitted by the brown dog tick (Rhipicephalus sanguineus). The ticks act as both vectors and reservoirs of the disease, and humans are accidental hosts.

Typical symptoms of African tick typhus, and less common symptoms The majority of patients with African tick typhus present with features common to most rickettsial infections, including fever, severe headache, and malaise. Inoculation eschars (ulcerated lesions with a central dark scab or ‘tâche noire’ at the site of the tick bite) are present in the majority of patients but can be easily overlooked, especially within the hairline. In addition, in African tick-​bite fever there is often prominent neck muscle myalgia, regional lymphadenitis (43%), and multiple eschars (49%). A  generalized cutaneous rash is much more common in MSF (97% vs 49%), and generally occurs on day 3 of the illness.

Demographics of African tick typhus Epidemiological data suggest that Rickettsia africae exists widely throughout sub-​Saharan Africa and the eastern Caribbean. It is the most widespread and commonest of the pathogenic spotted fever group of rickettsiae. It is thought that most rural indigenous populations are infected in childhood with mild clinical disease. However, it is increasingly reported amongst travellers to endemic areas, and seroprevalence studies in travellers have shown incidence rates of up to 5%. In Africa, Rickettsia conorii occurs mainly in Algeria, Morocco, Egypt, and Libya, but has also been isolated in countries such as Kenya, Zimbabwe, and South Africa. Infection in humans in

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sub-​Saharan Africa is much less common, however, as the ticks are more host specific.

Natural history of African tick typhus, and complications, of the disease The mean incubation period is usually 6 days for both infections and, in African tick-​bite fever, complications, such as reactive arthritis, are rare. However, in MSF, severe forms of the infection occur in up to 6% of cases; in addition, neurological, renal, and cardiovascular complications are common, with a mortality rate as high as 2.5%.

Approach to diagnosing African tick typhus African tick typhus should be considered in any febrile traveller returning from sub-​Saharan Africa, particularly when an eschar, lymphadenitis, or rash is present.

Other diagnoses that should be considered aside from African tick typhus Common infections in febrile returning travellers must be considered, particularly malaria (which does not cause a rash or lymphadenopathy), typhoid, other rickettsioses, and meningococcal disease. A risk assessment should also be undertaken for the possibility of a viral haemorrhagic fever.

‘Gold-​standard’ diagnostic test for African tick typhus Serology with immunofluorescence is the most commonly utilized technique for diagnosing African tick typhus and is available in specialist centres. Diagnostic antibody titres are often only seen in convalescent samples and may not appear in those treated early with appropriate antibiotics.

Other diagnostic methods for African tick typhus PCR of serum and in tissue, such as from a biopsy or swab of an eschar site, is increasingly utilized in diagnosing African tick typhus. Cell culture can also be performed from clinical specimens but has several limitations and is not routinely undertaken.

Other relevant investigations for African tick typhus In African tick typhus, elevated levels of C-​reactive protein and liver enzymes are often seen in combination with mild thrombocytopenia and lymphopenia.

Treatment of African tick typhus, and its effectiveness The treatment of African tick typhus should be based on clinical suspicion and should not be delayed for confirmatory serology. The tetracycline class of antibiotics is most commonly utilized, with a high degree of efficacy and minimal toxicity. A standard regimen is doxycycline 200 mg daily for up to​ 14 days. Alternatives include chloramphenicol and macrolides.

Q fever Definition of Q fever Q (for ‘query’) fever is so called because, for many years, its cause was unknown. It is a zoonosis caused by the Gram-​negative intracellular coccobacillus Coxiella burnetii. Its diagnosis can be difficult, due to the variety of clinical presentations, and the delay involved in serological confirmation.

Aetiology of Q fever

‘Gold-​standard’ diagnostic test for Q fever

Coxiella burnetii is widespread globally, except in New Zealand, and has a resistant spore-​like form which survives for prolonged periods in the environment. A wide variety of ticks, birds, rodents, and wild mammals can be infected, but domestic ruminants (sheep, cattle, and goats) are the most frequent sources of human infection. Aerosols are the major route of transmission to humans, either from direct exposure to infected tissues or from indirect exposure through contaminated dust. However, direct contact with animals is not required.

Serology using indirect immunofluorescence is the most accurate and readily available diagnostic test for Q fever. Antibodies may be detected 2–​3 weeks after the onset of the disease, and tests should be performed on both acute and convalescent samples. Phase I IgG of ≥1:800 at 6 months is considered diagnostic of chronic infection and is one of the major modified Duke criteria for endocarditis.

The most typical manifestation of Q fever is an undifferentiated febrile illness similar to influenza, but other common presentations include atypical pneumonia and hepatitis. The hepatitis is usually asymptomatic; however, patients with only mild biochemical abnormalities may have significant histological changes, and hepatic coma and death has been reported. Neurological symptoms are recognized in 4%-​22% of all Q fever cases, with meningoencephalitis, meningitis, and myelitis being the most common neurological presentations. Chronic malaise and fatigue may persist for months after the acute illness.

Demographics of Q fever In the UK, 5% of the population have serological evidence of past exposure to Q fever, rising to ~15% in farmers. However only 50–​ 100 cases of Q fever are reported each year, due to many cases being asymptomatic, or mild and under-​investigated. Outbreaks have occurred in a variety of settings. Q fever is associated with certain risk occupations, including farming, working in an abattoir, and meat packing, but, frequently, there is no history of obvious exposure. Pregnancy, valvular heart disease, and immunosuppression are factors associated with more severe disease and progression to chronic infection.

Natural history of Q fever, and complications of the disease The incubation period of Q fever is between 7 and 30 days; most patients make a complete recovery, and death is rare. The main complication is chronic infection that presents months to several years after the initial infection. This occurs in 1%–​5% of patients, and in 60%–​70% results in endocarditis, which develops more slowly than other forms of infective endocarditis and which frequently relapses, despite prolonged antibiotic treatment.

Approach to diagnosing Q fever Q fever should be considered in any acute febrile illness, atypical pneumonia, or aseptic meningitis. Laboratory clues include raised transaminases and thrombocytopenia. Chronic infection should also be considered in all those with a ‘culture-​negative’ endocarditis.

Culture for Q fever is not routine, and requires Biosafety Level 3 laboratories, but is available from specialist laboratories. PCR can also identify Coxiella burnetii in blood, urine, and tissue samples. Complement fixation tests are available but are less specific and sensitive.

Other relevant investigations for Q fever All patients with confirmed Q fever should have a transthoracic echocardiogram, but it is recognized that cardiac vegetations are evident in only 12% of patients with chronic infection. Repeat serological testing looking for evidence of progression to chronic infection should be undertaken.

Prognosis for Q fever Death is rare in acute infection and, with effective antibiotic therapy for endocarditis, mortality is less than 10%. However, relapse rates of over 50% after cessation of antibiotic therapy can occur, and delay in diagnosis has an important effect on the prognosis of chronic Q fever.

Treatment of Q fever, and its effectiveness Tetracycline or doxycycline is the treatment of choice in acute Q fever, but fluoroquinolones should be used for patients with neurological symptoms because of their better penetration of the CNS. Co-​trimoxazole is used in women who are pregnant or breast feeding, and in children under 12. Rarely, severe cases of hepatitis may require additional treatment with corticosteroids. The first line treatment of Q fever endocarditis is a combination of doxycycline and hydroxychloroquine, for a minimum of 18 months depending on serological response.

Further Reading Jensenius M, Fournier PE, Kelly P, et al. African tick bite fever. Lancet Infect Dis 2003; 3: 557–​64. Kersh GJ. Antimicrobial therapies for Q fever. Expert Rev Anti Infect Ther 2013; 11: 1207–14. Paris DH and Dumler JS. State of the art of diagnosis of rickettsial diseases: the use of blood specimens for diagnosis of scrub typhus, spotted fever group rickettsiosis, and murine typhus. Curr Opin Infect Dis 2016; 29: 433–9. Schneeberger PM, Wintenberger C, van der Hoek W, et al. Q fever in the Netherlands - 2007-2010: what we learned from the largest outbreak ever. Med Mal Infect 2014; 44: 339–53.

CHAPTER 314  Rickettsial infection

Typical symptoms of Q fever, and less common symptoms

Other diagnostic methods for Q fever

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315 

Fungal infection

Stacy Todd and Nick Beeching

the most common pathogenic species, but an increasing number of non-​fumigatus species are known to cause disease.

Introduction Fungi, comprising yeasts, moulds, and higher fungi have a worldwide distribution and are uncommon causes of disease in healthy individuals. However, over the last 20 years invasive fungal disease (IFD) has become an increasing cause of morbidity and mortality. This is probably due to the increasing numbers of patients with underlying host conditions, which predispose to opportunistic IFD (e.g. transplant and anti-​tumour necrosis factor immunosuppression, HIV, or chronic lung disease), and to increased recognition of endemic IFD (e.g. histoplasmosis), which cause disease in both immunocompetent and immunocompromised hosts in selected geographic locations. Diagnosis of IFD remains a challenge. Symptoms are often non-​ specific, and a definite diagnosis requires invasive sampling with appropriate laboratory testing of these samples. Non-​invasive tests are being developed, but their positive and negative predictive values still need validation. Diagnostic criteria (‘proven, probable and possible’ (see Table 315.1) established primarily for use in research, and clinical trials can also prove useful in clinical environments. However, the most important step in identifying patients with IFD is to consider the diagnosis in those at risk. This chapter will focus on the commonest causes of IFD: Candida spp., Aspergillus spp., Cryptococcus spp., and histoplasmosis.

Aspergillus infection Definition of aspergillosis Aspergillosis is classically divided into invasive, saprophytic, and allergic disease. Invasive aspergillosis typically enters via the respiratory tract, sinuses, or skin, and can reach other tissues via direct extension or haematogenous spread. Saprophytic disease includes otomycotic disease and aspergilloma. Allergic disease includes aspergillus sinusitis and allergic bronchopulmonary aspergillosis (ABPA).

Aetiology of aspergillosis Aspergillus spp. comprise a globally recognized family of moulds which grow in oxygen-​rich environments such as air-​conditioning units, hospital environments, and decaying vegetation. Aspergillus fumigatus is

Invasive aspergillosis typically presents with non-​specific features of pneumonia, such as fever, cough, and dyspnoea. Pleuritic chest pain and haemoptysis are reported, particularly when there has been vascular invasion. Tracheobronchitis can cause lobar collapse if pseudomembranes develop. In neutropenic patients, persistent fever may be the only symptom of invasive aspergillosis. Extra-​pulmonary aspergillosis can cause sinusitis or skin lesions, progressing to local invasion to cause meningitis, renal, and hepatic dysfunction. Chronic saprophytic disease presents with haemoptysis, or may be found incidentally when imaging is performed for other reasons. Osteomyelitis, prosthetic device infections, and endophthalmitis have been reported. ABPA presents with wheeze, chronic productive cough, fever, and anorexia, or may be suspected due to inappropriately high eosinophilia in asthmatics.

Demographics of aspergillosis Host factors which predispose to invasive aspergillosis include: • decreased quantity or function of neutrophils due to myeloablative chemotherapy and corticosteroids • immunological biological agents such as anti-​ tumour necrosis factor agents • haemopoetic stem cell transplant patients, particularly those who have acquired cytomegalovirus or have severe graft versus host disease • solid organ transplant patients. Invasive aspergillosis has also been reported in critically ill patients without preexisting immunocompromise. Conditions which increase the risk of other forms of aspergillus disease include preexisting structural lung disease (bronchiectasis/​previous tuberculosis) leading to a chronic necrotizing aspergillosis, and/​or aspergilloma. Patients with asthma and cystic fibrosis are at increased risk of ABPA, although there is likely to be a genetic component involved in whether a patient will go on to develop ABPA after colonization.

Table 315.1  Diagnostic classification of non-​endemic invasive fungal disease

Natural history of aspergillosis, and complications of the disease

Diagnostic Classification of IFD

Diagnostic Criteria

PROVEN (a OR b)

a. Histopathological documentation of infection

Invasive aspergillosis is almost universally fatal if it is not identified and if appropriate treatment is not commenced early. The initial presentation is normally with pulmonary disease, which can progress to haemorrhagic infarction and necrotizing pneumonia. Inadequate therapy can lead to CNS involvement or direct extension into intra-​ thoracic structures. Recent improvements in survival have been due to alterations in the levels of immunosuppression used for transplantation, increased awareness of the disease, use of prophylaxis, and early empirical treatment.

b. Culture of fungal species from a normally sterile site PROBABLE (c, d AND e) POSSIBLE (2 from c, d OR e)

c. Host factors including immunosuppression (neutropenia, corticosteroid use, anti-​TNF agents) d. Clinical manifestations e. Microbiological evidence (direct/​indirect tests, not meeting proven diagnostic criteria)

Abbreviations: IFD, invasive fungal disease; TNF, tumour necrosis factor. Reproduced with permission from Ben De Pauw et al., Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/​Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/​MSG) Consensus Group:, Clinical Infectious Diseases, Volume 46, Issue 12, pp. 1813–​21, Copyright © 2008 Oxford University Press.

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Typical symptoms of aspergillosis, and less common symptoms

Approach to diagnosing aspergillosis There is a high index of suspicion of aspergillosis in patients who are potentially at risk of the disease.

Other diagnoses that should be considered aside from aspergillosis Other diagnoses that should be considered aside from aspergillosis are other causes of pneumonia, including bacterial community and

‘Gold-​standard’ diagnostic test for aspergillosis The gold-​standard diagnostic test for aspergillosis is a fungal culture and/​or histopathology from tissue samples, typically taken at bronchoscopy or rhinoscopy, or samples taken from a normally sterile environment (e.g. pleural fluid).

Acceptable diagnostic alternatives to the gold-​standard test for aspergillosis Chest X-​rays are often normal, so it is important to perform to chest CT early. Characteristic (but not pathognomonic) changes of invasive aspergillosis include early pulmonary nodules, macro-​nodules with surrounding ground-​glass changes (‘halo sign’), and air crescent signs. Other non-​ specific pulmonary signs include consolidation, infarcts, and cavitation. In patients with tracheobronchitis, collapse and pseudomembranes are seen, along with ‘tree and bud’ appearances. Fungal balls and cavities can also be seen on CT, when investigating aspergillomas. Increasing availability of galactomannan antigen testing provides a useful adjunct to diagnosis of invasive aspergillosis. It can be measured in bronchoalveolar lavage fluid, CSF, plasma, and fluid, with a sensitivity of 71% and specificity of 89% in serum for patients with haemopoetic stem cell transplants. False positives occur with concomitant use of piperacillin/​tazobactam, and there is cross-​reactivity with other fungal species. Serial testing is preferred. Identification of fungal elements in sputum, bronchoalveolar lavage fluid, and sinus aspirate can also indicate invasive aspergillus disease.

Other relevant investigations for aspergillosis CT of the head and sinuses may also be helpful. Bronchoscopy is useful, not only to obtain samples for culture and histology, but also to look for typical macroscopic appearances of tracheobronchitis. Elevated IgE aspergillus-​precipitins are useful for the diagnosis of ABPA, but not for the diagnosis of invasive aspergillosis. Blood cultures are seldom positive, even in cases of endocarditis.

Prognosis of aspergillosis, and how to estimate it Invasive aspergillosis can rapidly be fatal. Improved outcomes at 6 weeks are reported in those not having myeloablative treatments, and those not requiring invasive ventilation or renal support.

Treatment of aspergillosis and its effectiveness First-​line treatment for invasive aspergillosis is normally with voriconazole, which is superior to liposomal amphotericin B. Newer agents such as caspofungin and other echinocandins can be used as salvage therapy. Oral itraconazole has been used particularly in chronic cavitatory pulmonary aspergillosis. Fluconazole is not effective against Aspergillus spp., but there may be a role for newer agents such as posaconazole or isavuconazole in some patients. Aspergillomas do not respond to antifungal medication and may require surgical resection. ABPA is usually treated with corticosteroids alone; occasionally, systemic antifungal drugs such as itraconazole are used, but only in the context of severe disease and after consultation with experts.

Candida infection Definition of candidiasis Candidiasis can be divided into mucocutaneous disease, focal infection in specific organs, or fungaemia/​invasive disease.

Aetiology of candidiasis Candida spp. are the commonest cause of IFD worldwide. Although the dominant pathogen has been C. albicans, other species including C.  glabrata, C.  tropicalis, and C.  krusei have emerged over the last 15 years. Candida spp. are commensal organisms of the gastrointestinal tract and, occasionally, of the skin. Infection is normally due to invasion by these commensal organisms, rather than new infection.

Typical symptoms of candidiasis, and less common symptoms Typical symptoms depend on the site of infection. In mucocutaneous disease, classical white plaques are seen on the hard palate; dysphagia and odynophagia are the hallmarks of oesophageal candidiasis. Genitourinary candidiasis presents with dysuria, vaginal discharge, and itch. Visual loss is a presenting feature of endophthalmitis. Invasive candidiasis normally presents as fever and/​or sepsis syndrome with no obvious source. Some patients, particularly those who are neutropenic, can present with a disseminated papulonodular rash, which is a sign of disseminated disease.

Demographics of candidiasis As the pathogen is normally a commensal, the precipitating factor is a change in the patient’s own host defences, especially the development of neutropenia. Others at a higher risk include those who have had broad-​spectrum antibiotics, or who have total parenteral nutrition, recent gastrointestinal surgery, haemodialysis, or indwelling vascular catheters. Although mucocutaneous candidiasis is relatively common in HIV, invasive candidiasis only tends to occur when a patient is extremely immunosuppressed.

Natural history and complications of candidiasis Untreated candidaemia has a high mortality. Even with treatment, mortality can be as high as 50% in neutropenic patients. Candidaemia which is not detected early can result in dissemination to other tissues, leading to endophthalmitis, endocarditis, bone and joint involvement, and meningitis. Chronic mucocutaneous candidiasis can be a sign of underlying immunosuppression, and should prompt further investigation. Depending on the cause, it does not normally affect mortality, but can cause considerable morbidity and distress to patients.

Approach to diagnosing candidiasis There is a high index of suspicion of candidiasis in patients who are potentially at risk of this disease. Ophthalmoscopy should be performed in all patients with suspected or proven candidaemia.

Other diagnoses that should be considered aside from candidiasis Other diagnoses that should be considered aside from candidiasis are other causes of fever in neutropenic patients, including bacteria (community and nosocomial organisms (e.g. Nocardia spp.)), mycobacteria, and viruses. Non-​resolving mucocutaneous lesions should also prompt investigations for underlying malignancy, HIV, and diabetes mellitus.

CHAPTER 315  Fungal infection

nosocomial organisms (e.g. Nocardia spp.), mycobacterial, and viral causes. Pulmonary emboli and adult respiratory distress syndrome can also present with similar symptoms in critically ill patients.

‘Gold-​standard’ diagnostic test for candidiasis Candida spp. grow readily in standard culture media and on blood agar plates, as well as special media such as Sabouraud’s agar. Identification of these organisms in normally sterile fluids such as blood or CSF should prompt early treatment. Production of germ tubes in culture is a simple test to distinguish C. albicans from other species, which are more likely to have antifungal resistance.

Acceptable diagnostic alternatives to the gold-​standard test for candidiasis Identification of Candida spp. in environments such as sputum, bronchoalveolar lavage fluid, urine, and skin swabs should be interpreted with caution, as most isolates will be commensals rather than pathogens. When Candida spp. have been isolated, clinicians should consider whether the patient is in a high-​risk group, whether the organism has been isolated on more than one occasion, and whether there are any other causes for the symptoms.

Other relevant investigations for candidiasis Histological findings consistent with candidiasis, such as hyphae and pseudohyphae in tissue samples, can help with diagnosis. However, there is no role at present for serological assays in the diagnosis of candidiasis, although tests are in development.

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Prognosis of candidiasis, and how to estimate it Invasive candidiasis has a poor outcome. Patients with a Candida spp. isolated from blood cultures have a twofold higher mortality rate than those with non-​candidal blood stream infection. Worse outcomes are associated with delayed commencement of therapy and inadequate antifungal regimens.

inflammatory syndrome (IRIS). In non-​ HIV immunosuppressed states, acute mortality is 15%–​21%. Up to 40% of patients who survive the initial illness have significant neurological complications such as hydrocephalus, blindness, and cognitive impairment. Relapses can occur in 20%–​25% of patients, particularly if they remain immunosuppressed.

Treatment of candidiasis and its effectiveness

Approach to diagnosing cryptococcosis

Empirical treatment for candidaemia/invasive candidiasis is with an echinocandin agent such as caspofungin. Fluconazole can be considered for non-neutropenic patients who are not critically ill and who are not considered to be at high risk for fluconazole resistance. Liposomal amphotericin B is an alternative in the case of intolerance or lack of availability of other treatments. Best practice is to remove all invasive venous catheters and to treat for a minimum of 14 days after blood culture clearance. Oral step down to fluconazole can be considered once the patient is clinically stable but should be managed in consultation with an infection specialist. For oesophageal candidiasis, oral fluconazole or amphotericin are the first choice, although echinocandins may be used. A single dose of fluconazole is normally sufficient for uncomplicated vaginal candidiasis.

There is a high index of suspicion in patients who are potentially at risk of invasive cryptococcosis.

Cryptococcal infection

‘Gold-​standard’ diagnostic test for cryptococcosis

CHAPTER 315  Fungal infection

Definition of cryptococcosis

In CNS disease, other causes of meningoencephalitis with a long prodrome, such as syphilis, toxoplasmosis, and tuberculosis, should be considered, in addition to cryptococcosis. Pulmonary cryptococcosis can easily be confused with pneumocystis pneumonia or other causes of pneumonia in the immunocompromised host. Skin manifestations of cryptococcosis can easily be mistaken for malignancy, molluscum contagiosum, or invasive yeast infections other than cryptococcosis, such as histoplasmosis or talaromycosis (penicilliosis). HIV testing should always be performed. The gold-​standard diagnostic test for cryptococcosis is fungal culture from CSF, blood, urine, or skin.

Cryptococcosis, also known as cryptococcus disease, is caused by dissemination of Cryptococcus spp.

Acceptable diagnostic alternatives to the gold-​standard test for cryptococcosis

Aetiology of cryptococcosis

An acceptable diagnostic alternative to fungal culture is the cryptococcal antigen (CrAG) assay, which is available for testing both serum and CSF. Serum tests are positive in >99% of patients with disseminated invasive cryptococcosis. Although this assay is highly sensitive when used to test the CSF, it may be negative when there is non-​ meningeal disseminated cryptococcosis. India ink stains of the CSF are less sensitive than the CrAG assay but may be more readily available in low-​income settings.

Cryptococcus neoformans and C.  gatti are the major causes of disseminated cryptococcosis. They are encapsulated yeasts, which are inhaled from the environment. C.  neoformans is found worldwide and, although C. gatti was thought to be tropical and subtropical in origin, it has recently been implicated in outbreaks in the north-​west United States and Canada. The clinical disease pattern caused by these organisms is similar, and laboratories do not normally speciate further than Cryptococcus spp.

Typical symptoms of cryptococcosis, and less common symptoms The primary route of infection is via inhalation and subsequent haematogenous dissemination. CNS infection is the most dangerous presentation, and often has a prolonged, indolent course with headache, mild confusion, or behavioural change. Focal neurological signs are a sign of late disease and should prompt rapid investigation and treatment. Pulmonary disease can vary from asymptomatic infection, to typical pneumonic symptoms, to disease patterns which can mimic pneumocystis pneumonia. Cutaneous manifestations of disseminated disease are relatively common, with pustular, nodular, umbilicated, or ulcerated lesions. Cryptococcal infection can also disseminate to other organs, including the long bones, the liver, the kidneys, and the spleen. However, it is unusual for such dissemination to present symptomatically in the absence of other signs. There is a relative lack of inflammation associated with invasive cryptococcosis, so high fever and very high inflammatory markers are not common.

Demographics of cryptococcosis The majority of patients presenting with cryptococcosis are immunosuppressed in some way, but some patients with invasive disease (particularly C.  gatti) have a normal immune system. Cryptococcal disease is an AIDS-​defining illness, and its increase in prevalence over the last 35 years has mainly followed the HIV pandemic.

Natural history and complications of cryptococcosis Untreated cryptococcal meningitis is universally fatal. Since the introduction of antiretroviral therapy and combination antifungal treatment, this has improved dramatically, but there is still an acute mortality of 6%–​ 15% related to complications, such as raised intracranial pressure and immune reconstitution

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Other diagnoses that should be considered aside from cryptococcosis

Other relevant investigations for cryptococcosis CT or MRI brain scans are useful to rule out cryptococcomas and should be considered prior to lumbar puncture, due to risks associated with raised intracranial pressure. When a lumbar puncture is performed, there is generally a marked increase in opening pressure with mild increase in protein, lymphocytosis (although the white-​cell count can be normal), and low glucose ratio. For pulmonary disease, chest CT should be considered.

Prognosis for cryptococcosis, and how to estimate it CNS cryptococcosis can be rapidly fatal if not identified. Better outcomes can be expected if immunosuppression can be reversed. Patients with positive CrAG and evidence of disease elsewhere should have a lumbar puncture, even in the absence of CNS symptoms, to assess for evidence of meningitis.

Treatment of cryptococcosis, and its effectiveness For patients with CNS disease and/​or severe respiratory disease, the standard first-​line treatment is IV amphotericin (liposomal if high risk of renal disease), with IV/​oral flucytosine for a minimum of 2 weeks. This should be followed by up to 8 weeks’ oral fluconazole 400 mg daily, to give a total 10-​week induction course. This is then followed by long-​term prophylaxis oral fluconazole 200 mg daily for at least 12 months, and until the CD4 cell count is >100 x 106/​l. For mild/​ moderate pulmonary disease, treatment is with fluconazole 400 mg daily for 6–​12 months, and then prophylaxis until the CD4 cell count is >100 x 106/​l. In HIV-​negative immunosuppression, treat CNS disease with a 10-​week induction period. Fluconazole prophylaxis should continue for 6–​12 months after this induction phase. Most immunocompetent people who have only pulmonary disease will settle with no treatment, but some require short courses of fluconazole to prevent haematogenous spread.

Acceptable diagnostic alternatives to the gold-​standard test for histoplasmosis

Histoplasmosis is caused by infection with variants of the fungus Histoplasma capsulatum.

An acceptable diagnostic alternative to fungal culture is histology of body tissue, as this will often show the characteristic appearances of histoplasmosis (small, oval budding yeasts), especially when silver-​ based or other special stains are used. Paired antigen testing of urine and serum has proved helpful in diagnoses, but there is cross-​reactivity with other fungal diseases; in addition, these tests are not readily available.

Aetiology of histoplasmosis

Other relevant investigations for histoplasmosis

Histoplasma capsulatum is an endemic dimorphic fungus that is found worldwide. The disease is most commonly reported in North and Central America (var. capsulatum), and Africa (var. duboisii).

Other relevant investigations in histoplasmosis include plain chest X-​rays or CT scans, as these can show a diffuse reticulonodular picture in acute disease with some perihilar lymphadenopathy. However, these changes are often fleeting, and may be absent by the time the patient presents. Chronic disease typically causes calcified cavities in the apices. In disseminated disease, other infected tissues beyond the lungs can also be abnormal. In meningitis, multiple enhancing lesions are often located around the basal meninges.

Histoplasmosis infection Definition of histoplasmosis

Typical symptoms of histoplasmosis, and less common symptoms Acute pulmonary histoplasmosis most commonly occurs when an individual is exposed to histoplasma organisms for the first time. Symptoms typically include dry cough, chest tightness, fevers, headaches, and malaise. Joint and skin involvement is seen in 5% of patients, and erythema nodosum or erythema multiforme can occur. In more severe cases, it can progress to acute respiratory distress syndrome. Chronic cavitatory histoplasmosis presents with symptoms and signs similar to pulmonary TB with apical cavitatory changes. Disseminated histoplasmosis involves an indolent course with progressive hepatosplenomegaly, bone marrow involvement, and non-​ specific symptoms of fever, malaise, and weight loss. Less commonly, histoplasmosis can cause pericarditis, meningitis, and granulomatous mediastinitis. Compared with other disseminated fungal diseases, histoplasmosis is more likely to cause peri-​oral or mucous membrane involvement. It can present with addisonism, due to adrenal necrosis. Disseminated skin lesions may be papular or umbilicated.

Demographics of histoplasmosis Within endemic areas, up to 80% of the population have serological evidence of exposure. The fungus is found in nitrogen-​rich soil, in association with bird or bat faeces. Disease tends to occur when a person from an endemic area becomes immunosuppressed, or in non-​immune visitors to endemic settings. Outbreaks have been reported when soil has been disturbed on a large scale, causing aerosolization. Exploration of bat-​infested caves is a risk factor.

Natural history and complications of histoplasmosis Histoplasmosis is usually a self-​limiting condition which does not require treatment, but is occasionally fatal in severe disease. Chronic cavitatory disease is often fatal, because of pulmonary damage, rather that unopposed infection. Progressive disseminated disease is fatal in >90% of patients if untreated.

Approach to diagnosing histoplasmosis There is a high index of suspicion of histoplasmosis in patients who are potentially at risk of the disease.

Other diagnoses that should be considered aside from histoplasmosis In acute pulmonary disease, other causes of atypical pneumonia, aside from Histoplasma capsulatum, should be considered, including other fungi and Mycoplasma pneumoniae. In chronic cavitatory disease, major differential diagnoses include TB, non-​TB mycobacteria, sarcoidosis, malignancy, and other chronic fungal lung conditions. Disseminated histoplasmosis can mimic a variety of conditions (e.g. miliary TB), particularly in the immunocompromised. Skin lesions due to histoplasmosis can mimic umbilicated lesions from other infections, such as cryptococcosis. HIV testing should be done.

‘Gold-​standard’ diagnostic test for histoplasmosis The gold-​standard diagnostic test for histoplasmosis is fungal culture from blood or body tissue. The CSF usually remains sterile in histoplasma meningitis.

Prognosis for histoplasmosis, and how to estimate it Histoplasmosis is usually a self-​limiting condition, but patients on immunosuppressive treatments and those with HIV have a more rapid disease onset and worse prognosis. Even with treatment, up to 50% of HIV-​positive patients die from disseminated disease. Other predictors of a worse outcome include fungaemia, renal impairment, and extremes of age.

Treatment of histoplasmosis and its effectiveness Acute pulmonary histoplasmosis For mild-​to-​moderate acute pulmonary histoplasmosis, no treatment is required, unless symptoms persist for >1 month; in this case, use itraconazole 200 mg three times daily for 3 days, and then 200 mg daily for 6–​12 weeks. For moderately severe to severe disease, use liposomal amphotericin B (3–​5 mg/​kg) daily for 1–​2 weeks, and then itraconazole 200 mg, initially three times daily for 3  days and then daily for a total of 12 weeks; methylprednisolone should also be used during the first 1–​2 weeks if severe respiratory compromise is a problem.

Chronic cavitatory pulmonary histoplasmosis For chronic cavitatory pulmonary histoplasmosis, use itraconazole 200 mg three times daily for 3 days, and then once or twice daily for 12 months (some recommend for 18–​24 months).

CHAPTER 315  Fungal infection

Management of complications such as raised intracranial pressure (via therapeutic lumbar puncture, often repeatedly) and IRIS (via corticosteroids) should always be considered.

Disseminated histoplasmosis For mild-​to-​moderate disseminated histoplasmosis in adults, use itraconazole 200 mg three times daily for 3  days, and then twice daily for 12  months. For moderately severe to severe disease, use liposomal amphotericin B (3 mg/​ kg) daily for 1–​ 2 weeks, then itraconazole 200 mg three times daily for 3  days, and then daily for total of at least 12 months. Patients may need to stay on long-​term suppressive therapy if it is not possible to correct/​stop immunosuppression. Complications, such as joint involvement and skin manifestations, should be treated with NSAIDs or prednisolone if uncontrolled.

Further Reading Adams P. Cryptococcal meningitis: a blind spot in curbing AIDS. Lancet 2016; 387: 1605–6. Denning DW and Chakrabarti A. Pulmonary and sinus fungal diseases in non-immunocompromised patients. Lancet Infect Dis 2017; 17: e357–e366. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/​Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/​ MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–​21.

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Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62: e1–e50. Perfect JR, Dismukes WE, Dromer F, et  al. Clinical practice guidelines for the management of cryptococcal disease:  2010 update by the Infectious Disease Society of America. Clin Infect Dis 2010; 50: 291–​322. Patterson KC and Strek ME. Diagnosis and treatment of pulmonary aspergillosis syndromes. Chest 2014; 146: 1358–68.

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Patterson TF, Thompson GR, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63: e1–e60. Segal BH. Aspergillosis. N Engl J Med 2009; 360: 1870–​84. Wheat LG, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45: 807–​25.

316 

Protozoal infection: Gut organisms

Pavithra Natarajan and Nick Beeching

Definition of the diseases Protozoa are single-​celled (unicellular) eukaryotic organisms. There are many protozoa causing parasitic infection in humans. This chapter will concentrate on the three that most commonly cause gastrointestinal disease worldwide and have the biggest impact in the UK: Giardia lamblia, Cryptosporidium spp., and Entamoeba histolytica. These three infections are of great significance worldwide, but are less common in Western settings. In the UK, they tend to be seen in more commonly in travellers returning from endemic countries, migrant populations, men who have sex with men, and the immunocompromised. The clinical features of all three infections vary from asymptomatic small-​or large-​bowel carriage with passage of cysts to infect others, to more serious manifestations.

Giardiasis Aetiology of giardiasis Giardia lamblia (also known as Giardia intestinalis and Giardia duodenalis) is a flagellated, binucleated protozoan that attaches to the small bowel mucosa and can cause subtotal villous atrophy. Infection is complicated by transient lactase intolerance. Transmission is by ingestion of cysts that are relatively resistant to chlorination and remain viable for several weeks in water, and is most commonly from contaminated water. Person-​to-​person spread can occur in settings of poor faeco-​oral hygiene; less commonly, food-​borne spread can occur. Chronic recurrent infections complicate inherited disorders of immunoglobulin production (e.g. Bruton’s disease.) but not HIV infection.

Typical symptoms of giardiasis, and less common symptoms The incubation period for giardiasis is 1–​2 weeks. The spectrum of disease ranges from asymptomatic infection to chronic diarrhoea or steatorrhoea, with cramping upper abdominal pain and flatulence. This may result in malabsorption and weight loss, especially in children with a poor underlying level of nutrition, or those with preexisting lactase small bowel deficiency. Prolonged illness can cause folate and vitamin B12 deficiency.

Demographics of giardiasis

hamper diagnosis and require examination of multiple stool samples. The laboratory request should always include travel history or other reasons to request parasitological investigation. Multiplex real-​time PCR tests are being introduced by many laboratories to detect all three pathogens simultaneously. Giardia cysts and trophozoites can usually be seen on faecal microscopy, the sensitivity of which is improved using direct antibody fluorescence. Faecal antigen detection (e.g. by EIAs) is more sensitive, and a variety of molecular assays are increasingly being used. Serology has no role in diagnosis. Trophozoites may be seen in aspirates of contents or biopsies from small bowel.

Treatment for giardiasis, and its effectiveness Giardiasis is often self-​limiting, but treatment of symptomatic patients reduces the severity and duration of the disease. Metronidazole or tinidazole are the treatments of choice, and alternatives include paromomycin, albendazole, or nitazoxanide. Rarely, mepacrine (called quinacrine in the US) is used, for severe cases. Refractory cases may respond to exclusion of dietary lactose for 2 weeks during treatment, and treatment of close contacts to prevent reinfection.

Cryptosporidiosis Aetiology of cryptosporidiosis Cryptosporidium parvum and Cryptosporidium hominis are the two most common species causing human infections. They are acquired through the faeco-​oral route, by ingestion of oocysts containing infective sporozoites. Oocysts are highly resistant to chlorination and can survive for prolonged periods in water and damp soil. Person-​to-​ person spread can also occur. Cryptosporidiosis is a zoonosis which can be contracted from contact with a variety of animals, especially calves in petting zoos and other farm animals, or by ingestion of water contaminated by animal faeces. The sporozoites of cryptosporidia invade the epithelial cells of the small bowel and undergo a complex life cycle that includes auto-​reinfection, as well as a sexual life cycle leading to shedding of oocysts in faeces. Severe infections occur in a variety of immunosuppressive states, including severe combined immunodeficiency (SCID), advanced HIV, and inherited immunoglobulin deficiency states, as well as in transplant and chemotherapy patients. In some of these patients, biliary carriage occurs and is difficult to eradicate.

Giardiasis has a worldwide distribution, with an estimated 2–​3 million infections per year. It is a common cause of post-​travel diarrhoea.

Typical of cryptosporidiosis, and less common symptoms

Natural history of giardiasis, and complications of the disease

The typical incubation period of cryptosporidiosis is 3–​6 days. The spectrum of disease ranges from asymptomatic infection to watery diarrhoea, which is often associated with abdominal cramps and sometimes with nausea and vomiting. It is more severe than most types of childhood gastroenteritis, and symptoms typically continue for 10–​12 days, with prolonged cyst shedding. In immunosuppressed patients, persistent, frequent large-​volume watery stool output may be life-​threatening. In these patients, especially those with SCID or HIV, biliary involvement can present as pancreatitis or cholangitis leading to biliary stenosis.

Infection is usually self-​limiting, but it has been suggested that giardiasis may trigger functional irritable bowel disease.

Approach to diagnosing giardiasis, and other diagnoses that should be considered Apart from other bowel infections, causes of malabsorption should be considered, including coeliac disease and pancreatic disease.

‘Gold-​standard’ diagnostic test for giardiasis, and acceptable diagnostic alternatives Microscopic examination of concentrated faecal samples is the gold standard for all three of these infections. This is labour intensive and requires specific expertise, and intermittent excretion of cysts can

Demographics of cryptosporidiosis Cryptosporidiosis occurs worldwide and is the most common protozoal cause of acute gastroenteritis in the UK, with 3000–​6000 laboratory-​confirmed cases annually. It can be responsible for large waterborne outbreaks caused by contaminated drinking water (as

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ordinary water disinfection processes do not kill cryptosporidia), as well as outbreaks associated with swimming pools. It can affect any age group, although it is more common in children under 5 years of age, and more severe in the immunosuppressed. The incidence in people with HIV has decreased since the introduction of highly active antiretroviral therapy.

Natural history of cryptosporidiosis, and complications of the disease In the immunocompetent host, cryptosporidiosis lasts for about 12  days and then tends to settle. Recurrence of symptoms can occur in up to a third of cases, due to relapse or reinfection. Immunocompromised hosts suffer from intractable diarrhoea that can be very difficult to treat and can lead to substantial weight loss and occasional biliary or pancreatic disease.

Approach to diagnosing cryptosporidiosis, and other diagnoses that should be considered

CHAPTER 316  Protozoal infection: Gut organisms

Cryptosporidiosis should be considered in the differential diagnosis of any community-​acquired diarrhoea, especially when prolonged. Coeliac disease should be considered.

‘Gold-​standard’ diagnostic test for cryptosporidiosis, and acceptable diagnostic alternatives Detection of oocysts in faeces by microscopy requires special stains such as auramine, modified Ziehl–​Neelsen, or trichrome stains. Such staining is not part of routine faecal microscopy in many laboratories and may need to be requested specifically. Sensitivity is improved by direct antibody fluorescent techniques and/​or examination of multiple samples. Faecal antigen detection by EIA, and direct detection by PCR, are increasingly used in many laboratories. The organisms can be seen in small bowel biopsies, or in brushings from the biliary tree in immunosuppressed patients with biliary complications. Serology has no role in clinical diagnosis.

Demographics of amoebiasis There are 48  million clinical cases of amoebiasis per year, with at least 70 000 deaths worldwide. It can be responsible for outbreaks in schools.

Natural history of amoebiasis, and complications of the disease Amoebic dysentery is usually self-​limiting, but fulminant amoebic colitis carries a high mortality. ALA can cause thoracic complications, such as pleural effusion and rupture into the bronchial tree or pericardium. In addition, ALA may rupture into the abdomen or become secondarily infected. Uncommonly, an amoeboma may develop as a granuloma, often localized in the ascending colon.

Approach to diagnosing of amoebiasis, and other diagnoses that should be considered When diagnosing amoebiasis, exclude other infections that can cause blood in stool, such as shigellosis or campylobacteriosis. Intestinal amoebiasis may mimic inflammatory bowel disease, from which it must be distinguished, because giving corticosteroids to patients with amoebic infection can have disastrous consequences, such as toxic megacolon, or perineal invasion. The main differential diagnoses of ALA are pyogenic liver abscess, and liver neoplasm.

Treatment for cryptosporidiosis, and its effectiveness

‘Gold-​standard’ diagnostic test for amoebiasis, and acceptable diagnostic alternatives

Cryptosporidiosis is self-​ limiting in immunocompetent hosts, and treatment is not usually required. In immunosuppressed patients, reducing the degree of immunosuppression is the key to management. In patients with immunoglobulin deficiency, replacement immunoglobulin therapy stops the diarrhoea, as does raising the CD4 cell count by 50 × 106 cells/​l in patients with HIV, by giving antiretroviral therapy. Protease inhibitors may have additional direct anticryptosporidial activity. Although combinations of paromomycin and azithromycin have been used in the past in severely immunosuppressed patients, there is no direct effect of these or most antimicrobials. Nitazoxanide, a cheap, broad-​spectrum, antiparasitic agent available in the tropics, is effective in children and in patients with less severe immunosuppression. It is less easy to obtain and more expensive in Europe and other Western settings.

Invasive colonic disease is confirmed by immediate examination of fresh faeces or scrapings of rectal mucus (i.e. within 30 minutes or less after stool passage (the ‘hot stool’)). This is essential to visualize mobile trophozoites containing ingested red cells: these rapidly encyst once exposed to the cold. Cysts of Entamoeba histolytica are morphologically identical to those of the non-​ pathogenic amoeba Entamoeba dispar, which is much more common, and a frequent reason for over-​diagnosis of amoebiasis. The two can be distinguished using commercial antigen detection kits or PCR. Serology is useful in diagnosis of ALA and severe colonic disease, but may be negative in uncomplicated dysentery. In ALA, peripheral neutrophilia is common, and changes at the right lung base are common on chest X-​ray. Ultrasonography of the liver is essential if ALA is suspected. Faecal examinations have no role in diagnosing or excluding ALA.

Amoebiasis Aetiology of amoebiasis In amoebiasis, Entamoeba histolytica invades the colonic mucosa, producing characteristic ulceration and dysentery (bloody diarrhoea). The first stage is attachment of the trophozoite to the human target cell. Infective cysts are passed in the stool, and transmission is by the direct faeco-​oral route. Patients with abnormal lower bowel mucosa (e.g. those with inflammatory bowel disease) are more likely to experience invasive disease, especially if using topical and/​or systemic steroids. There is no direct link with other types of immunodeficiency.

Typical symptoms of amoebiasis, and less common symptoms Most Entamoeba histolytica infection is asymptomatic, and only a small proportion of patients go on to develop clinical disease. Intestinal

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manifestations include amoebic colitis, which causes diarrhoea with blood and mucus, tenesmus, and colicky abdominal pain. Up to 10% of patients infected with Entamoeba histolytica may develop invasive amoebic disease. Amoebic liver abscess (ALA) is the most common form of extra-​intestinal disease. This is caused by spread of infection via the portal vein to the liver, and further haematogenous spread. Patients with ALA are usually acutely unwell, presenting with symptoms including upper abdominal pain, right shoulder tip pain, and fever.

Treatment for amoebiasis, and its effectiveness Asymptomatic carriers should be treated with a bowel luminal agent to minimize the spread of disease. The most effective agents are diloxanide furoate or paromomycin, which are poorly absorbed from the intestine and reach optimal amoebicidal concentrations within the intestinal lumen. Symptomatic colonic or liver disease is treated with ‘tissue amoebicides’ such as metronidazole or tinidazole, which are efficiently absorbed from the small intestine and reach high tissue concentrations. These do not work against remaining intra-​luminal amoebae, which must then be eliminated with a bowel luminal agent. ALA cure can usually be managed with medical therapy alone, but therapeutic aspiration may be needed for large cysts (>10  cm in diameter), especially the minority that involve the left lobe of the liver and have a risk of sudden rupture into the pericardium, causing tamponade.

Checkley W, White AC Jr, Jaganath D, et al. A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium. Lancet Infect Dis 2015; 15: 85–94. Life cycles and information for patients can be found on the websites of the American Centers for Disease Control and Prevention (https://​www.cdc.gov/​parasites/​) and Public

Health England https://www.gov.uk/topic/health-protection/ infectious-diseases) Minetti C, Chalmers RM, Beeching NJ, et al. Giardiasis. BMJ 2016; 355: i5369. Pritt BS and Clark CG. Amebiasis. Mayo Clin Proc 2008; 83:1154–60

CHAPTER 316  Protozoal infection: Gut organisms

Further Reading

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317 

Protozoal infection: Malaria

Nick Beeching, Lynsey Goodwin, and Joanna Peters

Definition of the disease Malaria is a devastating protozoal infection that affects more than 200  million people worldwide each year, killing up to a million. Five species of Plasmodium are recognized causes of human disease:  Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. In the UK, malaria is the most common imported tropical infection.

Aetiology of the disease Malaria parasites (‘sporozoites’) are injected into the human bloodstream by the bite of female Anopheles mosquitoes (see Figure 317.1). The sporozoite is rapidly taken up by the liver, where it can multiply silently for weeks to months (extra-​erythrocytic schizogony) to form a cyst-​like ‘pre-​erythrocytic schizont’ containing thousands of ‘merozoites’. Eventually, the schizont ruptures, releasing merozoites into the bloodstream to invade red blood cells, where they mature and multiply in a cyclical pattern, lasting from 24 hours (Plasmodium knowlesi) to 72 hours (Plasmodium malariae). This culminates in development of intra-​erythrocytic schizonts containing 8–​32 merozoites,

MOSQUITO

Parasites develop to sporozoite stage in mosquito

Some do not multiply but become gametocytes to be taken up by mosquitos

depending on the species. The erythrocytes and schizonts are then disrupted, releasing merozoites to invade further red cells and start another multiplicative cycle. After several cycles, some intra-​erythrocytic parasites differentiate into gametocytes, which fuse and undergo further multiplication within a mosquito to complete the infection cycle. Symptoms that occur during the erythrocytic cycle are related to red-​cell lysis; the release of parasite toxins/​antigens; red-​cell sequestration; and related tissue anoxia. The degree of parasitaemia (percentage of infected red cells) rarely exceeds 1% for all species except Plasmodium falciparum, which can rapidly multiply from a 1% parasitaemia to a >30% parasitaemia and also induces red-​cell sequestration in the capillaries of organs such as the brain, the liver, and the kidneys, resulting in organ dysfunction. This combination of massive parasite load and red-​cell sequestration makes Plasmodium falciparum potentially lethal in non-​immune patients (i.e. those seen in the UK). Malaria may also be transmitted by blood products, needle-​stick injury, and IV drug use; in addition, occasionally, it can be transmitted transplacentally. Both perinatal transmission and the deleterious effects of malaria on intrauterine fetal growth are exacerbated by concurrent maternal HIV infection. Heterozygous haemoglobinopathies

Sporozoites injected

Taken up by the liver

All 5 species develop in the liver

Schizont in the liver

Vivax and ovale malaria also have a dormant (hypnozoite) stage in the liver

Parasites multiply in red blood cells leading to clinical illness Parasites released to invade and develop in red blood cells

Hypnozoites ‘awake’ and become schizonts (months after exposure)

Figure 317.1  Simplified life cycle of malaria. Adapted with permission from Public Health England: Chiodini P, Hill D, Lalloo D, et al. Guidelines for malaria prevention in travellers from the United Kingdom. London, Health Protection Agency, January 2007. ISBN: 0 901144 83 5.

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Typical symptoms of the disease, and less common symptoms In an endemic area, partial immunity develops in survivors of repeated childhood infection, and asymptomatic parasitaemia is not uncommon. The main effects on children in these settings are fever with severe anaemia, respiratory distress, or coma. Rarer sequelae of chronic malaria include hyper-​reactive splenomegaly and malarial nephropathy (the latter is caused by Plasmodium malariae). In non-​immune people who are returning to Europe from countries where malaria is endemic, the symptoms of uncomplicated malaria are similar those for influenza and may include the abrupt onset of malaise, intermittent rigors, chills, myalgia, and headache. Cough, diarrhoea, and jaundice may also be seen, and patients may not have fever at presentation. The symptoms of malaria are protean. The classical fever patterns (tertian, quartan, etc.) related to the cycle of red-​cell lysis and parasite release may not be present in the first 7–​10 days of infection. However, severe malaria can rapidly develop in Plasmodium falciparum infections, with failure of one or more organs, and may manifest as renal failure, acidosis, haemolytic anaemia, liver failure, respiratory distress syndrome, or brain involvement leading to convulsions and/​or coma. Altered consciousness may also occur, due to unrecognized hypoglycaemia (see Box 317.1). Vivax malaria can occasionally cause severe disease; this is usually respiratory distress syndrome or renal, or brain involvement. Splenic rupture is also reported. The pathophysiology of severe non-​falciparum infection is poorly understood but does not relate to erythrocyte sequestration.

Demographics of the disease Malaria is found throughout the tropics, and is making a comeback in areas where control programmes have failed. Local transmission in Greece in 2012 served as a reminder that malaria used to be endemic around the whole Mediterranean basin, extending as far north as the UK until the 1920s. Seventy-​five per cent of cases in the tropics occur in children, especially in Africa. In European settings, the majority of cases occur in people who travel to visit friends or relatives in the tropics. Other tourists, business travellers, and special groups such as military personnel account for about 25% of approximately 2000 cases imported to the UK each year. Overall, about 75% of these are Plasmodium falciparum infections, related mostly to travel to sub-​Saharan Africa, in contrast to the case in the 1970s and 1980s, when the majority of malaria cases were Plasmodium vivax infections imported from South Asia.

Box 317.1  Features of severe falciparum malaria in the European setting Parasitaemia > 2% Acidosis (pH