Clinical Gastroenterology: A Practical Problem Based Approach [3rd Edition] 9780729539487, 9780729579483, 9780729582551

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Clinical Gastroenterology: A Practical Problem Based Approach [3rd Edition]
 9780729539487, 9780729579483, 9780729582551

Table of contents :
Front Cover
......Page 1
Clinical gastroenterology......Page 4
Copyright
......Page 5
Dedication......Page 6
Foreword
......Page 8
Contents......Page 10
Preface......Page 12
Contributors......Page 14
History......Page 16
Pathophysiology of GORD......Page 18
Investigation of Heartburn and Acid Regurgitation......Page 19
Treatment......Page 22
Non-cardiac Chest Pain......Page 27
Key Points......Page 29
Pain on Swallowing (Odynophagia)......Page 30
Dysphagia......Page 31
Key Points......Page 41
Hiccups......Page 42
Sore Mouth......Page 46
Bad Breath......Page 48
Key Points......Page 50
Introduction......Page 52
Pathological Causes......Page 53
Generalised Abdominal Pain......Page 55
Acute Abdominal Colic......Page 61
Acute Epigastric Pain......Page 65
Acute Pancreatitis And Its Complications......Page 66
Right Upper Quadrant Pain......Page 70
Right Iliac Fossa Pain......Page 76
Left Iliac Fossa Pain......Page 78
Key Points......Page 79
Pathogenesis......Page 81
Management Guidelines......Page 82
Key Points......Page 87
Mechanisms Underlying Epigastric Pain......Page 88
Clinical Assessment......Page 89
Chronic Peptic Ulcer......Page 90
Management of Dyspepsia......Page 91
Diseases Associated With Epigastric Pain or Discomfort......Page 93
Key Points......Page 101
History......Page 103
Differential Diagnosis......Page 105
Clinical Evaluation......Page 109
Irritable Bowel Syndrome (IBS)......Page 110
Key Points......Page 113
Investigations......Page 115
Laboratory Tests......Page 117
Symptoms Associated with Intestinal Gas......Page 118
Key Points......Page 120
Physiology of Vomiting......Page 121
History......Page 122
Investigation......Page 123
Important Diseases that may cause Nausea and Vomiting......Page 125
Principles of Treatment......Page 127
Key Points......Page 128
Introduction......Page 130
Vomiting Blood......Page 131
Passing Melaena Alone......Page 137
Bright Red Blood Per Rectum......Page 138
Iron Deficiency Anaemia......Page 141
Positive Faecal Occult Blood Test......Page 142
Key Points......Page 143
Introduction......Page 145
Clinical Approach to Patients with Constipation......Page 146
Investigations......Page 147
Approach to Management......Page 150
Surgical Treatment......Page 151
Clinical Approach to Specific Types of Constipation......Page 152
Key Points......Page 154
Case
......Page 156
Examination......Page 157
Fissure-in-Ano......Page 158
Anal Sepsis......Page 160
Haemorrhoids......Page 165
Pruritus Ani......Page 169
Chronic Perianal Pain Syndromes......Page 170
Key Points......Page 171
Introduction......Page 173
Clinical Approach to Acute Diarrhoea......Page 174
Conditions Causing Food-borne Illnesses......Page 177
Travellers’ Diarrhoea......Page 179
Conditions Causing Acute Watery Diarrhoea......Page 180
Conditions Causing Acute Blood Diarrhoea......Page 182
Antibiotic-associated Diarrhoea and C. difficle Colitis......Page 186
Diarrhoea Associated with AIDS......Page 187
Key Points......Page 188
History......Page 189
Physical Examination......Page 190
Malabsorption......Page 191
Clinical Approach to the Patient with Malabsorption......Page 195
Disorders that may Cause Chronic Diarrhoea or Malabsorption......Page 198
Inflammatory Bowel Disease......Page 203
Key Points......Page 204
Introduction......Page 205
Ulcerative Colitis......Page 206
Crohn's Disease......Page 213
Key Points......Page 219
Definitions......Page 221
Examination......Page 222
Physiological Anorectal Assessment......Page 223
Conditions Causing Incontinence with a Normal Sphincter......Page 226
Conditions Causing Incontinence with an Abnormal Sphincter......Page 228
Key Points......Page 233
Introduction......Page 235
Pathophysiology of Anorexia and Weight Loss......Page 236
Clinical Approach to Anorexia and Weight Loss......Page 237
Management of Patients with Weight Loss......Page 241
Nutritional Support......Page 243
Diseases Associated with Weight Loss......Page 246
Key Points......Page 252
A Clinical Approach......Page 253
Identification of Food Allergens......Page 254
Food Intolerance......Page 257
Summary......Page 258
Key Points......Page 259
Introduction......Page 261
Masses within the Abdominal Wall......Page 262
Intraabdominal Masses......Page 264
Imaging......Page 270
Other Investigations......Page 276
Key Points......Page 277
Preliminary Examination of the Abdomen......Page 278
Clinical Features......Page 279
Investigations......Page 282
Diagnosis of Ascites......Page 283
Management of Ascites......Page 284
Key Points......Page 285
History......Page 286
Physical Examination......Page 287
Management of Groin Lumps......Page 291
Key Points......Page 293
Rectal or Perianal Mass......Page 294
Tumours of the Colon and Rectum......Page 296
Anal Canal Cancer......Page 305
Key Points......Page 306
Introduction......Page 308
Clinical Syndromes......Page 311
Diagnostic Tests......Page 313
Management of Suspected Obstructive Jaundice......Page 316
The Postsurgical and Critically Ill Jaundiced Patient......Page 318
The Immunocompromised Patient who is Jaundiced......Page 319
Key Points......Page 320
An Approach to the Patient with Liver Disease......Page 322
Liver Function Test Interpretation......Page 323
Tests of Liver Injury......Page 324
The Well Patient with Abnormal Liver Function Profile......Page 327
The Sick Patient with Jaundice: Acute Liver Disease......Page 330
Acute Liver Failure......Page 331
Patients Presenting with Cirrhosis and its Complications......Page 333
Complications of Portal Hypertension in the Patient with Chronic Liver Disease......Page 334
Ascites in the Cirrhotic Patient with or without Renal Impairment......Page 337
Ascites, Fever and Pain: Spontaneous Bacterial Peritonitis......Page 338
Hepatic Encephalopathy in the Cirrhotic Patient......Page 339
Liver Disease in Pregnancy......Page 340
Specific Hepatic Diseases......Page 342
Key Points......Page 359
End-stage Liver Disease......Page 361
Orthotopic Liver Transplantation......Page 368
Key Points......Page 369
Diagnosis and Management......Page 371
Biliary Incidentalomas......Page 373
Pancreatic Incidentalomas......Page 376
Hepatic Incidentalomas......Page 379
Retroperitoneal Masses......Page 386
Mesenteric Masses......Page 388
Key Points......Page 389
Medical Management......Page 390
Surgical Management......Page 391
Conclusions......Page 393
Key Points......Page 394
Introduction......Page 396
Preparing Patients for Endoscopy......Page 397
Principles of Anaesthesia for Endoscopy......Page 400
Key Points......Page 404
Index......Page 406

Citation preview

Clinical gastroenterology A practical problem-based approach

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Clinical gastroenterology A practical problem-based approach

Editor

Nicholas J Talley

Pro Vice-Chanceller and Professor, Faculty of Health, University of Newcastle, NSW, Australia Adjunct Professor of Medicine, Mayo Clinic, USA Adjunct Professor, University of North Carolina, USA Adjunct Professor of Gastroenterology, Karolinska Institute, Stockholm, Sweden

Sydney  Edinburgh  London  New York  Philadelphia  St Louis  Toronto

Churchill Livingstone is an imprint of Elsevier Elsevier Australia. ACN 001 002 357 (a division of Reed International Books Australia Pty Ltd) Tower 1, 475 Victoria Avenue, Chatswood, NSW 2067 This edition © 2011 Elsevier Australia This publication is copyright. Except as expressly provided in the Copyright Act 1968 and the Copyright Amendment (Digital Agenda) Act 2000, no part of this publication may be reproduced, stored in any retrieval system or transmitted by any means (including electronic, mechanical, microcopying, photocopying, recording or otherwise) without prior written permission from the publisher. Every attempt has been made to trace and acknowledge copyright, but in some cases this may not have been possible. The publisher apologises for any accidental infringement and would welcome any information to redress the situation. This publication has been carefully reviewed and checked to ensure that the content is as accurate and current as possible at time of publication. We would recommend, however, that the reader verify any procedures, treatments, drug dosages or legal content described in this book. Neither the author, the contributors, nor the publisher assume any liability for injury and/or damage to persons or property arising from any error in or omission from this publication. National Library of Australia Cataloguing-in-Publication Data _________________________________________________________________________________________ Author: Talley, Nicholas Joseph. Title: Clinical gastroenterology : a practical problem-based approach / Nicholas Talley. Edition: 3rd ed. ISBN: 9780729539487 (pbk.) Notes: Includes bibliographies and index. Subjects: Gastrointestinal system--Diseases. Gastroenterology. Digestive organs--Diseases. Gastrointestinal system--Diseases--Diagnosis. Dewey Number: 616.33 _________________________________________________________________________________________ Publisher: Sophie Kaliniecki Developmental Editor: Neli Bryant Publishing Services Manager: Helena Klijn Project Coordinator: Geraldine Minto Edited by Joy Window Proofread by Sarah Newton-John Cover and internal design by Trina McDonald Index by Annette Musker Illustrations for 3rd edition by TNQ Books and Journals Pvt. Ltd.; other illustrations by Alan Laver Typeset by TNQ Books and Journals Pvt. Ltd. Printed by China Translation & Printing Services Ltd.

Dedication

This edition of Clinical Gastroenterology is dedicated to the late Christopher J Martin, Foundation ­Professor of Surgery, University of Sydney at Nepean Hospital, 1993–2006. Chris was a world-class oesophagologist and gastrointestinal surgeon; the Whiteley–Martin Research Unit at Nepean Hospital, which studies upper gastrointestinal cancer, was named after him.

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Foreword It is a great honour and privilege to write the Foreword for the third edition of Clinical gastro­ enterology: a practical problem-based approach, edited by Professor Nicholas J Talley. This book has proven to be a wonderful addition to our educational repertoire in gastroenterology. A myriad of books and educational electronic tools (e.g. Up-to-Date) exist to help the practitioner with disease-oriented questions. However, very few educational media bring us back to the patient. In this wonderful book, Professor Talley and colleagues focus on symptom-based medicine. After all, it is symptoms and the sense of feeling unwell which brings patients to the practitioner for relief and improvement in their health. In our current era of applying a barrage of imaging and endoscopic technologies to patient’s problems, we often lose track of a rational and symptom-based approach in evaluating a patient’s symptoms. Indeed this is one of the few books to address these issues from a presenting complaint perspective. In addition to its erudite approach to the patient, this book also employs problem-based learning methodology. This is a highly successful educational tool to improve recognition and retention of medical information. It takes a

great deal of care and foresight to develop an educational forum using this approach. Again, Professor Talley and his colleagues have done a remarkable job of incorporating the problembased learning approach into all of their chapters. His team of largely Australian doctors and colleagues with whom he has interacted in the Mayo Clinic system in the United States of America have done a really stellar job in adhering to the goals and objectives of this learning approach. Obviously the success of this book is highlighted by the need for a third edition. From my perspective this book will ultimately be used worldwide by medical students and practitioners trying to understand the relationship between symptoms and pathophysiological processes in gastrointestinal diseases. Professor Talley and his colleagues simply need to be congratulated on helping to promote outstanding education in gastroenterology! Gregory Gores MD, FACP Reuben R Eisenberg Professor of Medicine Chair, Division of Gastroenterology and Hepatology 18 November 2010

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Contents Foreword Preface Contributors

1 Heartburn, regurgitation and non-cardiac chest pain K DeVault

vii xi xiii

1

11 Constipation N Talley

130

12 Perianal pain D Lubowski and D Kozman

141

13 Acute diarrhoea V Duncombe and J Almeida

158

2 Difficulty swallowing and pain on swallowing I Cook

15

3 Hiccups, sore mouth and bad breath N Talley

27

14 Chronic diarrhoea and fatty stools 174 V Duncombe and J Almeida

37

15 Inflammatory bowel disease M Picco

4 Acute abdominal pain M Cox 5 When to test for Helicobacter pylori and what to do with a positive test N Talley

66

6 Indigestion (chronic epigastric pain or meal-related discomfort) J Tack

73

7 Chronic lower abdominal pain or discomfort J Kellow

88

8 Wind and gas P Kerlin

100

9 Nausea and vomiting N Talley

106

10 Vomiting blood, black stools, blood per rectum, occult bleeding M Weltman and N Phung

115

190

16 Faecal incontinence (leakage of stool) D Lubowski and D Kozman

206

17 Loss of appetite and loss of weight N Talley

220

18 Food allergies and intolerance G Whelan and P Allen 19 Palpable asymptomatic abdominal masses N Tait

238

246

20 Abdominal distension M Cox

263

21 Lumps in the groin and hernia N Talley

271

22 Rectal/perianal mass and colorectal cancer M Weltman and N Phung

279 ix

Contents

23 Jaundice and pruritus A Keegan

293

24 Abnormal liver function test results 307 A Keegan and N Talley 25 Management of end-stage liver disease and liver transplantation 346 M Leise and K Watt 26 Abdominal incidentalomas N Tait and S Lynch

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356

27 Obesity and anti-obesity medical and surgical management 375 CD Smith 28 Patient preparation and principles of sedation in gastrointestinal endoscopy 381 I Norton and A Gupta Index

391

Preface ‘We expect too much of the student and we try to teach him too much. Give him good methods and a proper point of view, and all other things will be added, as his experience grows.’ Sir William Osler Welcome to the 3rd edition of Clinical gastroenter­ ology: a practical problem-based approach! The last edition was published in 2006, and it is very gratifying to see its success translate into another edition so soon. The production of a 3rd edition of a textbook normally indicates it has survived childhood and adolescence and has reached adulthood, reflecting its acceptance as a valuable education tool. The editor and authors have strived to ensure that this new edition remains a learning gem. The aim of the book is unchanged: to provide an up-to-date, systematic, highly integrated yet very practical account of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. With  this in mind, the book retains its clinical focus, starting with a common (or uncommon but important) problem, and working through the assessment, differential diagnosis, pathophysiology and management, complementing a problembased learning approach now so popular around the world. A number of new features have been added in this edition. Each chapter now starts off with a case to set the scene and illustrate some essential principles. At the end of each chapter is a list of key points to promote learning, followed by a list

of current, important references. Every chapter has been carefully revised and edited to ensure the material is current, reflects best practice and is easy to understand. A new two-colour layout enhances the readability of the text and tables. Five new chapters have been added covering when to test and treat Helicobacter pylori, inflammatory bowel disease, obesity, preparing for endoscopy and sedation, and management of end-stage liver disease and liver transplant. This is an international textbook with contributors from Australia, Europe and the USA, all of whom are experts in the field; I remain very grateful for their efforts. We have relied on feedback from peer reviewers and readers as we have prepared this new edition; please do not hesitate to contact us with your suggestions and recommendations. We have missed the input of the late Professor Christopher Martin into this edition, but believe the book will live up to his high standards. Gastroenterology is an exciting hands-on specialty that has seen very considerable advances over the past few decades. Whether you are a medical student, resident, registrar or general practitioner, this volume will provide valuable management guidance when you next encounter a  particular gastrointestinal symptom, sign, laboratory test or x-ray. Nicholas J Talley Newcastle, December 2010

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Contributors Patrick Allen MBBChBAO, MRCP, BSc

Consultant Gastroenterologist, Causeway ­Hospital, Northern Trust, NI, UK

John Almeida MD, DNB, FRACP

Consultant Gastroenterologist, Prince of Wales Hospital, Randwick, Sydney, NSW, Australia

Ian Cook MBBS, MD (Syd), FRACP

Professor of Medicine, University of New South Wales Director, Gastrointestinal Motility Service and Swallow Centre Department of Gastroenterology and Hepatology St George Hospital, Sydney, NSW, Australia

Michael Cox MBBS, MS, FRACS

Professor and Head of Surgery Head of Upper Gastro-Intestinal Surgical Unit Head of Whitely-Martin Research Centre, Nepean Hospital, Sydney, NSW, Australia

Kenneth R DeVault MD

Professor and Chair, Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA

V Duncombe MD, MSc, FRACP

Consultant Gastroenterologist, Prince of Wales Hospital, Randwick, Sydney, NSW, Australia

Arun Gupta MBBS

Gastroenterology Advanced Trainee, Royal North Shore Hospital, NSW, Australia

Andrew Keegan MBBS, BSc (Med), PhD, FRACP

Paul Kerlin BA, MBBS (Hons), MD, FRACP,

FACG, FAICD, AGAF Clinical Professor of Medicine Gastroenterologist and Hepatologist, the Wesley Hospital, Auchenflower, Qld, Australia

Daniel R Kozman MBBS, FRACS

Colorectal Surgeon, St George Hospital and ­Bankstown Hospital, NSW, Australia

Michael D Leise MD

Instructor in Medicine, Division of ­Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

David Z Lubowski MBBCh, FRACS

Associate Professor of Surgery, University of   New South Wales Head, Department of Colorectal Surgery,   St George Hospital, Sydney, NSW, Australia

Scott A Lynch MD, MPH, FAAFP

Director, Bariatric Center, Bariatric Medicine, Mayo Clinic, Jacksonville, Florida, USA

Ian Norton MBBS, PhD, FRACP

Senior Staff Specialist, Royal North Shore ­Hospital, NSW, Australia Clinical Associate Professor, University of ­Sydney, NSW, Australia

Nghi Phung MBBS, PhD, FRACP, FAChAM

Senior Staff Specialist, Westmead Hospital,   NSW, Australia

Adjunct Associate Professor, Sydney Medical School Nepean, University of Sydney Consultant Gastroenterologist, Nepean Hospital, NSW, Australia

Michael F Picco MD, PhD

John Kellow MD, FRACP

C Daniel Smith MD, FACS

Associate Professor and Head, Discipline of Medicine, Sydney Medical School Northern Director, Gastrointestinal ­Investigation Unit, Royal North Shore Hospital, Sydney, NSW

Assistant Professor of Medicine Consultant, Department of Medicine,   Mayo Clinic, Jacksonville, Florida, USA Professor and Chair, Department of Surgery Surgeon-in-Chief, Mayo Clinic, Jacksonville, Florida, USA

xiii

Contributors Jan Tack MD, PhD

Professor of Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium

Noel Tait MBBS, FRACS

Professor of Surgery, University of Wollongong, NSW, Australia Consultant General Surgeon, Wollongong ­Hospital, NSW, Australia

Nicholas J Talley MD, PhD, FRACP, FAFPHM, FRCP, FACP, FACG, AGAF Pro Vice-Chancellor, Faculty of Health,   University of Newcastle, NSW, Australia

Martin Weltman MBBCh, PhD, FRACP, FAChAM Director of Endoscopy, Nepean Hospital, NSW, Australia Head of Department Gastroenterology and ­Hepatology Services, Nepean Hospital, NSW, Australia

xiv

Greg Whelan AM, MD, MBBS, MSc, FRACP,

FAFPHM, FAChAM Professor of Addiction Medicine, Monash ­University, Melbourne, Vic, Australia Medical Director, Addiction Rehabilitation ­Service, The Melbourne Clinic, Vic, Australia

Kymberly DS Watt MD, FRCPC

Associate Professor of Medicine Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, USA

1 Heartburn, regurgitation and non-cardiac chest pain Case A 52-year-old male presents with intermittent, retrosternal burning. This tends to occur after meals, but occasionally is worsened by exercise. He gets relief with drinking water and with antacids. The symptom has been present for years, but has become progressively more severe over the past 6 months. He has also developed what he describes as ‘slow swallowing’, which on further questioning sounds like mild dysphagia to solids that happens about once a week. He has gained 10 kg in the past year and has no evidence of gastrointestinal bleeding. His examination is unremarkable except for mild obesity (BMI = 31) and his stool has no occult blood. He had a normal exercise stress test as part of a recent executive physical. He is started on omeprazole 20 mg daily and scheduled for an upper endoscopy due to his dysphagia and duration of disease. The endoscopy is performed after he was on the omeprazole for 4 weeks and demonstrates a 3 cm hiatal hernia with a lower oesophageal ring of about 15 mm diameter. There is no evidence of Barrett's oesophagus. Dilation is performed to 20 mm. On follow-up questioning, he states that his reflux symptoms are 90% improved on the omeprazole and his dysphagia has resolved. He is counselled on dietary changes including, most importantly, smaller meals with lower fat content with a goal to improve both his weight and reflux symptoms. In 4 months, he returned with recurrent symptoms after stopping his omeprazole. He was counselled that he probably would need longterm maintenance, and the surgical and medical options were reviewed. He elected to remain on omeprazole and quickly became asymptomatic.

History ‘Indigestion’ is a commonly used but poorly understood term that means different things to different patients. Careful questioning may

allow the examiner to determine if the patient is describing heartburn, acid regurgitation, belching, bloating, abdominal pain, halitosis or even flatus. Some patients even use the work ‘gas’ to describe indigestion. Heartburn, regurgitation and, to a lesser extent, chest pain are symptoms that imply oesophageal disease. The type of oesophageal disease responsible for these symptoms can often be anticipated on the basis of history alone. Physical examination rarely contributes to the diagnosis. Heartburn and regurgitation will be discussed together as they often co-exist in patients with gastro-oesophageal reflux disease (GORD). Chest pain does not imply a particular disease process, but rather a group of disorders and will be discussed separately. In this chapter, the features of and approach to symptoms best described as heartburn and regurgitation will be outlined and associated symptoms supporting the diagnosis of GORD and its complications will be discussed. Thereafter, a practical guide to the use of investigations to confirm the clinical diagnosis will be presented as well as an outline of the principles of clinical management. Similarly, a practical approach to the diagnosis and management of chest pain will be discussed.

Heartburn Heartburn is a pain or discomfort typically described as burning in nature. Its primary position is usually lower retrosternal, deep to the xiphisternum. Heartburn commonly radiates upwards, retrosternally, occasionally as far as the neck. There may be associated epigastric pain. The timing of heartburn is characteristic. It occurs intermittently, either postprandially or when the patient bends forward or lies flat in bed, when the gastric contents are level with, or above, the lower end of the oesophagus. When it occurs

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Clinical gastroenterology: a practical problem-based approach

postprandially, it is most commonly in the early postprandial period, 5 to 30 minutes after a meal. The postural changes that initiate heartburn do so by raising the level of the gastric contents above the level of the gastro-oesophageal junction. The duration of an individual attack, when untreated, rarely exceeds an hour. Factors that precipitate an attack vary considerably from patient to patient. For some, the size of the meal is important, such that it will occur with large meals but not small meals. For others, particular foodstuffs will precipitate an attack. Foodstuffs more commonly incriminated include curries, garlic, red wine, fatty foods, chocolate and citrus juice. The combination of a meal and lying down can be additive in effect. Some patients will describe waking from sleep with severe heartburn a few hours after retiring to bed, particularly following dietary indiscretions. Attacks may occur when the patient lies on the right side but not on the left side or supine. Exercise, either isometric, including straining, or isotonic, such as brisk walking or running, can trigger heartburn. Retrosternal burning pain that is triggered by exercise needs to be closely scrutinised to ensure that symptoms of coronary ischaemia are not being overlooked. Response to medication is often predictive of whether the patient's complaints are secondary to GORD and, therefore, qualify as heartburn. Retrosternal burning pain that is not at least partially relieved by appropriate medication is unlikely to be caused by the reflux of acid into the oesophagus, unless there is some other strong evidence supporting reflux as the cause of the symptom. Heartburn is usually relieved within several minutes by antacids. Discomfort relieved within much shorter periods or after much longer periods is less likely to be secondary to gastro-oesophageal reflux. Similarly, heartburn usually improves with agents that diminish gastric secretion of acid such as H2-receptor antagonists and proton pump inhibitors, although relief with these agents is not as immediate as the relief produced by antacids. The time course, severity and frequency of heartburn will vary considerably from patient to patient. Some patients have the recent onset of symptoms, while others will have symptoms dating back over many years; some describe symptoms as occasional only, while others are inconvenienced many times a day. It is important to ask about nocturnal symptoms since those patients may have more severe mucosal disease, a poorer healthrelated quality of life and more difficult to treat disease. Heartburn is very common, reported by

one-third of the population at least once a month; 10% have daily heartburn. Only a minority of those with reflux symptoms present for medical care.

Regurgitation Regurgitation is the second ‘typical’ symptom of GORD. Patients with regurgitation often, but not always, also have heartburn. Although the two symptoms can be closely linked temporally, heartburn tends to be more frequent. Regurgitation describes the intermittent, sudden and often spontaneous sensation of material moving from the stomach proximally towards the oesophagus and throat. Individual patients tend to regurgitate about the same volume of bolus each time. The usual precipitants of heartburn for a particular patient are also the precipitants of acid regurgitation. They include meals (especially larger meals), assumption of a horizontal posture, rises in intraabdominal pressure, and belching. Food regurgitation is described as the predominant form of regurgitation by some patients. This will obviously occur mostly after eating. Regurgitation occurring within the first 30–60 minutes after a meal usually will not be acidic in character, while regurgitation occurring more distant in time from a meal will usually be acidic. Regurgitation may persist in a treated patient even if the heartburn has resolved with acid suppression. ‘Waterbrash’ is a term used to describe the sudden appearance of a volume of salty or tasteless fluid in the mouth. It is the result of salivary gland stimulation in response to gastro-oesophageal reflux or peptic ulcer disease. At times, it is difficult to distinguish from regurgitation, but since both are reflux symptoms, that distinction is not always critical. There are several other symptoms that can be confused with regurgitation. Rumination is the effortless return of food into the oesophagus or mouth. This usually occurs during meals and the food is often reswallowed. Patients with bulimia are also occasionally misdiagnosed as having GORD. Finally, burping and belching involve the ‘reflux’ of air, not liquids, and can also be confused with regurgitation. Patients with rumination, bulimia and aerophagia (excessive belching and burping) can usually be diagnosed with a carefully taken history and will, at times, have false positive ambulatory reflux testing.

Complications of acid regurgitation Severe acid regurgitation can be associated with other problematic symptoms including choking attacks, cough, asthma, hoarseness of voice, a foul taste in the mouth in the morning, bad breath, a

1 Heartburn, regurgitation and non-cardiac chest pain sore tongue, dental caries and nasal aspiration. Some patients complain of waking up episodically with a sensation of choking such that they will cough vigorously, but rarely produce sputum, get up out of bed and even go to an open window to catch their breath. These symptoms subside fairly rapidly. For some, the history suggesting episodic tracheal aspiration will be less dramatic. They may describe a chronic cough, perhaps worse in the morning, but without sudden exacerbations. When that is the case, other causes of cough will need to be considered and excluded as part of a respiratory work-up. Asthma usually has an allergic basis but, occasionally, can be precipitated by gastrooesophageal reflux. Such patients may present later in life without any obvious cause for obstructive airways disease. In these patients, the symptoms of gastro-oesophageal reflux are commonly not severe. Acid regurgitation can result in a chemical laryngitis and cause hoarseness of voice. Usually the regurgitation occurs at night so hoarseness is most evident in the morning, and gradually settles as the day passes. Similarly, waking up with a foul taste in the mouth or bad breath can be attributed to nocturnal gastro-oesophageal reflux. Nasal aspiration is a particularly unpleasant consequence of regurgitation, again usually occurring at night.

Problems with swallowing Odynophagia GORD is one of the causes of odynophagia (pain on swallowing). It is usually reported in response to hot or cold foodstuffs (see Ch 2). Dysphagia The sensation of obstructed swallowing is unusual in patients with heartburn and regurgitation and, when present, is worthy of special clinical attention. Oesophageal stenosis secondary to severe, long-standing erosive peptic oesophagitis is the most common cause of reflux-induced dysphagia. An undiagnosed oesophageal carcinoma should be considered in appropriate clinical settings. It is the implied severity of the reflux disease and the possibility of malignancy that makes investigation by barium swallow and upper gastrointestinal endoscopy mandatory in these patients. The features of dysphagia usually associated with a benign stenosis secondary to peptic oesophagitis are: ll exclusively for solids (not liquids); ll experienced at the lower end of the sternum; ll little variation in severity from day to day given the same-sized bolus;

3

slow progression in severity over months to years; and ll minimal to no weight loss. There are patients with symptoms of dysphagia and reflux for whom an organic cause will not be found by endoscopy or barium swallow; dysphagia in these cases may be caused by a motor disorder of the oesophageal body. It is usually not clear whether this dysmotility is due to chronic reflux or if motility is the primary problem. If confirmation is required (after more serious disease has been excluded by barium testing or endoscopy), an oesophageal manometry and ambulatory reflux test may be required. Alternatively, resolution of dysphagia after a trial of proton pump inhibitor therapy is nearly diagnostic of a reflux association. ll

Examination A typical history of heartburn or acid regurgitation is usually sufficient to diagnose GORD. There are no specific signs on physical examination that support the clinical diagnosis. Deep epigastric tenderness may be present, but is not specific and is not of any particular clinical significance. The role of the examination in GORD is mainly to exclude other issues such as pulmonary disease, cardiac auscultation abnormalities and severe tenderness (unlikely to be present with GORD).

Pathophysiology of GORD The oesophagus and the stomach are separated by a high-pressure zone produced by tonic contraction of specialised smooth muscle of the lower oesophageal sphincter (LOS) and the phasic contraction of the cural diaphragm. In normal individuals, this functional barrier is maintained except to allow antegrade flow with swallowing and retrograde flow with belching and vomiting. Reflux is likely when the LOS has a very low basal pressure. In patients with a weak sphincter, increases in intraabdominal pressure can easily overcome that pressure and produce pathological amounts of reflux. On the other hand, most patients with reflux have relatively normal pressure and it is felt that the LOS tends to relax at inappropriate times, leading to reflux (transient LOS relaxations). Hiatus herniation predisposes to reflux as a result of a dissociation of a weak LOS with the added pressure provide by the diaphragm. In addition, a hernia predisposes to inadequate clearance of gastric contents away from the lower oesophagus. Most of the fluid volume of refluxate is promptly cleared from the oesophagus by one or more swallows. Small amounts of residual acid are neutralised by

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Clinical gastroenterology: a practical problem-based approach

weakly alkaline saliva with subsequent swallows. Clearance is delayed during sleep when swallowing is less reliably triggered by reflux. Smoking exacerbates the effects of reflux by inhibiting salivation, thereby delaying acid clearance. Repeated and prolonged exposure to gastric secretions can result in erosion and ulceration of the oesophageal mucosa. The occurrence of injury, expressed as erosive oesophagitis, is dependent on three factors: (1) duration of exposure; (2) the chemical composition of the refluxate; and (3) the natural resistance of the individual. Thereby, we can explain several well-known clinical observations. First, the severity of oesophagitis tends to be worse when oesophageal acidification is prolonged, and reducing gastric acid secretion promotes healing of peptic oesophagitis. Secondly, two patients with similar levels of reflux, as measured by pH monitoring, may have marked differences in mucosal appearance at endoscopy. One may have severe erosive oesophagitis while the other, a normal-looking mucosa. The role of bile and pancreatic juice in producing oesophagitis in patients with an intact LOS and pylorus is limited. This mechanism is of considerable importance in patients without an intact pylorus. Heartburn, on the other hand, is dependent primarily on mucosal sensitivity, not mucosal ulceration. Thus, some patients with symptomatically severe heartburn may have no peptic oesophagitis, while others with no heartburn can present with a peptic stricture secondary to longstanding peptic oesophagitis. Therefore, the severity of heartburn is a poor predictor of oesophagitis. This is a particular problem in older patients who often present with advanced oesophageal damage despite relatively modest symptoms.

certain patients (particularly older patients with chronic symptoms) should undergo endoscopy to screen for Barrett's oesophagus. The characteristic endoscopic signs of reflux oesophagitis are shown in Table 1.1 and Figure 1.1. As mentioned above, there is only a weak correlation between the severity of oesophageal acidification and the degree of peptic oesophagitis. On the other hand, it is clear that more severe grades of esophagitis are more difficult to heal. Oesophagitis should never be diagnosed based on anything short of mucosal erosion and never should be based on erythema of the distal oesophagus. The diagnostic endoscopic examination is always carried as far as the first part of the duodenum looking for incidental pathology. The finding of a Table 1.1  Classification of reflux at endoscopy (Los Angeles—LA—System) Grade

Feature

Grade A

At least one mucosal break (erosion) each ≤ 5 mm

Grade B

At least one mucosal break > 5 mm but not continuous between the tops of two mucosal folds

Grade C

At least one mucosal break that is continuous between the tops of 2 mucosal folds, but which is not circumferential (< 75%)

Grade D

Circumferential mucosal break (≥ 75%)

Investigation of Heartburn and Acid Regurgitation Upper gastrointestinal endoscopy The finding of peptic oesophagitis at endoscopy confirms that symptoms of heartburn and regurgitation are due to GORD. On the other hand the absence of oesophagitis in no way excludes GORD. Patients with typical symptoms that occur occasionally and that are completely controlled by simple measures, such as attention to lifestyle (see below) or antacids, do not need upper endoscopy. On the other hand, patients with reflux symptoms and alarm features (such as vomiting, bleeding, weight loss or dysphagia) should always be investigated. In addition,

Figure 1.1  Endoscopic view of linear erosive peptic oesophagitis (Grade D) of the distal oesophagus. From plate 20-4 of the online edition of the Merck Manual, with permission from Dr D Martin.

1 Heartburn, regurgitation and non-cardiac chest pain chronic duodenal ulcer is significant as this may be the underlying cause of gastro-oesophageal reflux symptoms (see Ch 5).

Oesophageal biopsy at upper gastrointestinal endoscopy Biopsy of a normal-appearing oesophagus was once suggested to aid in the diagnosis of GORD, but is not advocated by most experts in adult GORD. Microscopic changes suggestive of GORD include: ll relative increase in papillary height; ll relative increase in thickness of the basal layer of the epithelium; ll the presence of intraepithelial neutrophils and eosinophils. These microscopic findings can be relatively difficult to quantify on routine biopsy specimens and the diagnostic value of these findings continues to be disputed, so biopsy is not recommended routinely. Recently, some experts have suggested obtaining midoesophageal biopsies in patients with any unexplained oesophageal symptom (especially dysphagia) to search for histological evidence of eosinophilic oesophagitis (Ch 2).

Upper gastrointestinal radiology Before the establishment of flexible upper gastrointestinal endoscopy, upper gastrointestinal contrast radiology with barium was the initial investigation for dyspepsia and reflux symptoms. It has been downgraded to a second-line investigation, mainly because it is not a sensitive detector of oesophageal mucosal damage. It does, however, offer complementary information, which is sometimes useful. Some advocate routine radiological testing in any patient with dysphagia. It also allows better definition of the presence and size of a hiatus hernia, which may be important if surgery for reflux is contemplated. The demonstration of barium refluxing into the oesophagus is neither specific nor sensitive for the presence of pathological acid reflux.

Ambulatory reflux monitoring Episodes of gastro-oesophageal reflux result in acidification of the distal oesophagus. Neutral pH is restored by oesophageal peristalsis. These episodes can be monitored and recorded by placement of a pH microelectrode in the distal oesophagus. In the past this test required prolonged nasal intubation, which is unpleasant. That discomfort can now be avoided by attaching the pH electrode to the lower oesophageal mucosa endoscopically. The pH recording then occurs by telemetry. The electrode subsequently detaches and passes spontaneously.

5

Summation of the duration of episodes over an extended period, usually 24–48 hours, gives a measure of the underlying pathophysiological process, which can be used to score the severity of the disease. Further, a correlation between symptoms and episodes of oesophageal acidification can be established (see Fig 1.2). The test is not required for diagnosis in the majority of patients with typical symptoms of reflux in whom the diagnosis can be made either endoscopically or, if there is no oesophagitis, on the basis of a successful therapeutic trial with a course of antisecretory treatment. Recently, another technology has been developed that has the potential to measure not only acid reflux, but also the reflux of other substances with a more neutral pH. This technology takes advantage of the conductivity of refluxed liquid and is measured with a specially designed catheter that not only measures the movement of that fluid using impedance, but also measures pH (acid reflux). The exact role of this testing remains to be completely defined, but has been suggested to be of particular benefit in patients requiring testing while on acid suppression. When contemplating performing an ambulatory reflux test, two questions must be answered: should the test be done on or off acid-supression therapy and should impedance monitoring be included? Off-therapy testing is the best way to determine if the patient has pathological gastro-oesophageal reflux. This testing can be performed with either a tube-based or tubeless system. If, on the other hand, the question is of ongoing reflux on therapy, some experts advocate a combined impedance pH test. An alternative, especially in the patient with either no or a modest response to therapy, is to stop medications and do a pH test off therapy. The application of the concept of pretest probability is important in that decision-making process. If the patient is believed to have reflux and a nonacid contribution to symptoms is to be excluded, on-therapy, impedance pH testing makes sense. If on the other hand, the patient is not believed to have reflux (often the case when there is a minimal response to therapy), stopping therapy and doing an off-therapy test is most reasonable. A negative off-therapy pH test and a failed therapeutic trial provide the best evidence that reflux is not the cause of an individual patient's symptoms.

Bernstein testing Bernstein testing is a test of mucosal sensitivity that is of mostly historical interest, although it may be available in a few referral centres. It involves transnasal oesophageal intubation and perfusion

6

Clinical gastroenterology: a practical problem-based approach

A

B

Figure 1.2

1 Heartburn, regurgitation and non-cardiac chest pain

7

Figure 1.2  24-hour oesophageal pH testing (pH probe 5 cm above lower oesophageal sphincter) A: Pathological upright reflux. The lines indicate the times at which the patient had reflux symptoms. These events all coincide with a decrease in pH to below pH 4. The symptoms of this patient are clearly caused by reflux. B: Pathological reflux during sleep. During sleep, in particular, the oesophageal pH persists longer at a low value due to disordered oesophageal clearance. A symptom index over 50% ([no. of symptoms with pH under 4 ÷ total no. symptoms] × 100%) is considered significant. The symptom-associated probability (SAP) is a more optimal method to estimate if acid reflux episodes are linked to symptoms. The 24-hour recording is divided into 2-min periods, and the 2-min periods before onset of symptoms identified for evidence of reflux (pH under 4.0). The probability (P) that events are unrelated is calculated (using Fisher's exact test). SAP = (1.0 – P) × 100% From Smout AJPM, Akkermans LMA. Normal and disturbed motility of the gastrointestinal tract. Petersfield: Wrightson Biomedical Publishing; 1972, with permission.

of the distal oesophageal mucosa with dilute (0.1 M) hydrochloric acid alternating with placebo (normal saline). The test is considered positive if the acid produces the patient's symptoms and the saline does not. It can be complementary to pH monitoring in patients whose atypical symptoms, particularly chest pain, are infrequent and do not occur during a pH-monitoring study.

Oesophageal manometry This test has no routine diagnostic role in the evaluation of symptoms of GORD unless antireflux surgery is being considered, where manometry is used to exclude achalasia and to tailor the tightness of the repair. It may sometimes be useful in the evaluation of patients with symptoms of dysphagia in addition to those of heartburn and regurgitation, where a barium swallow and endoscopy have been normal and the dysphagia remains unexplained (see Ch 2).

Treatment Clinical management of heartburn and regurgitation The intensity of reflux symptoms varies from a mild, occasional discomfort, for which the patient may want little more than antacid and reassurance, to a daily, incapacitating pain that prevents normal activity. Management needs to be commensurate with the magnitude of the clinical problem. Unlike duodenal ulceration, GORD is usually a persistent condition without exacerbations and remissions. Drug therapy has a hierarchy (see Box 1.1). Oesophagitis indicates a need for therapy to heal the mucosa and maintain healing; virtually all patients with severe oesophagitis (LA grade C and D oesophagitis; see Table 1.1) will relapse if medical therapy is stopped, as will most (80%) with milder oesophagitis. A review of the clinical management principles for patients with gastrooesophageal reflux is presented in Table 1.2.

Patient-directed therapy For most of the population who have occasional, mild symptoms of reflux, intermittent, patientdirected treatment is all that is required. Such treatment involves lifestyle changes including: ll weight loss, if overweight or in the face of recent weight gain; ll avoidance of large meals, particularly before retiring to bed at night; ll postural advice including elevation of the head of the bed by insertion of 20 cm blocks under the bed head and avoidance of bending; ll avoiding drugs, cigarettes, alcohol and foodstuffs that might precipitate reflux. Box 1.1  Effectiveness of drugs for gastro-oesophageal reflux Twice-daily proton pump inhibitors Once-daily proton pump inhibitor combined with H2-receptor antagonist Once-daily proton pump inhibitors Standard-dose H2-receptor antagonists Antacids

Most effective

Least effective

Table 1.2  Features of clinical management of gastro-oesophageal reflux Patient-directed treatment

Doctor-directed treatment

Weight loss, if overweight Avoidance of large meals Postural advice such as elevation of bed head at night Avoidance of foodstuffs that precipitate reflux On-demand antacids or H2-receptor antagonists for breakthrough symptoms

Continue lifestyle measures of low-level Regular or on-demand fulldose H2-receptor antagonist or proton pump inhibitor High-dose proton pump inhibitor Endoscopic or laparoscopic antireflux therapy

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Clinical gastroenterology: a practical problem-based approach

A foodstuff checklist includes spicy foods, alcohol, fatty foods, chocolates, nuts, tomatoes, as well as many others. Rather than prohibit ‘everything’ and risk losing patient compliance, it is wiser to establish with the patient which foodstuffs they recognise as triggers, ask them to avoid these, go through the checklist to identify triggers that the patient might not have previously considered and recognised, and then ask the patient to establish relationships between symptoms and triggers so that they might be avoided in the future. In addition, some aspects of the ‘reflux diet’ such as lower volume, lower fat and weight loss will provide added health benefits beyond the improvement in reflux symptoms. Of these various lifestyle changes, only weight reduction has the potential to change the natural history of the disease. Thus, some patients can clearly identify a critical weight above which they experience symptoms and below which they are free of symptoms. It makes good sense to encourage these patients to stay below their critical weight. Interestingly, even patients of normal weight may develop reflux symptoms when they gain weight but do not become overweight or obese. Additionally, patients on low-level treatment may benefit from intermittent medication for symptoms. The medication could be antacids if short-term (about 30 minutes) relief is required, or an H2-receptor antagonist or proton pump inhibitor if relief for several hours is required.

agents in this category, leaving acid suppression as essentially the only medical therapy for GORD. Some patients will have symptoms and/or oesophagitis that do not respond to standard doses of proton pump inhibitors. A common approach is to increase the dose to twice daily (before meals) for an additional 4–8 weeks to see if the disease is brought under control. This approach has not been tested in well-designed trials and it is not clear what proportion of patients will respond. An additional nocturnal dose of H2-receptor antagonists may be of assistance, but benefits often wear off if given continuously. An alternative is to study the patient using ambulatory reflux testing to either confirm control of acid (on therapy testing) or to determine if they actually have the disease (off-therapy testing or perhaps combined impedance/pH testing). The addition of a prokinetic agent is an attractive concept, but none of the currently available agents have been proven to be effective as either mono or ‘add-on’ therapy in this situation. There are several agents in development that may inhibit transient LES relaxation. Some of the possibilities to be considered when a patient is ‘failing’ proton pump inhibitor therapy are outlined in Table 1.3. Patients for whom medical therapy results in incomplete resolution of symptoms (especially regurgitation) can achieve that end point with antireflux surgery. Nevertheless, the majority of patients presenting for surgery present because they are keen to achieve long-term cure, without

Doctor-directed treatment When patients present to a physician, they often have tried the above manoeuvres. In some, it may be reasonable to simply emphasise the above and see if they can manage their symptoms on their own. On the other hand, most patients will be treated with a prescription medication. The end point of therapy should be complete or near-complete resolution of symptoms. H2receptor antagonists have an onset of action that is rapid, but rate of symptom relief is about 50% when standard doses are taken twice daily. There is no evidence that greater than standard doses provide additional benefit. Proton pump inhibitors taken once daily provide a higher rate of symptom relief (60–80%) and endoscopic healing (80–90%), but have a somewhat slower onset of action. Once symptom relief is achieved an attempt to step down the dose or change to an ‘as needed’ approach is reasonable. If the patients relapse at that point, they are likely to need long-term treatment. While a prokinetic would seem to be a rational approach to GORD, there are no available, safe and effective

Table 1.3  Failure of proton pump inhibitor therapy to control gastro-oesophageal reflux symptoms: management approach Mechanism to consider

Management

Misdiagnosis

Review history and investigations.

Not taken before meals

Advise taking 30 minutes prior to a meal.

Inadequate dosing

Trial twice-daily therapy.

Nocturnal acid breakthrough

Twice-daily proton pump inhibitor; if that fails, H2-receptor antagonist before bed as needed; consider surgery.

Acid hypersecretion Exclude Zollinger-Ellison syndrome. Drug resistance

Very rare; switch to H2-receptor antagonist or consider surgery.

Oesophageal hypersensitivity

Add a low-dose tricyclic antidepressant.

1 Heartburn, regurgitation and non-cardiac chest pain need for continuing medical therapy and follow-up. Most report the loss of reflux symptoms without the need to take medication from the day of surgery. There is complete control in up to 90% of patients with typical symptoms that responded to acid suppression in the hands of an experienced surgeon. However, in some studies up to 50% of cases eventually will have reintroduction of acid suppression therapy over the long term. The risk of postoperative sequelae has limited the more widespread utilisation of antireflux surgery. The more troublesome of these are painful abdominal distension (gas bloat), persistent dysphagia and, less commonly, persistent diarrhoea. The surgical approach for most will be laparoscopic. This conveys the advantages of less postoperative pain and early return to full activity. The procedure involves an initial restoration of normal anatomical relationships by reduction of the commonly associated sliding hiatus hernia

Sliding

(see Fig 1.3A) and then wrapping of the lower oesophageal sphincter region with the gastric fundus (see Fig 1.3B). There is still debate as to whether the fundoplication should be complete as shown in Figure 1.3B, or whether the wrap should be incomplete—surrounding less than the 360° circumference of the lower oesophageal sphincter. Current data suggest that patients having the so-called incomplete fundoplication are more satisfied with the outcome because of an apparent reduction in sequelae, even though the long-term control of reflux might not be quite as good as with complete fundoplication. Endoscopic therapies to treat gastro-oesophageal reflux, including radiofrequency therapy, injection of biopolymer and endoscopic sewing around the lower oesophageal sphincter, have been studied. Of these, the systems that place sutures to form a ‘plication’ at the LOS are the only currently available options, while most of the others

Rolling

Figure 1.3A  Schematic representation of a sliding hiatus hernia (left) and a paraoesophageal hernia (right). (a)

(b)

9

(c)

Figure 1.3B  Schematic representation of the Nissen fundoplication operation. From Smout AJPM, Akkermans LMA. Normal and disturbed motility of the gastrointestinal tract. Petersfield: Wrightson Biomedical Publishing; 1972, with permission.

10

Clinical gastroenterology: a practical problem-based approach

have been removed because of lack of efficacy, unacceptable side effects or both.

Maintenance therapy Once a patient's symptoms are controlled, they can be entered into a program of ‘maintenance’ in order to keep those symptoms under control. Some patients can be ‘stepped down’ to less complete acid suppression (from high dose proton pump inhibitor to standard dose or from standard dose proton pump inhibitor to H2-receptor antagonist or antacid therapy) and a few can discontinue treatment altogether, especially if they adhere to lifestyle changes. On the other hand, many patients require the same therapy that they needed to achieve remission in order to maintain that remission.

Risks of long-term acid suppression When they were first introduced, the use of proton pump inhibitors was limited to a short period of time. Subsequently, concerns over the potential adverse effects of proton pump inhibitor-induced hypergastrinaemia were discounted and longterm therapy was approved. Acid suppressants have been very safe, but recently a few concerns have arisen. In addition to aiding digestion, gastric acid helps to eliminate ingested bacteria. Infections that have a small increased incidence in proton pump inhibitor-treated patients include Clostridium difficile , community-acquired pneumonia and perhaps traveller's diarrhoea. Acid aids in the absorption of several nutrients (iron, calcium and vitamin B12), although clinically significant insufficiencies are very rare. Recent studies have found a very small increase in hip fractures in proton pump inhibitor-treated patients. Finally, there is no direct cardiovascular risk with acid suppression, although a negative interaction between proton pump inhibitors and the antiplatelet drug clopidogrel has been suggested.

Clinical management of dysphagia associated with reflux symptoms Dysphagia is a ‘warning’ symptom ('red flag') in the patient with reflux and must be respected as such. The possibilities include: ll a benign distal oesophageal stricture secondary to GORD; ll a benign distal oesophageal stricture secondary to GORD associated with a motility disorder (either primary or perhaps associated with a rheumatological condition such as scleroderma)

a malignant stenosis in a patient with GORD; dysphagia due to another problem not related to reflux (misdiagnosed achalasia or eosinophilic oesophagitis, for example). It is often helpful to define the presence and site of stenosis radiologically. Subsequently, the presence or absence of an oesophageal malignancy must be established or disproved by upper gastrointestinal endoscopy and biopsy of the stenosis and any mucosal irregularity. Once malignancy is excluded, oesophageal dilatation may be performed to relieve dysphagia. The dilatation may need to be staged if the stenosis is very narrow and additional care must be taken if the oesophagus has the typical ringed appearance associated with eosinophilic esophagitis. Assuming the patient has symptoms or endoscopy suggestive of GORD, they should start a proton pump inhibitor to achieve symptom control and healing. With this therapy, restenosis is less common. Antireflux surgery should be considered for those who require repeated dilatations or have poor control of heartburn and regurgitation. These patients are sometimes unsuitable for a laparoscopic operation, as oesophageal fibrosis may render the oesophagus short as well as narrow. Some surgeons will perform a Collis gastroplasty (oesophageal lengthening procedure) combined with a Nissen fundoplication in that situation. Patients with oesophageal involvement from scleroderma are usually readily identifiable by the characteristic appearance of their hands and face. These patients have a hypomotile oesophageal body in addition to a failure of the lower oesophageal sphincter. Aggressive highlevel medical therapy is to be preferred over surgical therapy. Oesophageal dysmotility is not isolated to scleroderma and may occur with many other rheumatologic and non-rheumatological conditions (long-standing diabetes, for example). ll ll

Hiatus hernia A hiatus hernia is a protrusion of intraabdominal contents through the oesophageal hiatus in the diaphragm. Two main types of hiatus hernia are recognised radiologically (see Fig 1.3A). Routine (sliding or fixed) hiatus hernia This type of hernia is extremely common (in 10– 15% of the population) and often asymptomatic. Its prevalence increases with age. It occurs as a result of circumferential telescoping of the segment of stomach that lies just distal to the lower oesophageal sphincter through the oesophageal hiatus. This type of hernia is not

1 Heartburn, regurgitation and non-cardiac chest pain prone to obstruction or strangulation, so specific surgical treatment of the hernia is not required; when it is found incidentally in association with GORD, attention should be directed at treatment of the reflux disease. Herniae are more common in more severe grades of esophagitis and are almost universally present in patients with Barrett's oesophagus. Paraesophageal (rolling) hernia This type of hernia is less common. It can range in size from just a small knuckle of fundus protruding alongside the non-displaced lower oesophageal sphincter to the whole stomach twisted and rotated within the posterior mediastinum. With larger herniae, there is a tendency for the lower oesophageal sphincter to be displaced proximally with the stomach. Such herniae should not be thought of as mixed herniae as the main component is usually the paraesophageal component. These herniae can cause dysphagia and uncommonly retrosternal pain due to ischaemia of the entrapped portion of stomach. There may be associated vomiting due to obstruction at either the lower oesophagus or at the gastric outlet. Early satiety and weight loss form part of a milder obstructive syndrome. Large herniae can cause dyspnoea by occupying part of the thoracic cavity, which would otherwise be available for expansion of the lungs. The only effective treatment is surgical repair of the hernia, but this is currently recommended only for patients with symptoms or complications from the hernia. There seems to be a higher than expected recurrence of herniae after repair of the paraesophageal type.

is not likely to be performed on clinical grounds. As a consequence, many patients remain unaware that they carry this malignant predisposition and present at a more advanced stage. The columnar lining of Barrett's oesophagus is salmon pink in colour and has a matt surface texture, distinguishing it from stratified squamous epithelium, which is pearly pink in colour and shiny in texture. Histological confirmation is necessary and specialised intestinal metaplasia in the oesophagus is the hallmark finding. Development of adenocarcinoma in Barrett's oesophagus is a staged process that occurs over several years. The precursors of invasive carcinoma (low-grade and high-grade dysplasia) can be detected reliably only by histological examination of multiple samples of the columnar epithelium. There are no reliable serological markers or even endoscopic appearances, although advances in endoscopic imaging may change that in the next few years. There is no evidence that control of continuing reflux, after the metaplastic epithelial change has occurred, stops progression down the dysplastic pathway, even though this is appropriate

Barrett's oesophagus One of the consequences of long-term gastrooesophageal reflux is a metaplastic transformation of the stratified squamous epithelium of the distal oesophagus to a columnar type epithelium. The affected oesophagus is termed Barrett's or columnarlined oesophagus. The significance of Barrett's oesophagus is its predisposition to malignant change. Clinically, much effort is expended to identify and treat such patients before they present clinically with an adenocarcinoma of the distal oesophagus (Fig 1.4), when the outlook is likely to be poor (Ch 17). It has been suggested that patients with the following characteristics are at greatest risk of developing Barrett's oesophagus and subsequently oesophageal adenocarcinoma: long-term reflux symptoms, male sex, Caucasian race and positive family history. Despite that, some patients will have reflux symptoms that are so minor that an endoscopy

11

Figure 1.4  Adenocarcinoma of the distal oesophagus (arising in Barrett's mucosa) on barium swallow.

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Clinical gastroenterology: a practical problem-based approach

for control of reflux symptoms. Preliminary data suggest that aspirin may slow the progression of Barrett's oesophagus to dysplasia and is safe when combined with a proton pump inhibitor. The aim of the management strategy of patients with Barrett's oesophagus is to identify patients with high-grade dysplasia. These patients are very likely to proceed in the near future to invasive adenocarcinoma. In patients with non-dysplastic Barrett's, it is recommended that endoscopic surveillance be conducted every 2–3 years, with biopsies (in each quadrant at 2-cm intervals) along the length of the Barrett's mucosa. If low-grade dysplasia is identified, the interval should be shortened to at least yearly with a more intensive biopsy pattern (each quadrant every 1 cm). If highgrade dysphagia is found and confirmed, there is a high risk of underlying adenocarcinoma and removal of the Barrett's epithelium is generally recommended. The traditional approach has been surgical resection of the oesophagus. If performed, as much of the oesophagus as possible should be removed to prevent recurrence of Barrett's in the residual segment. Recently, endoscopic ablative techniques have been developed and are becoming a recognised alternative in patients with dysplastic Barrett's epithelium.

Non-cardiac Chest Pain Non-cardiac chest pain is a diagnosis reached by excluding myocardial ischaemia as the cause of pain by a combination of history taking, physical examination and one or more investigations. Historically, cardiac pain due to ischaemia is primarily retrosternal in position. It may radiate to the neck and jaw, and/or down one or both arms. It is pain that is severe in intensity, crushing in nature and usually not prolonged in duration. It is commonly precipitated by exercise and causes the patient to stop exercising. Patients with cardiac pain are more likely to have evidence of arterial disease in the lower limbs and cerebral arteries, and cardiac risk factors such as hypertension, diabetes mellitus, obesity, hypercholesterolaemia and tobacco use. Severe retrosternal chest pain that radiates through to the back should lead to consideration of dissection of a thoracic aortic aneurysm. Chest pain of oesophageal origin is more likely to be prolonged, to radiate through to the back, to be precipitated by eating, and to be associated with dysphagia, heartburn and regurgitation. In spite of these differences, chest pain of oesophageal origin cannot be distinguished from cardiac chest pain with any degree of certainty on the basis of history alone. Further, physical examination is rarely of

any significant help in separating the two. Signs of heart disease such as cardiac murmurs and cardiac failure, or manifestations of peripheral vascular disease such as bruits and absent pulses, increase the likelihood that the pain is cardiac in origin. When there is any doubt investigation is initially focused on the heart. All patients should have an electrocardiogram (ECG) and cardiac enzymes measured if they are examined while they are having pain. Those without pain at the time of interview and normal resting ECG should have an exercise stress ECG performed. The extent of further cardiac investigation will depend on clinical judgment. This might include echocardiography, radionuclide studies and coronary angiography. Although coronary angiography remains the gold standard, its performance is sometimes delayed because of its invasive nature and slight risk of complications. The inconvenience and risk obviously need to be weighed against the likelihood that coronary disease will be uncovered and the likelihood that the findings will change the clinical management. One of the advantages of performing coronary angiography that reveals normal coronary arteries is that both patient and doctor can be reassured that sudden death becomes very much less likely. Once the patient is determined to not have occlusive disease of the coronary arteries, several other conditions (below) need to be considered.

Microvascular angina Microvascular angina is a cause of ischaemic chest pain in the presence of normal coronary arteries; abnormalities may be found on non-invasive cardiac function testing (e.g. radionuclide ventriculography or thallium exercise scintigraphy). It appears these patients have survival rates similar to controls and the pain will, at times, respond to nitrates and/or calcium channel blockers.

Musculoskeletal conditions Early in the clinical evaluation, before invasive cardiac investigations are performed, the possibility that the chest pain is musculoskeletal in origin should be considered. A history of chest wall injury might indicate a sternal fracture. Palpation of the anterior chest wall may reveal focal tenderness suggestive of costochondritis.

Panic attacks Panic attacks can cause chest pain. They result in discrete periods of intense fear that occur abruptly with at least four of the following

1 Heartburn, regurgitation and non-cardiac chest pain symptoms: chest pain, palpitations, sweating, trembling, shortness of breath, choking, nausea, dizziness, feelings of unreality or detachment, fear of losing control, fear of dying, paraesthesia and flushes or chills.

Oesophageal conditions Oesophageal conditions that can cause non-cardiac chest pain, in order of importance, include: ll GORD (most common); ll non-specific motility disorder or hypertensive lower oesophageal sphincter (uncertain significance); ll high pressure ‘nutcracker’ oesophagus (uncertain significance); ll diffuse oesophageal spasm (rare); and ll achalasia (rare). These conditions can be diagnosed either by endoscopy and pH monitoring in the case of GORD, and by oesophageal manometry in the remainder. Unfortunately it is often difficult to be sure that the oesophageal condition diagnosed is indeed the cause of the pain, as will be discussed below. The program of investigation for patients deemed to have non-cardiac chest pain that might be oesophageal in origin will depend on how significant the symptoms are in terms of both their severity and frequency. Some patients will do well if reassured that their heart is not the cause of their symptoms. GORD should be the first consideration for the aetiology of oesophageal pain. If the patient has co-existing heartburn or regurgitation, a reflux

13

aetiology is more likely. The diagnostic option is to either perform an ambulatory reflux test or offer a trial of proton pump inhibitor (PPI). The so called ‘PPI-test’ is a short-term (7–14 day) trial of a twice daily proton pump inhibitor that seems to have a reasonable sensitivity and specificity when compared to ambulatory pH testing. An ambulatory reflux test should be considered ‘positive’ if there is excess reflux or if symptoms occur in correlation with episodes of reflux. If proton pump inhibitor treatment is effective, it should obviously continue. The role of endoscopy in patients without typical symptoms in unclear, but the finding of erosive oesophagitis may clinch the diagnosis. If the patient fails a treatment trial or if the symptoms are clearly related to swallowing, an oesophageal motility test may be of benefit although the minority of patients will have a clearly definable motility disturbance. The manometric characteristics of motor disorders that may cause non-cardiac chest pain are shown in Table 1.4. Unfortunately, manometry has significant limitations in this clinical setting as it is performed in a laboratory over a short time frame (which is standard) and the chance that the abnormal manometric findings will be observed, except in the case of achalasia, is low. This likelihood can be increased by using provocative agents, such as edrophonium, or extending the period of observation utilising a portable ambulatory manometry system. Effective therapy for diffuse oesophageal spasm, nutcracker oesophagus, non-specific motility

Table 1.4  Manometric features of oesophageal motility disorders that may be associated with non-cardiac chest pain Disorder

Features

Achalasia (see Ch 2)

ll ll

Diffuse oesophageal spasm

ll ll ll ll

Nutcracker oesophagus

ll ll

Incomplete relaxation of the lower oesophageal sphincter Aperistalsis of the ­oesophageal body Simultaneous contractions (> 10%) High-amplitude contractions (> 180 mmHg) Repetitive synchronous oesophageal body ­contractions (> 2 peaks) Prolonged oesophageal body contractions (> 6 s) High-amplitude peristaltic contractions (> 180 mmHg) Prolonged oesophageal body contractions (> 6 s)

Hypertensive lower oesophageal sphincter

Elevated lower oesophageal sphincter pressure (> 45 mmHg)

Non-specific motility disorder

One or more of the following: ll non-transmitted contractions (> 20%); ll repetitive oesophageal body contractions (> 2 peaks); ll prolonged oesophageal body contractions (> 6 s); ll low-amplitude peristalsis (< 30 mmHg); ll frequent spontaneous contractions.

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Clinical gastroenterology: a practical problem-based approach

disorder and hypertensive lower oesophageal sphincter is currently not available. Therapeutic trials of nitrates or a calcium channel blocker are worthwhile, but should be discontinued if there is no apparent response. A group of patients will remain for whom no diagnosis will be achieved after all investigations have been completed and therapeutic trials undertaken. These patients probably have visceral hypersensitivity, a variant of irritable bowel syndrome. For the sufferer of chest pain, there is likely to be a significant degree of anxiety because of the fear of possible sudden death. Clearly, these patients need to be reassured sympathetically that it is very unlikely that their condition, although distressing, will be progressive or fatal and that continued observation is quite appropriate. Some of these patients will benefit from antidepressant therapy (e.g. low-dose tricyclic antidepressant).

Key Points ll

ll

ll

ll

ll

ll

ll

Heartburn, regurgitation or both are the cardinal symptoms of gastro-oesophageal reflux disease (GORD). Other GORD-related symptoms may include choking attacks, cough, asthma, hoarseness of voice, a foul taste in the mouth in the morning, bad breath, a sore tongue, dental caries and nasal aspiration. Dysphagia related to reflux is usually caused by a benign stricture, but endoscopy is required to rule out malignant causes and also allows dilation of any stricture. Endoscopy is required in GORD patients with alarm features such as vomiting, bleeding, weight loss or dysphagia. Patients with long-standing symptoms are at risk for Barrett's oesophagus and should also undergo endoscopy. Ambulatory reflux testing is used to confirm or refute reflux in difficult cases, particularly when surgery is being considered. The combination of lifestyle changes and medical therapy (usually with a once-daily proton pump inhibitor) will control GORD in the vast majority of patients. Barrett's oesophagus is a consequence of GORD and places patients at an increased risk of developing adenocarcinoma of the oesophagus.

ll

ll

ll

Fortunately, most patients with Barrett's oesophagus do not progress and patients in surveillance programs for Barrett's oesophagus usually progress slowly allowing for effective intervention using endoscopic or surgical approaches. The oesophagus may be the cause of chest pain similar to angina. Cardiac causes should be carefully excluded in any patient with chest pain prior to considering an oesophageal origin. Reflux is the most common cause of noncardiac chest pain, with some other patients suffering from spastic oesophageal motility disorders such as nutcracker oesophagus or diffuse oesophageal spasm.

Further reading Cremonini F, Wise J, Moayyedi P, et al. Diagnostic and therapeutic use of proton pump inhibitors in non-cardiac chest pain: a metaanalysis. Am J Gastroenterol 2005; 100:1226–1232. Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005; 54:710–717. DeVault KR, Castell DO; American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005; 100:190–200. DeVault KR, Talley NJ. Insights into the future of gastric acid suppression. Nature Rev Gastroenterol Hepatol 2009; 6:524–532. El-Serag H, Becher A, Jones R. Systematic review: persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Aliment Pharmacol Ther 2010; 32:720–737. Johnson DA, Fennerty MB. Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastroesophageal reflux disease. Gastroenterology 2004; 126:660–664. Kahrilas PJ, Shaheen NY, Vaezi MF, et al. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008; 135:1392–413. Sharma P, McQuaid K, Dent J et al. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology 2004; 127:310–330. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. New Engl J Med 2009; 360:2277–2288. Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 2008; 103:788–797.

2 Difficulty swallowing and pain on ­swallowing

Case A 28-year-old male presents with a 10 year history of intermittent (roughly 2 monthly), nonprogressive dysphagia for solids, but not liquids. He perceives bolus holdup in the neck. Sips of water help resolve minor dysphagia episodes. He has had two visits to the Accident and Emergency Department in 10 years for endoscopic disimpaction of meat boluses, but the endoscopist reported the oesophagus appeared entirely normal and the bolus had passed spontaneously on both occasions. He has had two barium radiographs performed in this time; both were normal. He denies heartburn, chest pain, regurgitation or weight loss. He suffered from asthma as a child. He takes no medications and has no prior medical history. He denies deglutitive cough and postnasal regurgitation, and has no need for multiple swallows to clear liquid from the pharynx. Although he describes bolus holdup in the neck, the problem is in his oesophagus because: (1) he has none of the cardinal features to suggest a pharyngeal disorder; (2) sipping water assists bolus passage; and (3) he has had no history (and is too young) to suggest underlying neurological diseases. The condition is benign because (1) the history is very long; (2) the condition is nonprogressive; and (3) he has no weight loss. The differential diagnosis is therefore most likely to be an oesophageal ring or peptic stricture. A stricture is less likely because he has had no heartburn and has had two normal endoscopies. His allergic history, male gender and age all favour a multiringed oesophagus secondary to eosinophilic oesophagitis. He underwent endoscopy, which again appeared completely normal. Oesophageal biopsies revealed marked eosinophilic mucosal infiltrate (> 50/high power field) in distal, mid and proximal oesophagus confirming the

diagnosis of eosinophilic oesophagitis. He had a significant reduction, but incomplete resolution of dysphagia episodes, following a 3 month course of fluticasone (500 mcg b.d. swallowed). Repeat endoscopy and oesophageal dilatation (11–14 mm Savary), resulted in several short mucosal tears in mid and distal oesophagus (e.g. Fig 2.9) and subsequent resolution of his dysphagia.

Pain on Swallowing (Odynophagia) Odynophagia is the symptom of pain on swallowing, generally arising from irritation of an inflamed or ulcerated mucosa by the swallowed bolus during its passage through the oesophagus. Mucosal injury causing odynophagia can be caused by infective (viral or fungal) oesophagitis or by mucosal ulceration secondary to corrosive agents (e.g. tablets or reflux oesophagitis) (Box 2.1). The symptom of odynophagia almost invariably warrants endoscopy to elucidate the cause, which may need biopsy confirmation.

Box 2.1  Causes of odynophagia Infections Herpes simplex virus Cytomegalovirus Candidiasis Chemical, inflammatory Drug-induced (potassium, tetracyclines, ­alendronate, quinidine) Radiation Graft vs. host disease Crohn's disease Dermatological diseases (e.g. pemphigus, pemphigoid, lichen planus) Severe reflux oesophagitis Xerostomia

15

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Clinical gastroenterology: a practical problem-based approach

Oesophageal candidiasis This infection usually occurs in patients receiving prolonged courses of antibiotics or who are immunosuppressed by therapy with systemic corticosteroids or other immunosuppressive drugs. It can be seen in patients using inhaled steroids, taken for nasal or respiratory conditions. Conditions commonly associated with oesophageal candidiasis include diabetes, AIDS, lymphoma and other malignancies particularly during chemotherapy when these patients are neutropenic. The oesophageal infection may be accompanied by an oral or pharyngeal candidiasis, particularly in the context of AIDS. The endoscopic features are white plaques on an erythematous mucosa, which can progress to necrosis and ulceration. Diagnosis is confirmed by brushings and biopsy demonstrating hyphae and tissue invasion by the organism. The features can be similar to those of infections due to herpes simplex virus (HSV) or cytomegalovirus (CMV), and biopsy is necessary to distinguish these conditions. Therapy is aimed at treating the underlying disease or conditions that predispose to the infection. Modification of drug therapy such as corticosteroids or antibiotics may be relevant, or the control of diabetes if present. The firstline treatment for oesophageal candidiasis is fluconazole, either oral or intravenous depending upon symptoms and tolerance for oral intake. Herpes simplex oesophagitis Malignancy, immunosuppressive drugs and immunodeficiency states are predisposing factors, but herpetic oesophagitis can occur spontaneously in the apparently healthy, immunocompetent individual. The causative agent is the herpes simplex virus type 1. The endoscopic appearances can vary from discrete, punched-out ulcers to confluent, extensive ulceration. Whitish plaques can also be a feature making differentiation from Candida by endoscopic inspection difficult. Endoscopic biopsy will confirm the diagnosis. Treatment involves suspension, if possible, of drugs such as corticosteroids or cytotoxic agents. The antiviral agent acyclovir is active against this virus. Cytomegalovirus oesophagitis This oesophageal infection is seen most frequently in patients with AIDS, bone marrow transplantation and other immunodeficiency states. Endoscopic features are of extensive ulceration, and characteristic inclusion bodies and giant cells are seen on biopsy.

Drug-induced oesophageal ulceration A number of medications, if allowed to dwell in the oesophagus, can cause severe local ulceration, pain and stricture. Factors predisposing to this phenomenon include swallowing tablets without water, particularly if taken immediately before lying down at night. Any condition that delays oesophageal transit, such as dysmotility or extrinsic compression, can result in tablet retention where it can cause oesophageal ulceration. Drugs particularly likely to cause this syndrome include tetracycline, potassium supplements, ferrous sulphate, alendronate and quinidine. The pain usually settles within a few days, but swallowed topical anaesthetic (e.g. xylocaine viscous) can provide symptomatic relief.

Gastro-oesophageal reflux disease Reflux oesophagitis can cause odynophagia. The patient typically describes a sensation of pain or discomfort coincident with passage of the bolus through the oesophagus, sometimes combined with a sense of transient bolus hold-up. The sense of bolus arrest can dominate the symptom complex if the oesophagitis has progressed to stricture formation, but is not infrequently perceived even in the absence of a stricture. For a detailed account of investigation and management of reflux disease, refer to Chapter 1.

Dysphagia Dysphagia is the symptom of difficulty with the act of swallowing usually causing a sensation of hold-up of the swallowed bolus, frequently accompanied by pain. It can be caused by structural or neuromuscular diseases of the pharynx or oesophagus. It may also manifest as complete oesophageal obstruction due to a bolus impaction, resulting in a visit to the emergency room where, typically, the patient will be distressed, will complain of chest discomfort or pain and will be spitting up saliva continuously.

Causes of dysphagia Because the physiological mechanisms controlling the different phases of swallowing differ, it is convenient to consider the aetiology of dysphagia under the categories of oral–pharyngeal and oesophageal causes, and whether the disease is structural or a motility disorder. Oral-pharyngeal dysphagia is most commonly related to neuromuscular dysfunction, most commonly stroke (Box 2.2). Head and neck surgery and radiotherapy, for malignant disease,

2 Difficulty swallowing and pain on swallowing

17

Box 2.2  Causes of oral-pharyngeal dysphagia Functional disorders Central nervous system Stroke Head injury Parkinson's disease Motor neurone disease Multiple sclerosis Drugs (e.g. phenothiazines) Malformations (e.g. syrinx, Arnold-Chiari) Neural Motor neurone disease Myasthenia gravis Radiotherapy Poliomyelitis Familial dysautonomia Muscle Autoimmune myopathy (polymyositis, ­dermatomyositis, SLE) Thyrotoxic myopathy Guillain-Barré motor neuropathy Muscular dystrophies Structural disorders Head/neck surgery Stricture Radiotherapy Tumour Pharyngeal pouch Web Extrinsic (e.g. osteophytes)

are also very commonly associated with oralpharyngeal dysphagia. Other structural disorders causing oral-pharyngeal dysphagia include strictures, mucosal webs (Fig 2.1) and pharyngeal diverticulum. Because gastro-oesophageal reflux disease is prevalent, peptic oesophageal strictures are a very common cause of oesophageal dysphagia (Figs 2.2 and 2.3, Box 2.3). In these cases, there is frequently a prior history of reflux symptoms. Mucosal rings, such as the Schatzki ring at the cardio-oesophageal junction, are a common cause of intermittent oesophageal dysphagia. Malignant oesophageal obstruction is usually evident on history by virtue of a short history of rapidly progressive dysphagia and significant weight loss (Fig 2.4).

Approach to the assessment of the patient with dysphagia It cannot be overemphasised how important the clinical history is in assessing dysphagia. A history alone should yield the likely site

Figure 2.1  Mucosal web in the cervical oesophagus seen in lateral view (left) and anteroposterior view (right).

and nature of the problem in 80% of patients. Investigational priorities will hinge on the history. The history and examination of the patient with dysphagia should address these four fundamental questions: 1. Does the patient have true dysphagia? 2. Is the dysphagia oral–pharyngeal or oesophageal in origin? 3. Is it due to a structural or motor disorder? 4. Is there an underlying related or causative disease? Is it true dysphagia? Dysphagia is defined as difficulty with the act of swallowing. The purely sensory symptom of globus can be equated inappropriately with difficulty swallowing by the patient. Globus is a non-painful sensation of a lump or fullness in the throat in which deglutitive food bolus transport is unimpaired. Indeed, globus sensation is usually alleviated by eating and is most noticeable between meals. The patient with globus sensation generally only requires otolaryngological evaluation to exclude local inflammatory or infiltrative disorders followed by explanation and reassurance. Some cases can be reflux-related and a trial of proton pump inhibitor therapy is reasonable although response rates to this approach are modest and variable.

18

Clinical gastroenterology: a practical problem-based approach

Figure 2.2  Severe erosive oesophagitis (right), in this case in a patient with scleroderma oesophagus, causing odynophagia and dysphagia. Note also in this patient the abnormal pooling of saliva seen endoscopically (left) indicative of poor oesophageal clearance due to aperistalsis secondary to scleroderma oesophagus. This can be a useful, endoscopic indicator of an underlying motility disorder. Box 2.3  Causes of oesophageal dysphagia Structural disorders Stricture (peptic, caustic, pill-induced, radiation-induced) Tumour Rings and webs Eosinophilic oesophagitis Extrinsic compression (e.g. aberrant R subclavian artery, mediastinal or bronchial tumour) Motor disorders Achalasia Pseudoachalasia (associated with tumour) Diffuse oesophageal spasm Scleroderma

Figure 2.3  Barium radiograph showing (arrows) a distal oesophageal stricture in a patient with longstanding severe reflux disease.

Age of onset, duration of dysphagia, frequency and progression The duration of symptoms is often an important clue to whether the underlying cause is benign or malignant or whether it is due to a recent, acute event such as a stroke. Malignant dysphagia usually presents with a short history of progressive dysphagia over weeks or a few months and is frequently associated with weight loss. A sudden onset of dysphagia, often in association with other neurological symptoms or signs, usually indicates a neurological cause such as stroke. Frequent dysphagia, which is progressive and predominantly for solids, is more likely to indicate an underlying structural disorder such as a peptic stricture or tumour.

2 Difficulty swallowing and pain on swallowing

19

be achieved in most instances from the history (Fig 2.5).

Figure 2.4  Endoscopic appearance of an oesophageal cancer in a patient with a short history of ­progressive dysphagia.

A long history of intermittent, non-progressive, solid bolus obstruction is the hallmark of an oesophageal mucosal ring. In a patient over the age of 40 years, this is generally due to a single mucosal (Schatzki's) ring at the squamocolumnar junction. In a young male this is commonly due to eosinophilic oesophagitis. Intermittent dysphagia, for both liquids and solids, is characteristic of a motility disorder such as achalasia, diffuse oesophageal spasm or scleroderma oesophagus. Perceived site of bolus hold-up The reported site of bolus hold-up can be helpful in finding the location of the underlying cause, but the patient's perception of the site of hold-up can be misleading. In cases of pharyngeal dysphagia, hold-up is reported in the neck. However, distal oesophageal pathology causing dysphagia can give rise to a sensation of the bolus catching either in the cervical or retrosternal region. Hence, a perception by the patient of apparent bolus hold-up in the neck does not help the clinician distinguish between pharyngeal and oesophageal causes of dysphagia. However, perceived hold-up in the low retrosternal region excludes a pharyngeal cause for the dysphagia. An algorithmic approach to determine site and likely aetiology of dysphagia With the abovementioned information to hand, the next logical step is to define more precisely the anatomical location of the problem. This can

More specific symptoms for oropharyngeal dysfunction Four symptoms are highly specific for oropharyngeal dysfunction: (1) delayed or absent oropharyngeal swallow initiation; (2) deglutitive postnasal regurgitation or egress of fluid through the nose during swallowing; (3) deglutitive cough indicative of aspiration; and (4) the need to swallow repetitively to clear swallowed material from the hypopharynx. If one or more of these symptoms is experienced, the cause of the dysphagia is probably oropharyngeal—either structural or neuromyogenic—and further history and investigation of a likely oropharyngeal problem should proceed accordingly (see below). Supportive but less specific symptoms of oropharyngeal dysphagia include bolus holdup perceived in the neck, piecemeal swallows, oral spill or drooling, dysphonia, throat clearing and garbled voice. Immediate expectoration (rather than regurgitation) of an offending bolus is indicative of bolus retention in the hypopharyngeal or cricopharyngeal region. Delayed regurgitation of old food is typical of a large pharyngeal diverticulum. Symptoms specific for oesophageal dysphagia If, based on the above, one strongly suspects an oesophageal cause for dysphagia, the next step is to determine whether the cause is a structural lesion or a motor disorder (Fig 2.5). Again, this can be achieved by the line of questioning in the following step-wise fashion. Is the dysphagia for solids or liquids? Typically a motor disorder (e.g. achalasia, diffuse spasm) will cause dysphagia for both liquids and solids whereas a structural disorder will cause dysphagia for solids only. As the calibre of the oesophagus narrows, the size of the solid bolus required to cause obstruction becomes progressively smaller. If the problem is likely to be a structural oesophageal disorder, the following enquiry will define the likely cause: ll How long has dysphagia been present; is it intermittent, is it progressive? Slowly progressive, longstanding dysphagia, particularly on a background of reflux, is suggestive of a peptic stricture. A short history of dysphagia, particularly with rapid progression (weeks or months) and associated weight loss, is highly suggestive of malignancy. Longstanding, intermittent, non-progressive

20

Clinical gastroenterology: a practical problem-based approach

Step I: Localise the problem to the pharynx or oesophagus ‘Difficulty swallowing’

What does it feel like?

‘Food sticks during meals’

‘Lump in throat between meals’

Where does it stick?

‘Neck’

‘Retrosternum’

Globus

Pharynx or oesophagus? Swallow initiation? Postnasal regurg? Deglutitive cough? Repetitive swallows?

Cardinal pharyngeal symptom(s)?

No

Yes

Pharyngeal

Oesophageal

Step II: Is it dysmotility or a structural problem? Oesophageal dysphagia

Solids or liquids?

Intermittent? Progressive?

‘Solids only’

‘Solids and liquids?’

Probably structural

Probable dysmotility

‘Intermittent, non-progressive’

Duration? Weight loss? Reflux? Ring/web

‘Progressive’

Slow ± Reflux

Rapid ± Wt loss

Stricture

Cancer

Pain + Regurg ++

Pain ++ Regurg ±

Achalasia

Spasm

Chest pain? Regurgitation?

Figure 2.5  An algorithmic approach in taking a history from the patient with dysphagia. The first step is to determine whether the problem arises from the pharynx or from the oesophagus. The italicised text boxes on the left denote the questions to ask the patient. The text boxes in the centre represent patient responses. Having determined that the likely source of the problem is oesophageal rather than pharyngeal in origin, the second step is to determine, on the basis of history, whether the problem is structural or whether it is due to dysmotility (refer to text).

2 Difficulty swallowing and pain on swallowing dysphagia purely for solids is indicative of a fixed structural lesion such as a distal oesophageal ring or proximal oesophageal mucosal web, or eosinophilic oesophagitis. ll What does the patient do when the bolus sticks? Sipping water will frequently relieve obstruction related to a bolus holding up at a structural lesion. However, immediate regurgitation of the swallowed water in this context is indicative of complete bolus obstruction. If the problem is likely to be an oesophageal motility disorder, the following enquiry will define the likely cause. The three cardinal features of oesophageal dysmotility are dysphagia (for solids and liquids), chest pain and regurgitation: ll Does the patient regurgitate? Regurgitation during the meal as well as spontaneous regurgitation between meals or at night is highly suggestive of dysmotility. Unlike regurgitation related to gastro-oesophageal  reflux, the regurgitated fluid/food in the context of dysmotility is generally not noxious to taste and is often described as bland, bubbly saliva or mucus. ll Does the patient experience chest pain or discomfort? Spasm or achalasia typically causes chest pain. While frequently described as heavy or crushing, it may be indistinguishable from the typical ‘heartburn’ of reflux. The pain frequently occurs during the meal, but can be quite unpredictable and sporadic or nocturnal. Sipping antacids or water can relieve dysmotility-related pain, thus further confusing distinction from reflux-related pain. If oesophageal dysmotility is strongly suspected, distinction between achalasia and oesophageal spasm can be difficult at times. Achalasia is much more common than spasm. In achalasia, chest pain is more prominent early in the disease, but over the years tends to diminish and may disappear as dysphagia and regurgitation worsen. Due to oesophageal dilatation and poor clearance, regurgitation is frequently more impressive in achalasia than it is in the case of spasm. Is there an underlying related or causative disease? Oral-pharyngeal dysphagia usually has a neurological basis. A prior history of stroke is often obtained. Symptoms of bulbar muscle dysfunction or other brain stem symptoms (such as vertigo, nausea, vomiting, hiccup, tinnitus, diplopia or drop attacks) should be sought. The patient may complain of tremor, ataxia or unsteadiness, which

21

might indicate an underlying movement disorder or may describe muscular weakness suggestive of myopathy (Box 2.2). Oesophageal dysphagia may present on a background of reflux; hence, history of heartburn and antacid use is relevant. Smoking, alcohol and prior caustic ingestion are risk factors for oesophageal carcinoma. Oesophageal dysmotility can be associated with connective tissue disease, particularly scleroderma when Raynaud's phenomenon and typical skin changes may be present. Eosinophilic oesophagitis is frequently associated with a history of atopy and asthma.

Physical examination of the patient with dysphagia Hands and skin Changes consistent with Raynaud's phenomenon, with or without sclerodactyly, are features commonly found in patients with scleroderma oesophagus. Calcinosis and telangiectasia, if present, complete the features of CREST syndrome, which is always associated with oesophageal dysmotility and reflux. The lilac-coloured (heliotrope) skin changes, typically around the nail beds, bridge of the nose and cheeks and forehead is a feature of dermatomyositis, which can cause severe pharyngeal dysfunction and, to a lesser extent, oesophageal dysfunction as well. Rarely, other skin disorders can cause oesophageal disease and include lichen planus, pemphigus, epidermolysis bullosa, Bechet's syndrome and acanthosis nigricans. Sweating, tremor and tachycardia of thyrotoxicosis may be present in patients with thyrotoxic myopathy causing pharyngeal dysfunction. The typical features of thyrotoxicosis, however, may not be present in the elderly or individuals taking beta-adrenergic antagonists. Head and neck The examiner should palpate the neck for masses, lymph nodes or a goitre. Rarely, a pharyngeal pouch can be felt, nearly always on the left, and may be compressed causing regurgitation of a small amount of food residue into the pharynx with an audible ‘gurgle’. Signs of prior surgery, tracheostomy and radiotherapy are obvious and should be noted. The oral cavity (including natural dentition or dentures, tongue and oropharynx) should be inspected. Eyes Thyrotoxic eye signs should be looked for. Ptosis might indicate a myopathy or myasthenia. Unilateral ptosis, if associated with Horner's

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Clinical gastroenterology: a practical problem-based approach

syndrome (descending sympathetic tract), is typical of lateral medullary infarction causing pharyngeal dysphagia. In addition to dysphagia, the lateral medullary (Wallenberg's) syndrome typically involves hoarseness (10th nerve), vestibular dysfunction (nystagmus, vertigo, vomiting, diplopia and tinnitus), cerebellar limb ataxia, contralateral loss of pain and temperature sensation over half the body (spinothalamic tract), and hiccups. Neuromuscular function Careful examination of cranial nerve function will sometimes detect bulbar muscle dysfunction, but normal palatal motion and an intact gag reflex does not exclude significant bulbar muscle dysfunction in a patient with pharyngeal dysphagia. Tremor and gait disturbances may reflect an extrapyramidal movement disorder such as Parkinson's. Muscle fasciculation, wasting and weakness or fatigueability should be sought to detect underlying motor neurone disease, myopathy or myasthenia. Watch and listen to the patient swallow. With the index and middle fingers resting lightly on the hyoid and laryngeal cartilages respectively, the axial motion of the larynx and hyoid bone should be noted while the patient swallows a mouthful of water. Inadequate laryngeal ascent is frequently seen in neurogenic dysphagia, impairs airway protection during the swallow and can be associated with aspiration. Aspiration will often (but not invariably) cause coughing or choking during the swallow. Respiratory and nutritional sequelae The patient's general nutritional state and body weight are important. The degree of weight loss is a good indicator of the severity of the disease and is most profound in malignant disease. Examination of the chest may reveal signs of respiratory infection, suggesting significant aspiration, which is common in patients with pharyngeal dysphagia.

Investigation of dysphagia The initial choice of investigations will depend on the provisional diagnosis determined on the basis of history and, in the first instance, will be determined by whether the clinician believes the dysphagia is oral–pharyngeal or oesophageal in location. Investigation of suspected oral-pharyngeal dysphagia The initial investigation should be a dynamic, radiographic examination—the videoradiographic swallow study of the oral-pharyngeal phase. This

examination should be complemented by static films, but video recordings are mandatory as the motor events of the oral-pharyngeal phase are too complex and too rapid to be resolved by simple observation of fluoroscopy or x-ray films. Static films are important in detecting mucosal defects and structural lesions such as strictures, rings, pouches, webs (Fig 2.1) and tumours. In cases of oral-pharyngeal dysfunction where the cause is not clear, the videoswallow study is a sensitive means of confirming the site of dysfunction; establishing whether a pharyngeal motor problem exists; defining the mechanisms of dysfunction; and detecting the presence and timing of aspiration. A clear idea of the mechanisms of dysfunction and severity of the disorder is vital in tailoring therapy. In the context of a recent stroke, head or neck surgery or radiotherapy, the underlying cause may be obvious. Nevertheless, in such cases an understanding of the patient's swallow mechanics is vital in deciding on the advisability and safety of oral feeding and the choice of therapy. For example, recognition of timing of aspiration has therapeutic implications. Preswallow aspiration results from poor tongue control and premature spill of the bolus over the back of the tongue before laryngeal protective reflexes have been elicited. Intraswallow aspiration frequently accompanies pharyngeal weakness. Postswallow aspiration is seen when residual bolus pools in the hypopharynx and spills over into the airway as it reopens following the swallow. Pharyngeal bolus transport abnormalities may be due to defective triggering of the pharyngeal motor response, pharyngeal peristaltic weakness or a combination of both. Pharyngeal muscle weakness may be seen as postswallow pooling in the pyriform sinuses. If weakness is unilateral, pooling is confined to the paretic side and is associated with pharyngeal bulging on the affected side. In such cases bolus transport can be facilitated by therapeutic strategies such as head turning towards the paretic side. Diminished upper oesophageal sphincter opening can be due to local stricture, inadequate pharyngeal propulsive forces or incomplete sphincter relaxation. Depending upon the relative contribution of one or more of these features, such patients may benefit from cricopharyngeal dilatation or myotomy. Laboratory tests are useful in confirming suspected underlying primary diseases that may cause oral-pharyngeal dysphagia. Serum creatine phosphokinase level, erythrocyte sedimentation rate, antinuclear antibodies, acetylcholine receptor antibodies and thyroid function tests

2 Difficulty swallowing and pain on swallowing will give a clue to most acquired myopathies, but electromyogram and muscle biopsy may also be necessary as 20% of cases of myositis will have normal biochemistry. Endoscopy will be required in most patients with pharyngeal dysfunction and certainly all cases in whom it is uncertain whether the problem is oesophageal or pharyngeal. Videoradiography should precede endoscopy as it may detect a problem that would make endoscopy hazardous or difficult (e.g. pharyngeal pouch, cricopharyngeal stricture or tumour). Furthermore, radiology may detect a structural lesion that is better appreciated radiologically than it is by the endoscopist and that may be successfully treated endoscopically (e.g. cricopharyngeal stricture or postcricoid web). If the cause for pharyngeal dysfunction is not apparent after the above investigation, careful ear, nose and throat evaluation is required to exclude pharyngolaryngeal malignancy. Tumours in the region can be easily overlooked by the radiologist, and lesions in some locations can be missed by the endoscopist using a standard gastroscope. Features highly suggestive of local malignancy, such as recent onset of throat pain on swallowing and hoarseness with dysphagia, should prompt early laryngoscopy.

23

Investigation of suspected oesophageal dysphagia With a few exceptions, endoscopy should be the first investigation in cases of suspected oesophageal dysphagia. Endoscopy is more sensitive than radiology in detecting mucosal disease. It also provides an opportunity to obtain biopsies and to combine a diagnostic with therapeutic procedure in cases where dilatation is required. One of the deficiencies of endoscopy in the assessment of dysphagia is that it cannot reliably diagnose motility disorders, although the endoscopic finding of a dilated oesophagus containing fluid or salivary residue is highly suggestive of dysmotility (Fig 2.6). Endoscopy does not always reliably pick up all benign structural abnormalities capable of causing dysphagia. This is because an accurate estimation of the narrow calibre oesophagus is not always possible at endoscopy. Hence, a negative endoscopy does not always exclude a structural cause of dysphagia. If a structural oesophageal abnormality is suspected strongly on history and the oesophagus has a normal macroscopic appearance, oesophageal biopsies should be taken to check for eosinophilic oesophagitis, which is commonly associated with one or more mucosal rings (Fig 2.8).

Figure 2.6  The endoscopic finding of fluid or salivary residue within the oesophagus, particularly if it is dilated (left), is highly suggestive of achalasia. Note the typical radiographic findings of achalasia (right): a dilated oesophagus with food and fluid retention, an air-fluid level (arrow) and the ‘bird beak’ tapering at the   cardio-oesophageal junction (arrow head).

24

Clinical gastroenterology: a practical problem-based approach mmHg Pharynx

Swallow

60 0 60 0 60 0 60

Oesoph

0 60 0 60

Sphincter

0 60

0 80 Gastric 40 0 5s

Figure 2.7  Manometry tracing from patient with oesophageal achalasia. Shown are pressures at 5 cm intervals along the oesophagus, and from the lower oesophageal sphincter and stomach, during a 5 mL water swallow. Note the hypertensive sphincter (pressure 30 mmHg) and the failure of lower oesophageal sphincter relaxation (circled). There is a complete loss of peristalsis. In its place is a synchronous low amplitude pressure wave (dashed line) with identical waveform along the entire oesophageal length, indicative of lack of lumen occlusion of a dilated oesophagus (as seen in barium radiograph, Fig 2.6).

In the investigation of oesophageal dysphagia, there are two situations in which a barium swallow should precede endoscopy—a suspected oesophageal ring and suspected oesophageal dysmotility. Preliminary barium swallow findings in these circumstances may permit definitive treatment of a ring or achalasia at the initial endoscopy, or dictate manometry prior to endoscopy if achalasia is suspected (Fig 2.6). In the patient with a typical history of an oesophageal ring (see above), a barium swallow can be an extremely useful adjunct to endoscopy, because mucosal rings are frequently not apparent endoscopically. An appropriately tailored barium swallow study, including prone-oblique views and if necessary a marshmallow swallow, will usually clearly demonstrate a ring and/or the site of bolus hold-up causing the patient's symptoms. The ring can then be dilated, even if it is not visible to the endoscopist, at the subsequent endoscopy. Oesophageal manometry is usually reserved for cases in whom endoscopy and radiology have failed to achieve a diagnosis. Manometry is the only way to diagnose achalasia with certainty; its manometric features are oesophageal aperistalsis, hypertonia and failure of the lower oesophageal sphincter relaxation during swallowing (Fig  2.7).

The manometric hallmark of diffuse oesophageal spasm is synchronous oesophageal contractions in at least 10% of water swallows in an oesophagus, which can demonstrate peristalsis. Additional features present to a variable extent include repetitive waves (swallow-induced or spontaneous); high amplitude contractions; and prolonged contractions (of more than 6 seconds). The scleroderma oesophagus demonstrates complete aperistalsis and absent lower oesophageal sphincter tone, both being due to profound smooth muscle degeneration in the distal oesophagus.

Treatment of dysphagia Specific therapy for dysphagia will be dependent on the cause. Detailed treatment of many problems causing dysphagia is beyond the scope of this chapter and the reader is referred to reviews of these diseases. Treatment of oesophageal dysphagia Oesophageal strictures, rings and webs are generally successfully treated by endoscopic dilatation. This is most commonly achieved by passing graduated sizes of Silastic™ (e.g. Savary-Gilliard®) or balloon dilators over an endoscopically placed guide wire. The underlying

2 Difficulty swallowing and pain on swallowing

A

B

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C

Figure 2.8  Case of a 23-year-old male with longstanding, intermittent dysphagia for solids. The barium swallow (A) shows multiple mucosal rings and a dominant narrowing in the proximal third of the oesophagus. The endoscopic appearance of the multi-ringed oesophagus (B) is typical of eosinophilic oesophagitis (proven on biopsy). Note also the mucosal tear following endoscopic oesophageal dilatation (C).

cause of the stricture must also be treated. Severe reflux disease causing stricture should be managed with potent acid suppression with a proton pump inhibitor. The more refractory cases may require antireflux surgery. Difficult strictures often require repeated dilatations. In the case of one or more oesophageal rings, eosinophilic oesophagitis must always be considered and diagnosis is achieved with endoscopic biopsies. Eosinophilic oesophagitis should be treated in the first instance with the topical (swallowed) steroid fluticasone. Controlled trials have shown comparable efficacy between topical and systemic steroids in eosinophilic oesophagitis, but the former is preferred as it has fewer systemic effects. Steroid therapy in eosinophilic oesophagitis may obviate the need for oesophageal dilatation. However, a proportion of cases, particularly with longstanding disease, may still require dilatation to achieve adequate symptomatic relief and avoid episodic complete bolus impaction. Great care must be exercised in these cases as the rings are often relatively tight and significant postdilatation tears are not infrequent (Fig 2.8). The management of oesophageal malignancy requires relief of dysphagia and, where appropriate, ablation of the tumour either by surgery, chemo- or radiotherapy, or laser ablation. Due to the advanced nature of the disease at the time of diagnosis,

the aim of therapy is palliative in the majority although surgery is an option in early cases. Relief of dysphagia in difficult circumstances can be achieved by placement of an expanding oesophageal stent. Covered stents are also useful in treating associated oesophagotracheal fistulae if they occur. Oesophageal achalasia is best treated by mechanical disruption of the non-relaxing lower oesophageal sphincter. This can be achieved either by surgical cardiomyotomy or by endoscopic, balloon (pneumatic) dilatation. The incidence of posttreatment gastro-oesophageal reflux is greater in those treated surgically; hence, surgical myotomy should be combined with fundoplication. Although smooth muscle relaxants, including the calcium channel blocker nifedipine, do reduce lower oesophageal sphincter pressure, therapeutic results are disappointing. Botulinum toxin (Botox) is simple and safe to infiltrate into the lower oesophageal sphincter at endoscopy with short-term efficacy approaching that of pneumatic dilatation. However, because Botox has limited durability requiring repeated injections it is reserved for the very elderly or those with significant associated comorbidity. Diffuse oesophageal spasm is best treated with smooth muscle relaxants such as nitrates and calcium channel blockers. If symptoms are

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relatively infrequent, sublingual nitrates to abort an episode of chest pain can be useful. Refractory cases with debilitating symptoms can be treated surgically by long oesophageal myotomy, which is effective in 50–70% of cases. Treatment of oral-pharyngeal dysphagia Identification and treatment of an underlying cause, if present, should be the primary aim. Thyrotoxic myopathy responds well to treatment of the thyroid disorder. Inflammatory myopathies (systemic lupus erythematosus and polymyositis) respond variably to steroids with or without other immunosuppressive agents. Dysphagia due to myasthenia, and to a lesser extent to Parkinson's disease, is also responsive to specific drug therapy. Avoidance of implicated drugs such as phenothiazines can be helpful, but the effects of these drugs are not always reversible. Structural disorders such as webs and some pharyngeal or cricopharyngeal strictures can be successfully dilated endoscopically. The dysphagia associated with the posterior pharyngeal pouch is almost invariably successfully treated by surgery (cricopharyngeal myotomy with or without pouch excision or suspension). Head and neck tumours causing dysphagia generally require surgery or radiotherapy. Pharyngeal dysphagia due to cerebrovascular accident is more difficult to treat. However, substantial spontaneous recovery can also be expected in many cases. Expert treatment of oralpharyngeal dysphagia requires close cooperation with a speech pathologist and careful assessment of the dynamics of swallowing as has been outlined. The aims of therapy are to establish a safe means of nutrition by avoiding or minimising aspiration and to promote swallowed bolus clearance from the pharynx by manipulation of food consistency, swallow technique or the use of prosthetic devices or surgery. The reader is referred to a detailed review of this topic. If aspiration is absent or minimal, oral feeding of modified food consistencies can continue safely. However, introduction of non-oral (enteral) feeding by nasogastric tube in the short term, or percutaneous endoscopic gastrostomy in the longer term, may be necessary to optimise nutrition if feeding via the oral route is considered unsafe. With the help of a speech pathologist, compensatory strategies can be implemented to minimise the symptoms of aspiration and dysphagia by manipulating the manner in which the food bolus flows through the oral and pharyngeal regions. These techniques involve manipulation of the position of the head and/or the body; or altering

the characteristics of administered food boluses including volume, rate and viscosity. Disorders of upper oesophageal sphincter opening may be amenable to cricopharyngeal myotomy, which disrupts the upper oesophageal sphincter and permits it to open more widely. The results from myotomy have been variable, however, and there is no current consensus on who should be selected for myotomy.

Key Points ll

ll

ll

ll

ll

ll

A careful history is the single most important step in evaluating the patient with dysphagia as it identifies the likely pathological process in over 80% of cases. A common mistake is to confuse the common, purely sensory symptom of globus with dysphagia. The swallow is completely normal in globus. A history will generally reliably distinguish pharyngeal from oesophageal dysphagia and distinguish a structural oesophageal disorder from dysmotility. The apparent site of bolus holdup, when perceived in the neck or throat, can be misleading because, 30% of cases of oesophageal dysphagia will localise holdup above the manubrium. The increasingly common condition of eosinophilic oesophagitis can have an entirely normal endoscopic appearance and, if suspected (e.g. intermittent unexplained dysphagia, food bolus impaction), oesophageal biopsies are mandatory to clarify. In some cases, a combination of endoscopy, radiography and oesophageal manometry is necessary to secure a diagnosis.

Further reading Bohm M, Richter JE. Treatment of eosinophilic esophagitis: overview, current limitations, and future direction. Am J Gastroenterol 2008; 103(10): 2635–2644. Cook IJ, Kahrilas PJ. American Gastroenterological Association clinical practice guidelines: management of oropharyngeal dysphagia. Gastroenterology 1999; 116(2):455–478. Francis DL, Katzka DA. Achalasia: update on the disease and its treatment. Gastroenterology 2010; 139:369–374. Pandolfino JE, Kaharilas PJ. American Gastroenterological Association medical position statement: clinical use of esophageal manometry. Gastroenterology 2005; 128:207–208. Spechler SJ. American Gastroenterological Association medical position statement on treatment of patients with dysphagia caused by benign disorders of the distal esophagus. Gastroenterology 1999; 117:229–232.

3 Hiccups, sore mouth and bad breath

Case A 51-year-old post-menopausal woman consults because of a feeling of burning inside her mouth. The pain in her mouth is present every day and persists for most of the day. She also describes dryness of the mouth but no dryness of the eyes. She has otherwise been in excellent health. She denies any history of heartburn or acid regurgitation. Her sense of taste and smell is normal. She has not had any mouth ulcers or trauma. There is no history of arthritis or skin rashes. Her dental history is unremarkable. She has been using mouthwash but only occasionally. She denies symptoms of anxiety or feeling depressed. Physical examination of the mouth and pharynx is normal. Neurological examination including lower cranial nerves and reflexes is normal. There is no thyroid enlargement, or signs of hypothyroidism. The patient is advised she has burning mouth syndrome. A tricyclic antidepressant, desipramine, beginning at a low dose of 10 mg at night, is prescribed after fully informing the patient of the potential side effects. The dose is increased to 25 mg at night after a week and then 50 mg at night after 2 weeks. Her symptoms completely resolved within a month. It was recommended she continue on the desipramine for 6 months and then the dose be titrated off and clinical course be observed.

Hiccups Introduction A hiccup is a common reflex characterised by the act of inspiration against a closed glottis. Almost all individuals experience hiccups. It occurs in utero late in fetal development and in the newborn, and becomes less frequent as the infant matures. Hiccups usually respond rapidly to simple therapeutic measures, but they can become protracted and are classified as intractable

if they persist for longer than 24 hours. Protracted hiccups may be indicative of serious underlying disease and may also have significant deleterious effects such as postoperative wound dehiscence, fatigue, dehydration, weight loss and even death.

Pathophysiology Electromyographic studies show the reflex involves a transient burst of intense inspiratory activity, involving excitation of the diaphragm and inspiratory intercostal muscles, with reciprocal inhibition of the expiratory intercostal muscles. The discharge burst lasts for approximately 500 ms, but the duration of the inspiratory air flow is very much shorter than this because inspiration is halted abruptly, in the presence of continued powerful inspiratory muscle contraction, by glottal closure 35 ms after the onset of inspiration. This phenomenon generates the noxious sensation and the characteristic sound of hiccups. Glottal closure persists for 1 second or more until the mechanical effect of the hiccups has subsided. Hiccups are most likely to occur during inspiration, suggesting the rate of change of lung volume may be a co-stimulus for the reflex. The reflex is mediated by afferent fibres primarily in the phrenic and vagus nerves as well as dorsal sympathetic fibres. These fibres synapse within the dorsolateral region of the medulla. The main efferent limb of the reflex causing spasm of the diaphragm is then mediated by motor fibres of the phrenic nerve but also via fibres in the vagus, cervical and thoracic nerves. Hence, hiccups can result from direct stimulation or irritation of the afferent or efferent vagal or phrenic pathways; from lesions in the medulla or they can be secondary to metabolic disturbances. A range of gastrointestinal stimuli can cause reflex excitation of visceral afferent vagal fibres. Vagal afferent receptors in the oesophagus can trigger the responsible medullary centres. This is

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Clinical gastroenterology: a practical problem-based approach

the proposed mechanism for hiccups occurring during swallowed bolus impaction at the site of a benign stricture or ring, or in response to oesophageal distension by retained food and fluid in oesophageal achalasia, or in the context of pill-induced oesophageal ulceration or stricture. Similar vagal afferent stimuli might originate in cases of hiatus hernia or gastro-oesophageal reflux disease, but the evidence implicating reflux as a cause of hiccups remains inconclusive. Although an association between hiccups and reflux has been well described, whether there is a cause-and-effect relationship remains controversial. The association may be fortuitous; reflux may cause hiccups or hiccups may cause reflux. Hiccups transiently create a pressure gradient that favours reflux of gastric content into the oesophagus. Hiccups acutely reduce intraoesophageal pressure by 20–40 mmHg and simultaneously reduce lower oesophageal sphincter pressure. Patients have been described in whom oesophageal acid infusion provoked hiccups, and in whom the treatment of reflux cured the hiccups. However, other investigators could not induce hiccups by acid infusion. Furthermore, there are numerous studies reporting failure of fundoplication to cure hiccups even in the context of demonstrable acid reflux, which argues against a causal relationship between reflux and hiccups. Are hiccups associated with oesophageal dysmotility? An achalasia-like picture during the symptomatic phase of intractable hiccups has been reported. This pattern reverted partially to normal with resolution of the hiccups. Achalasia, presumably secondary to oesophageal distension, can present with hiccups usually during consumption of a meal—a symptom that is alleviated following pneumatic dilatation. A range of non-specific oesophageal motor abnormalities can co-exist during the symptomatic phase. Oesophageal peristaltic abnormalities have been reported by some to be present during hiccups. Several manometric studies have demonstrated oesophageal aperistalsis in response to swallows while patients were symptomatic and a return to normal motility thereafter in the absence of hiccups. However, at least one study reported normal oesophageal peristalsis during hiccups. A non-specific oesophageal motor disorder, with some features consistent with spasm, was reported in one case.

However, most frequently the cause of transient hiccups is unknown. The cause of intractable hiccups can be classified into five groups (Box 3.1): 1. central irritation of medullary centres; 2. phrenic or vagus nerve stimulation or irritation; 3. metabolic/endocrine causes; 4. idiopathic causes. Structural or functional disturbances of the dorsolateral medulla, in the region of the vagal nuclei and the nucleus tractus solitarius, can cause hiccups. Medullary lesions causing hiccups include infarction in the territory of the posterior inferior cerebellar artery, tumour, abscess, syrinx, haemangioma, haematoma, aneurysm and demyelination. Central nervous system infections including viral encephalitis, syphilis and HIV encephalopathy are less common central causes for hiccups. Neurogenic hiccups due to brainstem disease are frequently accompanied by localising neurological signs. Stimulation of visceral afferent vagal fibres originating in the gastrointestinal tract will cause hiccups. Gastro-oesophageal reflux, achalasia, gastric distension, oesophageal or small bowel obstruction and even pancreatic or biliary disease can provide the stimulus in these cases. Vagal afferent stimulation of the auricular branch of the vagus nerve supplying the external auditory canal has reportedly caused hiccups—in one instance the stimulus arose from an insect trapped in the auditory canal. Mediastinal disease (e.g. tumour, thoracic aortic aneurysm or diaphragmatic irritation caused by subphrenic and hepatic disease, pleural or pericardial effusion, or myocardial infarction) can similarly result in hiccups by stimulation of vagal or phrenic nerve fibres within the mediastinum or by direct irritation of the diaphragm. Systemic and metabolic disorders including diabetes mellitus, chronic kidney disease, hypocalcaemia, hyponatraemia and Addison's disease can cause hiccups. Drugs, most commonly alcohol and general anaesthetic agents, can cause hiccups but others include corticosteroids, benzodiazepines, barbiturates and etoposide. Psychogenic hiccups have been described, although this is speculative as the reflex is truly involuntary.

Aetiology of hiccups

Approach to the patient with intractable hiccups

The relatively common self-limiting bout of hiccups is frequently induced by gastric distension, emotion, alcohol ingestion or sudden change in temperature.

A careful history should enquire about neurological symptoms, particularly headache and brainstem symptoms such as diplopia, vertigo, nausea,

3 Hiccups, sore mouth and bad breath Box 3.1  Causes of intractable hiccups Central irritation Medullary lesions ll Infarction (e.g. posterior inferior cerebellar artery occlusion) ll Haematoma ll Tumour ll Haemangioma ll Demyelination ll Abscess ll Syrinx Central nervous system infections ll Viral encephalitis ll Meningitis ll HIV encephalopathy ll Encephalitis lethargica ll Syphilis Phrenic or vagus nerve irritation Visceral vagal afferent stimulation ll Oesophageal obstruction (tumour, stricture, ring, pill-induced) ll Achalasia ll Gastro-oesophageal reflux ll Gastric distension ll Small bowel obstruction ll Pancreatic/biliary disease ll Foreign body in external auditory meatus (auricular branch of the vagus nerve) Irritation of thoracic path of phrenic or vagal nerves ll Mediastinal lesions (tumour, aortic aneurysm) ll Pleural/pericardial effusion ll Pneumonia ll Myocardial infarction ll Diaphragmatic irritation (tumour, subphrenic and hepatic lesions) Metabolic causes ll Chronic kidney disease ll Hyponatraemia ll Hypocalcaemia ll Addison's disease ll General anaesthesia ll Drugs (alcohol, short-acting barbiturates, methyldopa, steroids) Idiopathic causes

vomiting, hoarseness, ataxia or clumsiness, and disordered pain sensation. Chest pain, fever and cough are clues to cardiac, respiratory or mediastinal disease. Gastrointestinal causes may be suspected if heartburn, regurgitation, chest

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Box 3.2  Approach to intractable hiccups History Neurological enquiry (headache, brainstem symptoms such as vertigo, ataxia, diplopia, hoarseness, dysphagia, pain and temperature sensory loss) ll Cardiorespiratory (chest pain, cough, fever, dyspnoea) ll Gastrointestinal symptoms (reflux, regurgitation, vomiting, chest pain, dysphagia, abdominal pain) ll Known metabolic diseases (renal, diabetes, calcium) ll Drugs (methyldopa, barbiturates, alcohol, steroids) Physical examination ll Cranial nerve and cerebellar function, long tract signs, pain and temperature sensation ll Cognitive function (encephalopathic features) ll Fever ll Cardiorespiratory signs of pleural or pericardial disease, postural hypotension ll Aural examination for foreign body ll Abdominal examination (gastric splash, signs of bowel obstruction, hepatomegaly) Investigations (priority and extent dictated by above findings) ll Metabolic screen (urea, creatinine, electrolytes, calcium, glucose, liver function tests, Synacthen stimulation test) ll Blood leucocyte count ll Chest x-ray ll Electrocardiograph ll CT thorax (if suspect mediastinal lesion) ll CT abdomen (if suspect liver or subdiaphragmatic lesion) ll Gastroscopy (if suspect oesophageal or gastric pathology) ll Oesophageal motility studies ll

pain, dysphagia, vomiting or abdominal pain is reported. A history of metabolic disorders and drug enquiry are also important (Box 3.2). Physical examination should include examination of cranial nerve, long tract and cerebellar signs. Disordered cognitive function may relate to metabolic derangements or to central causes such as encephalitis. Cardiorespiratory examination should look for signs of pleural or pericardial disease and postural hypotension, which is present in Addison's disease. The external auditory canals should be examined for foreign

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Clinical gastroenterology: a practical problem-based approach

bodies. Abdominal examination should specifically look for signs of gastric stasis (e.g. succussion splash), bowel obstruction or tender hepatomegaly, which may indicate hepatic enlargement, or an intrahepatic lesion such as an abscess. The priorities with respect to investigations will be dictated by the historical and physical findings. Serum electrolytes including sodium, calcium, blood sugar level and liver function tests should be done. A leucocytosis may indicate an underlying infective process. Chest x-ray and electrocardiogram are important to detect pericardial, plural or myocardial disease such as myocardial infarction. A thoracic computed tomography (CT) scan can be performed if mediastinal disease is suspected. Imaging of the abdomen is indicated if a subdiaphragmatic abscess is suspected. Endoscopy is indicated if oesophageal disease or gastric stasis is apparent clinically. The approach to intractable hiccups is outlined in Box 3.2.

Treatment Treatments for intractable hiccups are many and varied and, due to the nature of the condition, virtually none have been subjected to randomised controlled therapeutic trial. There are at least 100 physical and pharmacological therapies described. Many of these cures are purely anecdotal and have included prayers to St Jude, the Patron Saint of Hopeless Causes; anger; sexual intercourse; pressing a finger firmly into each external auditory canal (to stimulate the auricular branch of vagus nerve); pharyngal stimulation by swallowing coarse-grain sugar; and laryngotracheal stimulation induced by a burst of coughing. Physical measures such as breath holding have been attributed to Hippocrates. There is some physiological basis for this as increasing the partial pressure of CO2 by rebreathing does reduce hiccup frequency. Other noxious afferent stimuli include strong traction on the tongue or phrenic nerve stimulation. Primary therapy of any identified underlying cause is appropriate and, in most instances, will lead to rapid resolution of the hiccups. In refractory or idiopathic cases, there are no established guidelines regarding drug therapy for hiccups. A very extensive list of drugs has been described with variable success in hiccups. Notwithstanding, there are numerous reported failures in response to a number of agents and therapy is largely a matter of trial and error. Efficacy studies are largely single case reports and uncontrolled. There is only one randomised, controlled therapeutic trial in hiccups. This study found the GABAB receptor

Box 3.3  Treatment of intractable hiccups Physical modalities Raise PCO2 by rebreathing Modification of vagal afferent stimulation ll External auditory canal pressure ll Pharyngeal stimulation by nasogastric tube ll Valsalva manoeuvre Modification of phrenic efferent traffic ll Transcutaneous electrical stimulation of cervical phrenic nerve ll Phrenic nerve crush Glossopharyngeal nerve block Pharmacological modalities ll GABAB agonist: baclofen ll Dopaminergic antagonists (chlorpromazine, haloperidol, metoclopramide, apomorphine) ll Anticonvulsants (carbamazepine, phenytoin, sodium valproate) ll Calcium channel blockers (nifedipine, nimodipine) ll Other (ketamine, lignocaine, nefopam)

agonist, baclofen, to be effective in four patients. There is little objective evidence suggesting that one pharmacological agent is superior to another. Substantial numbers of favourable case reports support the efficacy of dopaminergic antagonists such as chlorpromazine, haloperidol and metoclopramide in intractable hiccups. Other drugs most frequently reported to be effective include anticonvulsants (phenytoin, sodium valproate and carbamazepine); benzodiazepines (clonazepam); calcium channel blockers (nifedipine and nimodipine), anaesthetic agents (ketamine and lignocaine), and amitriptyline (Box 3.3). Finally, if pharmacotherapy is unsuccessful, disruption of phrenic nerve traffic by transcutaneous electrical stimulation of cervical phrenic nerve, or left phrenic nerve block may be necessary in severe, refractory cases.

Suggested sequential approach to suppression of hiccups 1. Identification and treatment of underlying cause. 2. Vagal afferent stimulation by pressure in both auditory canals; followed by other simple measures aimed at pharyngeal stimulation (coarse grained sugar, passage of nasogastric tube) or Valsalva manoeuvre. 3. Parasympathetic stimulation by per rectal massage.

3 Hiccups, sore mouth and bad breath 4. Pharmacotherapy: either baclofen 5–15 mg t.d.s. orally, if unsuccessful: add nifedipine 5–10 mg t.d.s.or chlorpromazine 20–50 mg IV; if unsuccessful: add metoclopramide 10 mg IV. 6. Phrenic nerve modulation (transcutaneous electrical stimulation) or blockade.

Sore Mouth The terminology describing oral sensations varies widely because there is no unanimity in relation to the terms applied. The terms used include glossodynia, glossopyrosis, stomatodynia and oral dysaesthesia. Soreness in the mouth can be due to objective alterations to the oral mucosa due to ulceration or inflammation. Very commonly, however, the symptoms are variable and there is no evidence of mucosal disease or any underlying pathology to account for symptoms. The latter situation is classified as the burning mouth syndrome. In contrast to conditions causing oral ulceration in which pain is aggravated by eating, the pain of burning mouth syndrome is often alleviated by eating.

Oral ulceration Oral ulcers are so common as to be almost universally experienced at one time or another. Serious or recurrent and painful oral ulceration can be an indicator of underlying systemic or gastrointestinal disease. Aphthous ulceration usually takes the form of multiple, small, painful, punched-out shallow ulcers and can affect the lips, buccal mucosa and tongue. These lesions can also be quite large, in which case they are usually single. Immunological responses seem to contribute to ulcer formation although trauma to the mucosa is also an important precipitant. The lesions are usually relatively minor and heal over a period of a few days up to 2 weeks. There is little controlled evidence that topical therapy is effective. However, topical steroid preparations, such as triamcinolone acetonide in dental base, or hydrocortisone hemisuccinate lozenges are often used with apparent benefit. Severe, persistent cases may respond to colchicine, dapsone or thalidomide. Herpes simplex ulcers are located primarily on the hard palate, gingival and alveolar ridges. They begin as small clusters of vesicles, which transform into small punctate ulcers. Treatment is analgesics in immunocompetent patients. If ulcers are frequently recurrent, oral acyclovir can be used to reduce recurrence.

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There are other causes of oral ulceration. Crohn's disease and coeliac disease may present with aphthous ulceration. Erythema multiforme is preceded by vesicles. Pemphigus and pemphigoid are preceded by bullae. Behçet's syndrome is a rare, multisystem disease in which recurrent oral aphthous ulceration occurs in conjunction with genital ulceration; the skin, eyes, joints and the gut can also be affected. Vitamin B deficiency, neutropenia, HIV infection and antimetabolites (e.g. methotrexate) can also cause frequent oral ulcers.

Burning mouth syndrome Burning mouth syndrome (glossodynia or glossopyrosis) is characterised by the prolonged sensation of unexplained pain or burning inside the oral cavity, often accompanied by other symptoms, such as dryness, paraesthesia, altered sense of taste (cacogeusia or dysgeusia) or smell. It is at least two or three times more common in women and is most prevalent among middleaged women. The oral mucosa looks normal, and neither local nor systemic disease is present. Aetiology Dentures are commonly implicated in glossodynia. Ill-fitting dentures are reported in 50% of patients with this symptom. It has been proposed that pressure is exerted by the dentures on oral tissues or that muscular tension influences sensory innervation and oral sensory perception. Monomers in the denture base material have also been linked to some cases. Deficiency states cause macroscopic mucosal alterations, but glossodynia can precede these mucosal changes. Glossitis is a characteristic feature of advanced deficiency of vitamins such as folate and B12 (Box 3.4). Glossodynia in diabetes mellitus can be caused by oral candidiasis; however, a form of oral sensory neuropathy is believed to be a factor in some cases in whom Candida infection is not a feature. Several neurogenic causes of glossodynia, including trauma to the lingual nerve, are described. Glossopharyngeal neuralgia is characterised by paroxysmal pain, not only in the tongue, but also in the entire distribution of the nerve. Glossopharyngeal neuralgia can be elicited by stimulation of trigger zones in the tonsils, pharynx, tongue base and ear. Gastro-oesophageal reflux is thought in some cases to be associated with glossodynia, but there is little objective evidence to suggest that reflux causes it.  Furthermore, the observation that reflux is extremely common and glossodynia

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Clinical gastroenterology: a practical problem-based approach Box 3.4  Aetiology of glossodynia Denture-related Dentures (ill-fitting, monomer from denture base) ll Dental plaque ll Oral parafunction Infective/dermatological ll Candidiasis ll Lichen planus Deficiency states ll Iron, B12, folate, B2 (riboflavin), B6 (pyridoxine), zinc Endocrine ll Diabetes mellitus ll Hypothyroidism ll Hormonal changes occurring during menopause Neurologically mediated ll Referred from tonsils, teeth ll Lingual nerve neuropathy ll Glossopharyngeal neuralgia ll Oesophageal reflux Iatrogenic ll Mouthwash Xerostomia Psychogenic Idiopathic ll

relatively uncommon argues against a strong association. Anecdotal experience suggests potent antireflux therapy is ineffective in the treatment of glossodynia. Xerostomia can be associated with a burning sensation in the tongue. Salivary secretion tends to fall with age but xerostomia is commonly caused by drugs with anticholinergic effects and is a significant problem after head and neck radiotherapy. Pathogenesis The cause of burning mouth syndrome is unknown. It is possible that burning mouth syndrome is caused by altered oral sensory function because lowered thresholds for sweet and sour taste, and for tongue pain tolerance, have been reported in these patients. A trigeminal small-fibre sensory neuropathy may underlie some cases; others may be dopamine-deficient. Some studies found regional temperature differences in the tongues of sufferers compared with controls as well as

Box 3.5  Approach to the patient with sore mouth History Psychological factors, stress ll Symptoms of systemic disease Examination ll Mouth, tongue, teeth ll Full examination for signs of endocrine, neurological or haematological disorders ll Otolaryngological assessment Investigations Haematological ll Full blood count ll Serum iron, B12, folate ll Blood glucose ll Thyroid function tests ll Serum zinc ll Erythrocyte glutathione reductase activity (riboflavin status)* ll Erythrocyte aminotransferase activity (pyridoxine status)* Bacteriology ll Swabs from tongue for microscopy and culture Radiology ll Orthopantomogram (for dental pathology) Dental opinion ll

*Not widely available

differences in blood flow to the tongue, lips and cheeks, suggesting that some form of vascular insufficiency might be implicated. Behavioural factors may be important. There is a high prevalence of anxiety, depression and somatic reactions to stress, suggesting a psychological basis, but a causal link has not been clearly established. Diagnosis The first step is to exclude an underlying treatable cause, although this will only be identified in the minority. History should include an assessment of the patient's behaviour and life stress factors. A careful inspection of the mouth, tongue and teeth is important. A full physical examination may reveal features of systemic disease such as diabetes mellitus, thyroid disease, haematological or neurological diseases (Box 3.5). An otolaryngological examination is also important. A dental opinion should probably be sought in most cases, unless an underlying, correctable systemic disease is found.

3 Hiccups, sore mouth and bad breath Treatment Identification and treatment of any underlying condition is the first step. Longitudinal studies indicate that the prognosis is poor in burning mouth syndrome, which persists long term in at least half the patients. It is associated with high levels of patient dissatisfaction and continuing consumption of healthcare resources. A tricyclic antidepressant may reduce the burning. If this fails, gabapentin or pregabalin can be tried. If psychopathology can be identified, such as a cancer phobia, therapy directed specifically at this aspect may be helpful.

Bad Breath Halitosis (bad breath), a disagreeable odour detectable in exhaled breath, is common in healthy individuals, particularly after sleep (morning breath) or after consumption of certain foods. Halitosis is most commonly caused by the action of oral microflora on oral debris located in gingival crevices, within tongue coating and periodontal pockets. Plaque organisms, particularly Porphyromonas gingivalis, fusobacteria and other anaerobes, cause putrefaction and subsequent release of volatile chemicals, particularly sulfide compounds. Halitosis may be physiological or pathological. Physiological halitosis is usually transient and an identifying agent, usually a food or drug, is apparent. For example, high sulfurcontaining foods such as garlic, onions, broccoli, radishes, leeks, or drugs such as isosorbide dinitrate, disulfiram and dimethyl sulfoxide can cause halitosis, as can dehydration or starvation. Halitosis may also be a manifestation of significant underlying local or systemic disease, a search for which may be necessary if an oral cause cannot be identified. Patients frequently do not perceive their own oral malodour, which may be apparent to others. The senses of taste and olfaction are subject to the phenomenon of adaptation, making the subject insensitive over time to the offensive odour or taste. Also, chemical senses can be affected by many factors that themselves can be associated with halitosis, such as normal ageing, poor oral hygiene, xerostomia, craniofacial abnormalities, psychiatric disorders and neoplasm.

Pathogenesis The majority of cases of halitosis arise from oral conditions (see Box 3.6). The odour is a result of sulfur-containing proteins and peptides being hydrolysed by gram-negative bacteria in the alkaline environment of the mouth. The resulting volatile

Box 3.6  Causes of halitosis Oral/dental Poor oral hygiene/failure to clean dentures ll Dental decay ll Periodontal disease ll Gingivitis ll Oral ulceration (aphthous, infective, traumatic) ll Oral candidiasis (corticosteroids, cancer, immune deficiency, diabetes), xerostomia (drugs, dehydration, ageing, anaemia, hypovitaminosis, diabetes, stress, autoimmune disease, mechanical blockage, malignancy, multiple sclerosis, AIDS, irradiation) ll Oral neoplasm Nasal/nasopharynx ll Neoplasm ll Rhinitis (atrophic, rhinitis medicamentosa) ll Tonsillitis ll Nasal foreign body ll Sinusitis Laryngo-pharyngeal ll Pharyngeal pouch ll Neoplasm Oesophagogastric ll Achalasia ll Oesophageal/gastric cancer Respiratory ll Bronchiectasis ll Bronchitis ll Tuberculosis ll Lung abscess ll Necrotic neoplasm Systemic/metabolic ll Starvation ll Chronic kidney disease ll Hepatic failure ll Diabetic ketoacidosis ll Inborn errors of metabolism (aminoacidurias, e.g. trimethylaminuria) ll Drugs (alcohol, nitrates, chloral hydrate, iodine-containing drugs) Psychogenic ll Delusional halitosis ll Hallucinatory feature of schizophrenia or temporal lobe epilepsy Idiopathic ll

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Clinical gastroenterology: a practical problem-based approach

sulfur-containing end-products include hydrogen sulfide and methyl mercaptan. Surprisingly, the usual compounds associated with putrefaction of biological tissues (ammonia, putrescine, indole, skatole and cadaverine) are not contributors to oral malodour. Under normal circumstances the odour of the oral cavity is not static and varies throughout the day and as a function of age, gender, hunger state and, perhaps, menstruation. It is affected by multiple factors, many of which are interdependent, including oral flora, salivary flow, pH, oral musculature and the presence of appropriate substrates. Conditions favouring production of putrid odours include low ambient oxygen concentration, a shift from gram-positive to gram-negative bacterial colonisation, reduced carbohydrates available as bacterial substrates, an alkaline oral pH and reduced salivary flow. Any oral inflammatory condition, by its association with tissue degeneration and necrosis, will promote bacterial putrefaction. Gingivitis and periodontal disease favour bacterial putrefaction by increasing local growth factors and substrates available from the inflammatory process. These two conditions produce a very potent halitosis and, because of the increased incidence of these two conditions in the ageing population, they may account for the oral malodour ascribed to ageing. The surface structure of the tongue provides a suitable environment for a biofilm serving as a repository for periodontal and other bacteria, including anaerobes. Deep fissures on the tongue dorsum, present in around 25% of the population, has been associated with higher mouth and tongue odour scores, although proof of higher bacterial counts in this population is lacking. The degree of tongue coating (containing a mix of desquamated cells, debris and bacteria) has some correlation with tongue bacterial counts and with halitosis. Nasal disease uncommonly causes halitosus (with a slight cheesy character); sinusitus or nasal polyps may or may not be present. Trimethylaminuria causes a fishy odour and is genetic (autosomal-recessive).

Approach to the patient The approach to the patient is detailed in Box 3.7. The first step is to determine whether the patient does actually have halitosis, by wafting the expired air towards the examiner's nose with the palm of the hand. It is important to be aware, however, that halitosis can be intermittent or reduced by recent antibiotic use. Therefore, if it is not apparent to the clinician, corroborative evidence should be sought from family members or close contacts. If the problem cannot be substantiated, the patient may

Box 3.7  Approach to halitosis History Onset, constant or intermittent, relationship to time of day, diet ll Dental history: oral habits/hygiene ll Symptoms: dysphagia, regurgitation or coughing; symptoms of systemic disease ll Associated taste disorders that might suggest central cause (7th, 9th, 10th cranial nerves, medulla, pons, thalamus, cortical taste centres) ll Drugs: corticosteroids, drugs causing xerostomia or halitosis Examination ll Confirm presence of halitosis (if neither detectable, nor supported by close contacts, suspect disordered chemoreception* or psychogenic) ll Odour predominantly during oral expiration = oral disease in majority (oropharyngeal, oesophagogastric also): – oral/dental inspection, oral candidiasis – ?upper gastrointestinal evaluation (barium swallow, endoscopy) ll Odour predominantly during nasal expiration = respiratory tract disease: – otorhinolaryngological evaluation (nasopharynx, nose, sinuses) – CT scan, sputum examination ll Expired air equally offensive via nose and mouth = metabolic disorder: – blood glucose level, electrolytes, urea, creatinine, liver function tests ll

*Test olfactory function (e.g. soaps, wintergreen, cloves).

have disordered chemoreception or the problem may be psychogenic (halitophobic). Neurosis can lead to compulsive use of mints, mouthwashes and oral deodorants in the absence of objective malodour. In such cases, halitosis is not physically based and counselling or psychiatric help may be needed. The next step is to determine whether the odour is perceived predominantly during exhalation via the mouth or via the nose. Ask the patient to breathe out each time through the mouth or the nose and count to 20; place your nose 10 cm away. A stronger odour from nasally expired air indicates a lesion or disease of the nose, nasopharynx, sinuses or respiratory tract. Common causes include local tumours, rhinitis, sinusitis, or nasal foreign body (Box 3.6). Bronchiectasis can cause halitosis. Other respiratory disorders, such as asthma requiring

3 Hiccups, sore mouth and bad breath systemic or inhaled corticosteroids, can result in oropharyngeal candidiasis that causes halitosis. Conditions in which oral candidiasis is common include cancer, immune deficiency states, diabetes mellitus and xerostomia. Tongue odour can be tested by using a plastic spoon to scrape the back of the tongue. Check whether the dentures smell foul. A more pronounced odour emanating from oral exhalation indicates an oral, oropharyngeal, hypopharyngeal or oesophagogastric source. Halitosis is rarely caused by gastrointestinal disorders. Gases from the upper gastrointestinal tract do not normally mix with those of the respiratory tract, but they can in the context of eructation, regurgitation or vomiting. Stagnation of food in a pharyngeal pouch or a dilated oesophagus in achalasia can cause regurgitation or eructation of partially fermented food and secretions. If the expired air is equally offensive whether exhaled by nose or mouth, a systemic or metabolic cause is suspected. Finally, a number of patients can present with halitosis and/or altered chemoreception for which no underlying cause can be found. Sophisticated breath analysis (gas chromatography and mass spectrometry) in some of these patients has identified higher than normal levels of volatile sulfur compounds. While some of these individuals have enzymatic or transport abnormalities, it is not known whether a subset of the remainder are heterozygous for sulfur-containing amino acidurias.

Treatment General Management of non-oral causes of halitosis requires treatment of the underlying cause. Dental and gingival disease will account for the majority and dental referral should be sought in most cases. Oral care Oral care will be dictated by dental opinion. Specific treatment of gingival or periodontal disease may be required. Regular brushing and flossing of teeth, brushing the tongue, dental review and prophylaxis and plaque removal are important. Adequate frequent cleaning of dentures is also important. If head and neck radiotherapy is planned for any reason, prior initiation of good oral hygiene practices and establishing optimal oral health will minimise the development of postradiation halitosis secondary to xerostomia. If present, oral candidiasis should be treated with antifungal agents such as nystatin and removal of

35

any removable oral prostheses, which can harbour the organism and recolonise the tissues. Oral mouthwashes Chemicals, such as chlorhexidine, chlorine dioxide, metal ions, triclosan or formulations containing essential oils and hydrogen peroxide, can reduce oral bacterial content. Although some mouthwashes are a useful adjunct in the prevention of halitosis, they are not a substitute for good oral hygiene practices and may only mask oral malodour. Their high alcohol content may further dry out the oral mucosa and, in the context of xerostomia, non-alcohol-based fluoridated washes are preferable. Mouthwashes containing chlorhexidine appear to be most effective at reducing plaque and gingivitis. Limited uncontrolled data also support the use of chlorhexidine mouthwashes specifically for halitosis. However, there are no controlled efficacy data and the durability of the effect on oral flora is unclear. Mechanical removal of debris coating the tongue may also be useful, although objective efficacy data are lacking. In severe, refractory cases, a trial of metronidazole for 10 days may be considered, although high-level evidence for efficacy is lacking for this approach. Dietary changes Eating regularly and avoidance of odiferous foods is important. Coffee and alcohol intake should be decreased, and the drinking of water increased. Low-fat diets and diets high in fruit and vegetables can be helpful. Treat xerostomia If xerostomia is a problem, a change in medications may be appropriate as drugs are the commonest cause of dry mouth. Saliva substitutes and sialagogues, such as pilocarpine or sugar-free chewing gum, are useful to increase saliva flow, optimise pH and clean the mouth.

Key Points ll

ll

ll

Aphthous (idiopathic) ulceration refers to multiple, small, painful, punched-out shallow ulcers affecting the lips, buccal mucosa and tongue. Crohn's disease and coeliac disease may present with apthous ulceration. Burning mouth syndrome is characterised by daily prolonged unexplained pain or burning inside the oral cavity. The first step is to exclude an underlying treatable cause. A tricyclic antidepressant may reduce the burning.

36 ll

ll

ll

ll

ll

Clinical gastroenterology: a practical problem-based approach Most cases of halitosis arise from oral conditions. Halitosis is rarely caused by gastrointestinal disorders. Stagnation of food in a pharyngeal pouch or a dilated oesophagus in achalasia may rarely cause the symptom. Halitosis is initially managed by good oral care – regular brushing and flossing of teeth, brushing the tongue, dental review and plaque removal, and treatment for xerostomia. The causes of intractable hiccups include central irritation of medullary centres, irritating lesions along the neuronal pathway, metabolic or endocrine disease, or occur for unknown reasons (idiopathic). If hiccups are intractable, try to find a primary reversible cause. The GABAB receptor agonist, baclofen, may be helpful.

Further reading Hiccups

Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol 2009; 7:122–127. Ramirez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, cross-over study. Am J Gastroenterol 1992; 87:1789–1791.

Walker P, Watanabe S, Bruera E. Baclofen, a treatment for chronic hiccup. J Pain Symptom Manage 1998; 16:125–132.

Sore mouth

Torgerson RR. Burning mouth syndrome. Dermatol Ther 2010; 23:291–298. Zakrzewska JM, Forssell H, Glenny AM. Interventions for the treatment of burning mouth syndrome. Cochrane Database Syst Rev 2005; (1):CD 002779.

Bad breath

Armstrong BL, Sensat ML, Stoltenberg JL. Halitosis:  a review of current literature, J Dent Hyg 2010; 84: 65–74. Porter SR, Scully C. Oral malodour (halitosis). BMJ 2006; 333:632–635. Quirynen M, Zhao H, van Steenberghe D. Review of the treatment strategies for oral malodour. Clin Oral Invest 2002; 6:1–10. Roldan S, Herrera D, Saaz M. Biofilms and the tongue: therapeutical approaches for control of halitiosis. Clin Oral Invest 2003; 7:189–97. VanderBroek AM, Feerstra L, deBaat C. A review of the current literature on management of halitosis. Oral Dis. 2008; 14:30–39.

4 Acute abdominal pain

Case A 72-year-old previously well woman presents with a 12-hour history of severe epigastric pain radiating to her back. There has been associated nausea and vomiting, but no fevers, jaundice or rigors. Until the onset of pain her bowel habit was unchanged and there were no complaints of abdominal distension. She has had no significant previous illness or surgery. She does not drink alcohol and does not smoke cigarettes. There was a strong family history of gallstones with her mother and two sisters having had surgery for gallstones. Examination revealed a woman that was in some distress with pain, was afebrile with a pulse of 92 beats/minute and was normotensive. She was not pale or jaundiced. There was tenderness across the upper abdomen with mild distension. Bowel sounds were normal and the remainder of the clinical examination was normal. A clinical diagnosis of acute cholecystitis or acute pancreatitis was made. A plain abdominal x-ray and a plain chest x-ray were normal. Routine bloods including amylase and lipase were performed. Results, with normal range in brackets, are shown in the table below. Sodium Potassium Creatinine Urea Haemoglobin White cell count Platelets

134 (130–144) 3.9 (3.6–4.5) 110 (75–110) 12 (6.5–10) 122 (120–135)

Bilirubin AST ALT GGT ALP

34 (5–20) 320 (12–35) 309 (12–35) 102 (15–50) 145 (70–120)

14 500 (5000–11 000) 340 (150–400)

Amylase

4500 (< 120)

Lipase

12 910 (< 150)

These results confirmed a diagnosis of acute pancreatitis with a probable biliary origin. An abdominal ultrasound revealed multiple small

stones in the gallbladder, with a common bile duct diameter of 7 mm (normal < 6 mm). This confirmed the aetiology as gallstones. She was treated by fasting, adequate parenteral analgesia, intravenous fluid resuscitation and deep venous thrombosis prophylaxis. There was no indication for antibiotics or nasogastric decompression of the stomach. Over the next 48 hours she improved clinically with much less pain and stable observations. Repeated assessment of the factors for severity of pancreatitis revealed only one positive factor; her age, which is over 55 years. By the fourth day the pain had completely resolved and she was commenced on a fluid diet. A laparoscopic cholecystectomy was performed the following day with the routine operative cholangiogram revealing two filling defects (5 mm) in a slightly dilated (8 mm) common bile duct. A transcystic stent was inserted to lie across the biliary ampulla and the cholecystectomy was completed. The stent facilitated an endoscopic retrograde cholangiopancreatography and sphincterotomy, which was performed the following day with the removal of the common bile duct stones. She was discharged the following day well.

Introduction Acute abdominal pain is a common ailment experienced by most from time to time. Some episodes of acute abdominal pain resolve spontaneously with analgesia and a period of observation. Acute abdominal pain is a source of anxiety as patients know that it may be the first sign of a serious clinical problem, which may be lifethreatening, and that surgery may be the only solution. Acute abdominal pain is defined as recent onset pain of such severity that medical attention is usually sought shortly after its onset. For the purpose of definition, pain persisting for up to

37

38

Clinical gastroenterology: a practical problem-based approach

3 months is classified as acute; pain lasting more than 3 months is classified as chronic and is considered in Chapters 5 and 6.

Mechanisms Of Abdominal Pain Visceral pain The abdominal organs are not sensitive to touch. Gentle direct palpation during a laparotomy or a herniorrhaphy performed after infiltration of the anterior abdominal wall with local anaesthesia causes no distress. However, distending or stretching the bowel at these operations causes vague abdominal discomfort, which is mediated by splanchnic sympathetic nerves. This visceral pain is poorly localised, usually to the midline. Distension or stretching of the capsule of the liver, as occurs in acute hepatitis, also causes pain.

Peritoneal pain The parietal peritoneum, but not the visceral peritoneum, is innervated by pain fibres, which pass to the spinal cord along the segmental nerves. Thus, inflammation of the parietal peritoneum causes abdominal pain that is localised to the inflamed area. Abdominal guarding occurs due to a reflex contraction of abdominal wall muscles in response to a noxious stimulus to the pain fibres of the same dermatome.

Referred pain Referred pain is pain experienced at a distance from the area of damage. The best known example is pain felt at the tip of the shoulder, when the parietal peritoneum on the inferior surface of the diaphragm is irritated by, for example, blood or gastric juice. This area of peritoneum is innervated by somatic nerves (C4) as is the skin over the tip of the shoulder.

Pathological Causes There are certain similarities in the pattern and type of pain that occur when a given pathological process affects different organs within the abdominal cavity. An understanding of these various patterns is important, as it provides a basis for interpreting the clinical effects and consequences of many of the conditions that result in acute abdominal pain. Important pathological causes of abdominal pain are acute inflammation, obstruction, ischaemia and increased pressure within a solid organ. Not uncommonly, an organ is affected by more than one pathological process during the evolution of an illness. An example is acute appendicitis, where the initial process is obstructive and the subsequent one is inflammatory.

Acute inflammation The common processes leading to intraabdominal inflammation are bacterial invasion, chemical irritation and ischaemia. The features of pain caused by inflammation depend on whether the organ it affects is intraperitoneal or extraperitoneal. Inflammation of intraperitoneal organs Acute inflammation of an intraperitoneal organ results in localised peritonitis if the process involves its peritoneal surface. Ensuing pain results from irritation of pain receptors in the parietal (but not visceral) peritoneum. This pain is described as peritoneal in type. Peritoneal pain is well localised; the patient can usually indicate its position with the palm of a hand or with the tip of a finger. The pain is typically aggravated by sudden movement, such as coughing, and minimised by avoidance of movement, such as lying still or using the diaphragmatic rather than the abdominal muscles for respiration. As an example, involvement of a segment of bowel with Crohn's disease, a transmural inflammatory process, can result in peritoneal pain. Inflammation restricted to bowel mucosa, as typically occurs in ulcerative colitis, does not result in peritoneal pain (Ch 12). A more common example of acute inflammation as the sole process resulting in peritoneal pain is acute salpingitis (inflammation of the fallopian tube). The pain is caused by acute inflammation secondary to a bacterial infection such as gonorrhoea or Chlamydia and usually develops over a period of hours. Intraperitoneal inflammation may result from an obstructive process. A well-known example is acute appendicitis. The early pain of acute appendicitis is periumbilical and due to obstruction of the appendix (visceral pain). As the inflammation becomes transmural, the pain becomes peritoneal in type and moves to the right iliac fossa over the inflamed organ. Intraperitoneal inflammation may be a consequence of perforation of a hollow viscus. Leakage of visceral contents causes pain by chemical irritation. The degree of irritation is dependent on the nature of the leaking material. Thus, leaking gastric juice from a perforated peptic ulcer causes marked irritation. By contrast, gas, which may be the main constituent of the material leaking from a perforated sigmoid diverticulum, causes less irritation and less pain. As the inflammation in response to chemical irritation is rapid, the onset of the pain is rapid or instantaneous. Whether the pain is localised or generalised depends on the degree of soilage.

4 Acute abdominal pain Maximum irritation is usually around the site of leakage (e.g. epigastric for a perforated peptic ulcer and in the left iliac fossa for a perforated sigmoid diverticulum). Other causes of perforation include ischaemia that has progressed to infarction (e.g. gangrenous cholecystitis) and malignancy (e.g. perforated gastric cancer). With ischaemic bowel, the peritoneal component of the pain is usually a relatively minor component of pain. The major component, which is severe, is visceral in type (see below). Peritoneal inflammation occurs only if the ischaemia of the bowel is transmural. The most sensitive component of the bowel wall to ischaemia is the mucosa. On the other hand, the pain resulting from a splenic infarct is predominantly peritoneal in type. Inflammation of non-intraperitoneal organs Acute pancreatitis results in chemical inflammation of retroperitoneal tissues and irritation of visceral nerves. The pain is constant, severe, and not aggravated by movement. If the inflammatory process of acute pancreatitis spreads anteriorly, the patient also complains of a peritoneal pain.

Obstruction If the bowel is obstructed, the pain is colicky unless there is some further complication such as gangrene, secondary infection or perforation, when the pain becomes continuous. The colicky pain is severe in degree and midline in position; it is usually epigastric if the organ originated from the foregut (down to the second part of the duodenum), periumbilical if the organ originated from the midgut (down to the splenic flexure of the colon), and hypogastric if the organ originated from the hindgut (left colon and rectum). The pain of biliary obstruction (gallbladder and extrahepatic biliary tree), described as biliary colic, is constant rather than colicky in nature. The onset of the pain of obstruction is related to the speed of obstruction. If the occlusion is sudden (e.g. gallbladder outlet obstruction due to a stone or a volvulus of the sigmoid colon), the onset of pain is over minutes. If the occlusion is slowly progressive (e.g. obstructing cancer of the sigmoid colon), the onset of the pain is much slower. If the occlusion is intermittent (e.g. gallbladder outlet obstruction due to a stone), the pain is intermittent. Obstruction of the gastrointestinal tract may be due to an intraluminal lesion (e.g. bezoar or calculus), a mural lesion (e.g. a benign or malignant tumour or a fibrous stricture), or an extraluminal lesion (e.g. a fibrous band or the neck of a hernia). The obstruction can occur anywhere

39

along the lumen of the gastrointestinal tract. The obstruction results in proximal distension and stasis. If the obstructed bowel is open-ended proximally, the distension progresses proximally. If the organ lumen has a ‘blind end’, the luminal contents and the organ itself can become infected (e.g. cholecystitis, cholangitis and appendicitis). Progressive distension can lead to venous obstruction followed by arterial obstruction, and then gangrene and perforation (e.g. closed loop obstruction of bowel).

Ischaemia Inadequate blood flow results in tissue death (infarction). Arterial ischaemia is caused by an arterial embolus, a thrombosis or a low cardiac output state. The pain is of sudden onset, over a few minutes, severe and continuous (visceral pain). The process of venous ischaemia is slower in onset. Consequently, the pain is slower in onset. Otherwise, it has the same characteristics as the pain of arterial ischaemia. When the venous occlusion is complete, as occurs to a loop of bowel strangulated by the neck of a hernia, the tissue drained by the occluded vein becomes oedematous and engorged with blood, and arterial obstruction and thrombosis may follow (Fig 4.1). With larger vein occlusion by a thrombus (e.g. the portal or the superior mesenteric vein, or occasionally with a volvulus of bowel), the occlusion may be incomplete and alternative venous drainage may save the tissue from necrosis. Acute major mesenteric venous obstruction causes transudation of fluid into the peritoneal cavity, which may be evident as ascites.

Tension in a solid organ Sudden swelling in solid organs results in a pain of visceral type due to stretching of the capsule of the organ. The pain is dull and constant. The severity of

Figure 4.1  Gangrenous small bowel due to a strangulated femoral hernia.

40

Clinical gastroenterology: a practical problem-based approach

Table 4.1  Sites and types of abdominal pain related to different organs

Table 4.2  Causes of abdominal pain seen at a hospital emergency unit

Position of pain

Nature or type of pain

Cause

Generalised Localised, e.g.: ll epigastric; ll right upper quadrant; ll central (periumbilical); ll right iliac fossa; ll left iliac fossa; ll lower abdominal (hypogastric).

Constant Peritoneal Colicky

Non-specific abdominal pain

34

Acute appendicitis

28

Acute cholecystitis

10

the pain depends on the speed and degree of swelling. Examples include haemorrhage into an ovarian cyst, necrosis of a hepatic metastasis and hepatic venous engorgement due to acute right heart failure.

Clinical Evaluation From the practical point of view, the clinician should have four goals when managing a patient with acute abdominal pain: 1. relief of symptoms; 2. prompt diagnosis and treatment of lifethreatening conditions; 3. early diagnosis and treatment of conditions having complications that can be averted by prompt treatment; and 4. early diagnosis of conditions for which there is specific rather than symptomatic treatment only. A simple practical approach to diagnosis of acute abdominal pain involves stratification as shown in Table 4.1. Clinical evaluation is performed with the knowledge that many of the patients who present with acute abdominal pain have a short-term, self-limiting illness for which nothing more than symptomatic and supportive treatment is required. Selection bias results in this proportion being small in patients admitted to hospital, larger in patients presenting to emergency units and largest in general practice. A list of causes of non-traumarelated abdominal pain seen in an English hospital is shown in Table 4.2. Clinical features are discussed under specific categories later in this chapter. It is important to consider that abdominal signs may be diminished or absent in patients with particular comorbidities. These would include patients with diabetes or who are immunosuppressed. Immunosuppressed patients include those on long-term steroids or other immunosuppressive medication, patients

Percentage

Small bowel obstruction

4

Acute gynaecological disease

4

Acute pancreatitis

3

Renal colic

3

Perforated peptic ulcer

2

Cancer

2

Diverticular disease

1

Miscellaneous

9

From de Dombal FT. Diagnosis of acute abdominal pain. 2nd edn. Edinburgh: Churchill Livingstone; 1991, with permission.

on chemotherapy or those with some specific haematological disorders, including AIDS. Radiological investigations are frequently used to augment clinical assessment and, increasingly, Computed tomography (CT) scanning is the investigation of choice for the investigation of acute abdominal pain. Provided the patient has normal renal function, the abdominal CT scan to assess acute abdominal pain should have intravenous (IV) contrast and be done in the precontrast, arterial and venous phases to provide the most information. Oral contrast should also be administered in order to outline the gastrointestinal tract, unless there is a specific contraindication, such as severe vomiting.

Generalised Abdominal Pain The common causes of generalised acute abdominal pain are listed in Table 4.3. The first issue to address is whether or not the patient has an abdominal catastrophe. On most occasions, differentiation of a patient with an abdominal catastrophe from one with non-specific abdominal pain is relatively straightforward. As indicated in Table 4.3, the patient with an abdominal catastrophe usually has generalised peritonitis, with generalised tenderness, guarding, rebound tenderness and absence of bowel sounds. However, there may be few signs initially to accompany a mesenteric embolus or thrombosis while the bowel is still viable. Further, the abdominal signs associated with acute pancreatitis may be mild.

4 Acute abdominal pain

Table 4.3  Causes and clinical features of conditions producing generalised acute abdominal pain Cause

Abdominal signs

Associated signs

Non-specific abdominal pain

Nil or mild

Nil

Perforated appendix

Generalised peritonitis, more tender in the right iliac fossa

± shock

Perforated diverticulum

Generalised peritonitis, possibly more tender in the left iliac fossa

± shock

Ruptured ectopic pregnancy

Generalised peritonitis

± shock

Ruptured pathological solid organ

± mass/organomegaly

± shock

Ruptured aortic aneurysm

Tender pulsatile mass

Shock

Strangulated bowel

Focal or generalised peritonitis

Bowel obstruction ± sepsis ± shock

Superior mesenteric thrombosis or embolus

Initially few or no signs (pain out of proportion to signs)

Atrial fibrillation or myocardial infarction ± shock

Ischaemic colitis

Often not severe unless there is transmural infarction

Bloody diarrhoea, atrial fibrillation or myocardial infarction

Pancreatitis

May be few signs (pain can be out of proportion to signs)

± shock

There are commonly signs of shock if there has been blood loss or dehydration. These include tachycardia, hypotension, oliguria and peripheral vasoconstriction (cool blue peripheral tissues and a thready pulse). Pallor may be indicative of blood loss. Dehydration is suggested by a dry tongue, reduced skin turgor, decreased eye turgor and postural hypotension. The signs of gramnegative shock are slightly different. Rather than the signs of peripheral vasoconstriction there may be peripheral vasodilatation, evidenced by a

41

bounding pulse and a warm periphery as well as clamminess. The previous history and associated signs that may be of help in distinguishing the various catastrophes are listed in Table 4.4. The management of an abdominal catastrophe includes urgent admission to hospital, cardiopulmonary resuscitation, some simple investigations depending on the gravity of the situation and early operative intervention on most occasions. Conditions for which early operative intervention might not be undertaken include ischaemic colitis and acute pancreatitis. The investigations that are usually performed are listed in Table 4.5. They include tests aimed at establishing the diagnosis and tests to assist resuscitation. Air under the diaphragm suggests a perforated viscus. It is most commonly present with a perforated peptic ulcer (80% of cases), less commonly present with a perforated diverticulum (20%) and rarely present with a perforated appendix. An amylase and lipase estimation is essential in all patients with generalised abdominal pain to avoid an inadvertent laparotomy for acute pancreatitis.

Specific management of conditions causing generalised abdominal pain Perforated peptic ulcer This is diagnosed by a sudden history of generalised severe abdominal pain of peritoneal type. The onset is usually instantaneous, with the patient able to recall exactly what he or she was doing at the time of onset of pain. On examination there is generalised tenderness and guarding, usually maximal in the epigastrium, board-like rigidity, loss of bowel sounds and loss of liver dullness to percussion. The diagnosis is supported by demonstration of gas under the diaphragm on an erect chest x-ray examination (Fig 4.2). A CT scan is more sensitive at detecting extraluminal (free) gas. If still uncertain, the diagnosis can be made with a limited gastrograffin meal or a laparoscopy. Initial treatment includes fluid resuscitation, nasogastric suction and broad-spectrum antibiotics. Thereafter, the perforation can be closed either laparoscopically or at open laparotomy. The peritoneal cavity is lavaged at the same time. Closure of the perforation is required to prevent continuing contamination of the peritoneal cavity. Laparoscopic closure of the perforation and lavage of the peritoneal cavity to prevent subsequent intraabdominal abscess formation is the therapy most commonly advocated.

42

Clinical gastroenterology: a practical problem-based approach

Table 4.4 Clinical clues to establish the cause of the abdominal catastrophe Abdominal catastrophe

Previous history

Possible differentiating signs

Perforated peptic ulcer

Dyspepsia or proven peptic ulcer

Lack of liver dullness to percussion Signs maximal in the epigastrium

Perforated appendix

Initial history consistent with appendicitis

Signs maximal in the right iliac fossa

Perforated diverticulum

Preceding history of diverticular disease

Lack of liver dullness to percussion Signs maximal in the left iliac fossa

Ruptured aneurysm

Recent backache Other history of vascular disease

Tender pulsatile midabdominal mass Vascular disease elsewhere

Ruptured ectopic pregnancy

Missed period

Signs maximal in the lower abdomen Tender pelvic mass on per vagina examination

Ruptured pathological organ

Organ specific

Organ specific

Strangulated bowel

Hernia Previous abdominal surgery

Tender hernia Abdominal scars

Mesenteric thrombosis or Atrial fibrillation embolus Myocardial infarction Other vascular disease

Vascular disease elsewhere

Ischaemic colitis

Other vascular disease Recent period of low cardiac output Irritable bowel syndrome symptoms

Bloody diarrhoea Signs maximal on the left side

Acute pancreatitis

Alcoholic binges Gallstones

Periumbilical or renal angle blood staining of subcutaneous fat

An alternative non-operative approach is possible for selected cases. It is based on the knowledge that in up to three-quarters of cases the perforation closes spontaneously. Some surgeons give selected patients with perforated duodenal ulcer a trial of non-operative treatment. This involves close clinical observation to detect failure of the peritonitis to resolve, continued fluid resuscitation and broad-spectrum antibiotics. A limited gastrograffin meal is required to identify the site of the leaking ulcer and that the ulcer is no longer leaking into the peritoneal cavity. If there is a leak of contrast or the diagnosis is a gastric ulcer, operative intervention is required. There is no need to perform a definitive antiulcer operation, as the ulcer diathesis can be cured after recovery from the perforation with medication (see Ch 5). Perforated appendicitis The diagnosis might be suspected by a history suggestive of appendicitis (see right iliac fossa pain described later in this chapter). The patient usually has symptoms for more than 48 hours, with progression of localised to generalised abdominal pain. The patient is toxic with signs of fever, and

has tachycardia. The abdominal signs are usually maximal in the right iliac fossa. Air should not be expected under the diaphragm. Appendicectomy and peritoneal lavage after fluid resuscitation and antibiotics is required. Perforated sigmoid diverticulum This may be diagnosed by CT scanning. Preceding pain in the left iliac fossa is supportive. The abdominal signs may be maximal in the left iliac fossa. There is often a large amount of gas under the diaphragm. The speed of onset may be slower than with a perforated peptic ulcer. After fluid resuscitation and antibiotics resection of the affected segment of bowel is required. In the usual case of a perforated sigmoid diverticulum, a proximal end colostomy is performed and the distal stump oversewn (Hartmann's procedure) as the bowel has not previously been cleansed of faeces. Ruptured abdominal aortic aneurysm The clinical picture is quite different to the conditions above. The patient is usually elderly with risk factors for vascular disease. The pain is central, constant, non-peritoneal in type and

4 Acute abdominal pain

43

Table 4.5  Investigations for patients with acute generalised abdominal pain Investigation

Possible findings

Routine Erect chest x-ray

Gas under the diaphragm Atelectasis

Erect and supine abdominal x-ray

Distended small or large bowel Thickened bowel Gas in bowel wall Calcified aneurysm

Haemoglobin

Anaemia Haemoconcentration

White cell count with differential

Leucocytosis with left shift

Electrolytes

Unexpected hypokalaemia

Urea and creatinine

Unexpected renal failure

Serum amylase Serum lipase

Hyperamylasaemia and hyperlipasaemia are suggestive of pancreatitis; marginal elevation seen in small bowel obstruction, acute cholecystitis and mesenteric infarction

Under appropriate clinical circumstances Limited gastrograffin meal

Confirmation of duodenal perforation if conservative treatment is contemplated

Beta human chorionic gonadotropin

Elevated in ectopic pregnancy

Abdominal ultrasound

Confirmation of ruptured aneurysm only if diagnosis in doubt and condition is stable; demonstration of intraabdominal fluid

CT scan

Limited gastrograffin enema

Confirmation of ruptured aneurysm only if diagnosis in doubt and condition is stable; confirmation of pancreatitis if doubt exists; confirmation of perforated bowel to plan intervention ‘Thumb printing’ due to mucosal oedema

Figure 4.2  Gas under the diaphragm from a perforated duodenal ulcer, shown on an erect chest x-ray.

often radiates through to the back. Cardiovascular collapse is a prominent feature. A tender, pulsatile epigastric mass is diagnostic. Signs of peritonism are not prominent. If the diagnosis is not made on clinical grounds and the patient is haemodynamically stable, the diagnosis may be made by CT scan, which shows retroperitoneal extravasation of blood as well as the aneurysm (Fig 4.3). Vascular grafting or stenting of the affected segment is urgently required. Ruptured ectopic pregnancy The diagnosis is suspected in a woman of childbearing age who has missed a period. The abdominal symptoms and signs are usually maximal in the lower abdomen. Shock may be a prominent feature. The diagnosis is supported by elevation of beta human chorionic gonadotropin levels and pelvic ultrasound. Local resection is required. Strangulated bowel The diagnosis may not be suspected prior to laparotomy, which is performed because of severe pain unrelieved by narcotics in a patient

44

Clinical gastroenterology: a practical problem-based approach

Figure 4.3  CT scan demonstrating a ruptured aortic aneurism with extravasation of blood and contrast.

with signs of peritonitis. The site of maximal symptoms and signs is dependent on the position of the strangulated loop of bowel. There may be associated symptoms and signs of small bowel obstruction. On plain radiology of the abdomen, the strangulated loop may be seen as thickwalled due to oedema. In addition, there may be radiological features of small bowel obstruction (see Fig 4.4). CT scanning prior to surgery may assist with the diagnosis, and even define the cause of the strangulation. Local resection is required if the loop of bowel remains non-viable after it is released intraoperatively (Fig 4.1). Bowel that is pink in colour and exhibits spontaneous peristalsis or peristalsis when stimulated is viable. Further, there should be pulsatile flow of bright red blood through feeding vessels. A ruptured pathological organ Presentation and treatment is dependent on the underlying pathology. A delayed splenic rupture due to recent trauma, for example, will usually require splenectomy. A splenectomy is required for a spontaneous rupture of an abnormal spleen. A ruptured ovarian cyst may require ovarian cystectomy or oophorectomy. A ruptured liver cell adenoma requires a liver resection. Often the underlying problem will become apparent only at laparotomy.

Figure 4.4  Plain abdominal x-ray examination of small bowel obstruction showing distended loops of small bowel with multiple air fluid levels and the absence of colonic gas.

Small bowel ischaemia This is caused by a superior mesenteric artery thrombosis or embolism. It initially presents with severe constant abdominal pain of non-peritoneal type in an elderly patient with risk factors for vascular disease or a patient with risk factors for arterial embolism (e.g. atrial fibrillation or recent myocardial infarction). Early on, when the bowel is still viable, there are minimal abdominal signs. Clinical suspicion in an elderly patient with associated atrial fibrillation, vascular disease elsewhere or a low cardiac output state is the key to early treatment. The diagnosis must be considered in an elderly patient if the pain is out of proportion to the signs as the abdominal signs are not marked and there are no specific diagnostic signs on plain abdominal radiology. A triple phase CT scan may be diagnostic and saves valuable time in the lead-up to surgery. Revascularisation of the bowel may be achieved with percutaneous therapeutic procedures that involve clot dissolution and possible stenting of the superior mesenteric artery. This would then

4 Acute abdominal pain be followed by an urgent laparotomy to assess the viability of the bowel. At laparotomy, if the bowel is viable and does not require resection, a second laparotomy is performed 24 hours later. If, at the laparotomy, there are segments of the bowel that are not viable these are resected and may be anastamosed. Once again, a relook laparotomy is performed at 24 hours to assess the ongoing viability of the residual bowel. The extent of bowel ischaemia depends on whether the main trunk of the superior mesenteric artery or a branch is occluded. When the main trunk is occluded, a variable length of proximal jejunum supplied by collaterals from the coeliac artery and a variable amount of the right hemicolon supplied by collaterals from the inferior mesenteric artery remain viable. There are two initial therapeutic options for extensive small bowel infarction: 1. resection with re-anastomosis of the viable ends. Thereafter the patient receives anticoagulation treatment to prevent extension of the thrombotic process. A ‘second-look’ laparotomy is usually performed after 24 hours to assess the viability of the remaining bowel. 2. diagnostic laparotomy only. There are some ­elderly and frail patients who have no realistic chance of returning to an enjoyable lifestyle ­after extensive small bowel resection. For these, a decision against massive resection may be made. After initial surgical recovery, there is gut adaptation and hypertrophy sufficient to allow maintenance of nutrition by oral means if the residual small bowel length is greater than 45 cm. Patients with shorter residual lengths usually require long-term parenteral nutrition (Ch 17). Superior mesenteric venous thrombosis usually results in a more subacute presentation. There can be associated ascites. The demonstration of a venous filling defect on the CT scan confirms the diagnosis (Fig 4.5). Management is determined by whether the affected bowel is viable or not. If the diagnosis can be made by CT scan and there are no signs of peritonism, the patient can be managed by anticoagulation and observation. Prior to commencement of anticoagulation therapy a predisposing cause is sought. Predisposing causes include the oral contraceptive pill, factor V Leidin mutation, antiphospholipid syndrome, antithrombin III deficiency, and protein S and protein C deficiency. Ischaemic colitis This condition is associated with severe central and lower abdominal pain, in association with risk factors for vascular disease and is often

45

associated with bloody diarrhoea. There may be localised signs in the left iliac fossa or generalised signs of diffuse tenderness. The clinical diagnosis is supported by the finding of gross oedema and ‘thumb printing’ in the left colon on plain abdominal x-ray examination (see Fig 4.6) or CT scan. If there is uncertainty, colonoscopy can

Figure 4.5  CT scan demonstrating a clot in the superior mesenteric vein (SMV) In this case there was no infarction of the small bowel and the patient was managed non-operatively with anticoagulation.

Figure 4.6  Plain abdominal x-ray showing gangrenous large bowel and thumb printing due to ischaemic colitis.

46

Clinical gastroenterology: a practical problem-based approach

be helpful. Ischaemic colitis often settles with non-operative treatment. If during close observation, however, the abdominal signs become more marked or the patient develops systemic signs of sepsis, laparotomy is required to exclude an occult perforation and resect the ischaemic segment as a Hartmann's procedure. Reanastomosis is then delayed until after full recovery. Anticoagulation treatment is contraindicated early because of the risk of massive colonic haemorrhage. Pancreatitis This is discussed below under ‘Acute epigastric pain’.

Acute Abdominal Colic Colicky pain is felt in the midline. It is associated with forceful smooth muscle contraction. It has a characteristic repetitive pattern. There is intense pain for a few minutes, followed by complete relief of pain for a few minutes. It is associated with gastric, small and large intestinal and uterine disorders. Gastric (foregut) colic is experienced in the epigastrium; small bowel and right hemicolon (midgut) colic periumbilically; and left hemicolon (hindgut) and uterine colic suprapubically. Socalled ‘biliary colic’ is a continuous rather than intermittent pain experienced in the epigastrium or the right upper quadrant. The causes of acute abdominal colic are listed in Box 4.1. The common causes are acute gastroenteritis, food poisoning, constipation and uterine disorders. The life-threatening causes are small and large bowel obstruction. The initial clinical question is: does this patient have an innocent or a serious cause of abdominal colic? Acute gastroenteritis is usually of viral origin, is associated with diarrhoea and is infectious so that it is likely to have affected others in the household. Food poisoning can usually be related to ingestion of a particular meal. The specific management of the problems that cause abdominal colic with diarrhoea is covered in Chapter 13. Simple analgesics are part of the management. Constipation of recent origin can often be related to ingestion of drugs (e.g. codeine-containing analgesics) or a change in dietary pattern (Ch 11). It is managed with simple analgesics, elimination of an identifiable cause and use of a bulking agent. Uterine causes are associated with vaginal bleeding and menstrual irregularities. Their management is beyond the scope of this book. Some patients with a non-specific cause may be difficult to distinguish from patients with early

bowel obstruction. When there is doubt after the initial clinical evaluation, the patient should have simple investigations, such as plain abdominal radiology, looking for a bowel obstruction. Continued clinical uncertainty may be managed best by close observation in hospital.

Bowel obstruction The four cardinal symptoms of uncomplicated complete bowel obstruction are colicky abdominal pain, vomiting, abdominal distension and absolute constipation, which includes failure to pass flatus (obstipation) as well as faeces. If the obstruction is incomplete, one of the cardinal symptoms, constipation, may be replaced by diarrhoea. The differential diagnosis of incomplete bowel obstruction is acute gastroenteritis. The degree of abdominal distension is high with colonic obstruction and low with high small bowel obstruction. In contradistinction, the severity of vomiting is less and occurs late with colonic obstruction, and is greater and occurs earlier with proximal small bowel obstruction. The vomitus, although initially bile-stained, becomes feculent as the obstruction progresses. If the obstruction continues untreated, a paralytic ileus may supervene and then the hypermotility of the bowel proximal to the obstruction (and the colicky pain) will subside. Alternatively, the unrelieved obstruction may become complicated by strangulation or perforation. These complications are also associated with paralytic ileus. However, rather than the pain settling, it becomes constant and peritoneal in type. The most common cause of small bowel obstruction is adhesions from a previous laparotomy. The next commonest cause is hernia, usually inguinal or femoral hernia (Ch 21). As well as eliciting the symptoms of obstruction, it might be possible to elicit the cause from the history (see Box 4.1). Physical examination is directed to the demonstration of: ll signs of obstruction (abdominal distension, hyperresonant abdomen, increased bowel sounds); ll cause of the obstruction (e.g. a previous laparotomy scar raising the possibility of adhesions; an irreducible hernia; an intraabdominal mass caused by a tumour, intussusception, Crohn's disease, or an appendiceal or diverticular inflammatory phlegmon; or blood mixed with mucus on rectal examination from an intussusception); ll degree of dehydration, so that fluid resuscitation can commence promptly; and ll signs that the obstruction has become complicated (localised peritonism, tenderness

4 Acute abdominal pain Box 4.1  Causes of acute abdominal colic



Acute gastroenteritis Food poisoning Non-specific causes Constipation Gastric outlet obstruction: – chronic peptic ulceration; – gastric cancer; – pancreatic cancer; – duodenal cancer. Small bowel obstruction: Adhesions: – postsurgical; – inflammatory (e.g. diverticular); – radiation; – Meckel's diverticulum—metastatic.



Hernia: – abdominal wall; – internal.

ll ll ll ll ll

ll





Neoplasm: – benign (e.g. leiomyoma); – malignant (e.g. carcinoid tumour, adenocarcinoma). Stricture: – ischaemic; – radiation; – inflammatory (e.g. Crohn's disease). Volvulus



Intussusception: – tumour (e.g. Peutz-Jegher's syndrome, gastrointestinal stromal tumour). Superior mesenteric artery syndrome

ll

ll



Intraluminal bolus: – gallstone; – bezoar. Large bowel obstruction: – colon cancer; – diverticular disease; – volvulus. Uterine: – missed abortion; – parturition; – period pain.

47

in an irreducible hernia), or signs of systemic sepsis (fever and tachycardia). Specific investigations include the following: ll Plain abdominal radiology reveals distended loops of small bowel with fluid levels and absence of colonic gas (see Fig 4.4). Occasionally the cause will be evident, as in Figure 4.7. ll Leucocytosis, particularly if there is a left shift, may indicate ischaemic bowel. ll An abdominal CT scan will show a small bowel obstruction earlier than plain radiology. It will often show the point of obstruction with a transition from dilated bowel to collapsed bowel. The cause may also be evident. Treatment is as follows. After initial fluid resuscitation and gastric decompression with a nasogastric tube, an urgent laparotomy may be required. Factors in favour of early laparotomy include: ll evidence of strangulated bowel (constant pain, focal tenderness, unexplained tachycardia [over 100 beats/min], fever [over 37.8°C], and leucocytosis [over 16,000]); and ll no history of previous surgery that may have caused adhesions. If a trial of non-operative treatment is selected, frequent re-evaluation is imperative lest clinical deterioration be overlooked. If there is no evidence of resolution after 48 hours laparotomy is required, as it is unlikely that spontaneous resolution will occur beyond this time. The duration of the nonoperative trial may be extended if the cause is thought to be radiation enteritis, Crohn's disease, involvement of small bowel in a diverticular mass or known peritoneal metastatic disease. There are three common causes of large bowel obstruction: colon cancer (75% of cases), diverticular disease (15%), and sigmoid and caecal volvulus (5%). When managing a patient with an apparent large bowel obstruction on clinical and simple radiological grounds, it is important to be sure that the diagnosis is not simple constipation or acute pseudo-obstruction of the colon, as these conditions are treated non-operatively. Constipation is associated with a loaded rectum, whereas the rectum should be empty with obstruction. If constipation is the likely diagnosis, bowel washouts from below with enemata should resolve the dilemma. If doubt persists, a limited gastrograffin enema will be conclusive. Acute colonic pseudo-obstruction (also called Ogilvie's syndrome) occurs most often in patients in hospital secondary to conditions such as sepsis,

48

Clinical gastroenterology: a practical problem-based approach

Figure 4.8  Plain abdominal x-ray demonstrating a large bowel obstruction with grossly distended caecum. There is an acute cut-off in the region of the junction of the descending colon and sigmoid (arrow).

Figure 4.7  Radio-opaque stones in the gall bladder (a) and the common bile duct (b).

acute pancreatitis, electrolyte imbalance, renal failure, spinal cord injury, hip fractures, hip replacement surgery or postoperatively. If acute pseudo-obstruction is the clinical diagnosis, a gastrograffin enema will confirm the diagnosis and exclude a mechanical obstruction. A gastrograffin enema may produce a return of bowel activity because of its cathartic action. Colonic pseudo-obstruction may mimic organic obstruction if acute pseudo-obstruction is the clinical diagnosis. Acute colonic pseudoobstruction usually resolves within 48 to 96 hours with non-operative treatment. This includes fluid resuscitation, correction of electrolyte abnormalities, withdrawal of medications (such as narcotics and antidepressants) that might be contributing, stimulation of colonic motility with intravenous neostigmine under cardiac monitoring, and colonoscopic decompression if needed. Continued competence of the ileocaecal sphincter prevents retrograde decompression of obstructed large bowel into the small bowel in more than 50% of patients, effectively producing a closed loop. Colonic distension proximal to the site of obstruction is greatest in the caecum and

ascending colon. Perforation is usually heralded by localised overlying tenderness. The other useful marker of imminent perforation is colonic distension greater than 10 cm as assessed by plain abdominal x-ray examination (Fig 4.8). A sigmoid or caecal volvulus is also a closed loop that may perforate if neglected. Diagnosis and management of large bowel obstruction Colon cancer is discussed in detail in Chapter 22. Presentation with complete obstruction is usually preceded by fluctuating incomplete obstruction for several weeks. The tumour is more commonly in the sigmoid or descending colon. The patient may also have noted rectal bleeding. The level of the obstruction may be evident on plain abdominal radiology (see Fig 4.9). Further management is dependent upon whether the obstruction is left-sided or right-sided. An obstructing cancer in the right hemicolon can be resected with immediate re-anastomosis. An obstructing leftsided colon cancer may be managed initially with an endoscopically placed expanding metal stent (Fig 4.9) to decompress the colon. The patient is then assessed for definitive care (Ch 22). If stenting is not available the bowel can be resected with immediate re-anastomosis if all the proximal colon is resected. If a more limited resection is to be performed in mechanically unprepared bowel, and an anastomosis is performed, either a covering colostomy or ileostomy, or an intraoperative antegrade colonic washout is required. Another approach is to resect the tumour and exteriorise the proximal end as a colostomy (Hartmann's

4 Acute abdominal pain

Figure 4.9  Radiological imaging of an expandable metal stent that was inserted endoscopically across a carcinoma of the sigmoid that presented with acute large bowel obstruction. This stent allowed for emergency decompression of the colon. The patient was able to be worked-up further and proceeded to an elective colonic resection 3 weeks later.

procedure). If the tumour is associated with extensive distant metastases, a colonoscopically delivered expanding metal stent may be the definitive treatment. The patient with diverticular disease has usually had previous episodes of diverticulitis (see below) prior to the onset of obstruction. Whether or not the patient has a sigmoid colon cancer that is the cause of the obstruction, as well as diverticular disease, can be resolved with colonoscopy. Local colonic resection is reserved for those with an obstruction that fails to settle with antibiotic therapy and bowel rest. The typical patient with a sigmoid volvulus is elderly, has chronic constipation and is institutionalised. The patient usually has gross abdominal distension but little vomiting and abdominal pain. The clinical diagnosis is confirmed with a plain abdominal x-ray examination, which has a typical appearance (see Fig 4.10). The single loop based in the left iliac fossa can extend to the right upper quadrant. The volvulus is decompressed using either a rigid or flexible sigmoidoscope by gently passing a soft rectal tube under direct vision through the point of the rotation at the level of the brim of the pelvis. The torted colon usually reduces spontaneously

49

Figure 4.10  Plain abdominal x-ray showing sigmoid volvulus. Note the large ‘coffee-bean’ shape gas-filled structure represents the distended, involved portion of the sigmoid colon with the apex in the left iliac fossa. This is the classic appearance of this abnormality.

Figure 4.11  Plain abdominal x-ray demonstrating a caecal volvulus, which can be seen as a large distended loop of bowel emanating from the right iliac fossa.

over 2–5 days, after which the rectal tube can be removed. As the condition is commonly recurrent, an elective resection of the redundant colon on its long mesentery is advisable unless contraindicated by other medical problems. A caecal volvulus involves the caecum, the ascending colon and the terminal ileum, which rotate on a long mesentery. Typically it affects younger and fitter patients. Radiologically the volvulus extends from the right iliac fossa towards the splenic flexure (Fig 4.11). The volvulus cannot be reduced radiologically, but may be reduced using the flexible colonoscope. Operative

50

Clinical gastroenterology: a practical problem-based approach

reduction and right hemicolectomy can then be performed electively.

Box 4.2  Causes of acute epigastric pain

Gastric outlet obstruction

ll

The dominant symptom is profuse vomiting. Pathognomonic features of the vomitus are the presence of foodstuffs consumed several days previously, lack of bile staining and a small amount of old blood (coffee ground vomitus). Epigastric pain, particularly colicky postprandial pain, may be a feature. When pain is present, it is relieved by vomiting. Weight loss may be marked. The main causes of gastric outlet obstruction are distal gastric malignancy, malignancy of the pancreatic head or proximal duodenum (rare), and oedema or scarring due to chronic peptic ulceration. In the latter case, there will often be a history of long-standing dyspepsia. The clinical diagnosis may be supported by demonstrating a gastric succussion splash. This is done by listening to the abdomen while shaking the patient from side to side. Initial management includes intravenous fluid replacement, correction of any electrolyte and acid–base disturbance and nasogastric decompression. There are several points that are salient during resuscitation: ll Gastric fluid losses that need replacement may be as high as 3 L/day. ll Gastric fluid losses may have resulted in a hypokalaemic, hypochloraemic metabolic alkalosis. These are corrected with normal saline and potassium supplements. ll Total parenteral nutrition may be appropriate if weight loss is greater than 10% (Ch 17). ll Blood transfusion may be required for severe iron deficiency anaemia. After gastric decompression the cause should be defined by upper gastrointestinal endoscopy. If active peptic ulceration is found, the gastric outlet obstruction is potentially reversible. Healing the ulcer with parenteral acid suppression may result in resolution of oedema around the ulcer and restitution of luminal patency. Otherwise, the stomach needs to be drained surgically. If the cause is peptic ulceration, this is done by vagotomy and distal gastric resection or gastroenterostomy depending on the position of the ulcer. If the cause is gastric malignancy, this is done by distal gastric resection if the tumour is potentially curable, or gastroenterostomy or insertion of an expanding metal stent if it is not curable (see Ch 17). When the cause is a pancreatic or duodenal malignancy resection should be considered. When the lesion

ll ll ll ll ll ll ll

ll

No specific cause found Peptic ulceration (uncomplicated)* Peptic ulceration (perforated)* Biliary colic* Choledocholithiasis* Acute pancreatitis* Abdominal aortic aneurysm Non-gastrointestinal causes: acute myocardial infarction Lower lobe pneumonia

*Conditions that cause right upper quadrant pain.

is not resectable resolution of the obstruction may be achieved with an endoscopic expanding metal stent or operative gastroenterostomy.

Acute Epigastric Pain Acute epigastric pain is a common complaint. Often the pain is short-lived and no organic cause is found. A list of causes is shown in Box 4.2. On the basis of an initial clinical evaluation the clinician must decide if: ll the patient requires hospitalisation; and ll further specific investigations, such as upper gastrointestinal endoscopy and/or upper abdominal ultrasound, are needed. The first of those decisions is difficult and requires clinical experience. It will depend on whether it is considered likely that there is a specific cause and the likely natural history. Factors that assist the clinician to decide include: ll the severity, duration of the symptoms and response to the treatment to date; ll associated systemic symptoms and signs; and ll the results of initial non-invasive investigations. There are few features that assist in differentiating specific from non-specific causes. The severity tends to be greater and continuous with organic causes. Radiation of pain to the back is supportive of pancreatitis or biliary stone disease. Migration to the right upper quadrant suggests cholecystitis. Migration around the side to the scapula or through to the back also suggests gallstones. Associated jaundice may indicate a stone in the common bile duct (Ch 23). On many occasions deep epigastric tenderness is the only abdominal sign. If there is focal epigastric peritonism, or more generalised peritonism, a perforated peptic ulcer or acute pancreatitis becomes more likely. The abdominal

4 Acute abdominal pain signs with acute pancreatitis may be unimpressive. Right upper quadrant tenderness or mass suggests a biliary cause for the epigastric pain. Associated signs of hypovolaemia or gramnegative sepsis (discussed above under generalised abdominal pain) suggest a perforated peptic ulcer, acute pancreatitis or cholangitis.

Initial investigations A routine initial screen includes plain radiology of the chest and abdomen, a blood film looking for anaemia and leucocytosis, liver function tests looking for evidence of hepatobiliary disease, and serum amylase and lipase. A marginal elevation of serum amylase (100–400 U/L) is not specific for pancreatitis. While an elevated lipase is more sensitive in acute pancreatitis it is also elevated in many other acute abdominal conditions and therefore is a less specific test for acute pancreatitis. Some uncommon but significant radiological signs are listed in Table 4.6. Basal pulmonary consolidation may rarely present with abdominal pain.

Further investigations The need to proceed with further investigation as either an inpatient or an outpatient depends on the degree of clinical suspicion that an organic cause will be found. For many, symptomatic treatment with antacids or antispasmodics or just simple analgesics is sufficient. The next tier of investigations includes upper gastrointestinal endoscopy and upper abdominal ultrasound. The order in which they are performed depends on the clinical features. The management of abnormalities found on upper gastrointestinal endoscopy is discussed under dyspepsia (see Ch 6). Hepatobiliary abnormalities found on ultrasound examination are discussed in the next

Table 4.6  Specific radiological findings to be looked for in acute epigastric pain Sign

Possible cause

Figure

Gas under the diaphragm

Perforated peptic ulcer

4.2

Radio-opaque gallstones

Biliary disease

4.7

Colonic cut-off sign

Acute pancreatitis

Sentinel loop

Acute pancreatitis

Pancreatic calcification

Chronic pancreatitis

4.12

51

section on right upper quadrant pain and also in Chapter 26.

Acute Pancreatitis And Its Complications Aetiology The causes of acute pancreatitis are listed in Table 4.7. The most common causes are passage of gallstones down the common bile duct and alcohol abuse. Pointers towards gallstones as the cause include female gender, older age and abnormal liver function tests. It is not uncommon for those with alcohol as the cause to deny alcohol abuse, at least initially. If no cause is apparent, check serum triglycerides, calcium levels and IgG4 (immunoglobulin G4) for autoimmune pancreatitis during convalescence, along with a three-phase CT scan to re-evaluate the pancreas.

Diagnosis Detection of elevated serum amylase levels is the usual means of diagnosis. The level rises within 12 hours of the onset of pain and gradually returns to normal over the next week. This test has a number of false positive and false negative results. False positive results include perforation of stomach or small bowel, small bowel obstruction, mesenteric ischaemia, acute cholecystitis or common bile duct obstruction, morphine, chronic Table 4.7 Aetiology of acute pancreatitis Cause

Incidence

Gallstones

50–60%

Alcohol

30–40%

Idiopathic

10%

Post-ERCP

2%

Medications, e.g. azathioprine, 6-mercaptopurine, frusemide. hydrochlorothiazide, tetracycline, sulfonamides, oestrogens, sodium valproate, L-asparaginase

Uncommon

Major abdominal trauma

Variable

Mumps

Rare

Hyperlipidaemia

Rare

Hypercalcaemia

Rare

Hereditary (familial)

Rare

Pancreatic tumours

Rare

ERCP = endoscopic retrograde cholangiopancreatography

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Clinical gastroenterology: a practical problem-based approach

pancreatitis, pancreatic carcinoma, end-stage renal failure and chronic alcoholism. Minor elevations can occur with parotitis, tumours (lung, oesophagus, ovarian and breast carcinoma), acute or chronic liver disease, diabetic ketoacidosis and HIV infection. Macroamylasaemia is rare; there are macromolecular aggregates of amylase or IgA and amylase that are not filtered by the kidneys so that the amylase-creatinine clearance is abnormally low. False negative results may occur in hypercholesterolaemia and recurrent alcoholic pancreatitis. If there is doubt, the diagnosis can be confirmed by CT scan, which shows swelling of the pancreas and peripancreatic oedema. In most centres, serum lipase in addition to amylase is used as the biochemical marker of pancreatitis due to its greater specificity. Its rise and fall after acute pancreatitis occur after the same changes in serum amylase.

Assessment of severity The height of the peak in serum amylase or serum lipase levels provides no useful measure of the severity of an attack of pancreatitis. Severity is scored by a combination of predominantly laboratory measurements (see Table 4.8) during the first 48 hours of hospitalisation, and this provides prognostic guidance. Severe pancreatitis is present if there are three or more poor prognostic factors. The mortality rate in cases of mild pancreatitis (less than three poor prognostic factors) is less than 1%, whereas the mortality with severe pancreatitis is greater than 50%.

Initial management Non-operative management is supportive and directed towards the prevention and treatment of complications. The complications of acute pancreatitis, the timeframe of their development and methods for prevention or treatment are listed in Table 4.9. The important early complications are acute renal failure due to inadequate fluid resuscitation, and respiratory embarrassment due to a combination of inadequate analgesia and physiotherapy, fluid overload and adult respiratory distress syndrome. Some of the causes are at least partly preventable. Patients at risk because of three or more poor prognostic signs, or because of other diseases, must be managed in a high-dependency or intensive care unit where fluid resuscitation can be managed aggressively with appropriate monitoring. Nasogastric suction to prevent tracheal aspiration, a respiratory

Table 4.8  Poor prognostic factors for acute pancreatitis according to the Glasgow scoring system Factor

Critical value

Age

> 55 years

AST/ALT

> 200 IU/L

White cell count

> 15 × 109/L (15,000/mm3)

Serum glucose

> 10 mmol/L

Blood oxygen (PaO2)

< 60 mmHg

Blood pH

< 7.35

Serum urea

> 16 mmol/L

Serum albumin

< 32 g/L

Serum calcium

< 2 mmol/L

Serum lactic dehydrogenase

> 600 U/L

ALT = alanine aminotransferase; AST = aspartate aminotransferase.

complication of paralytic ileus, is required only if the patient is vomiting due to ileus.

Severe pancreatitis The mortality and the morbidity in acute severe gallstone pancreatitis, as defined by the presence of three or more poor prognostic factors (see Table 4.8), can be reduced by urgent endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy. Thus an abdominal ultrasound is performed early in the admission to diagnose gallstones and if the pancreatitis is rated as severe an ERCP is performed urgently.

Pancreatic necrosis The chance of failure of early resolution of pancreatitis, and of development of complications, rises if pancreatic necrosis develops. This complication is usually apparent within 5 days of the onset of the attack if it is going to occur. Pancreatic necrosis is a radiological diagnosis made on a contrast-enhanced CT scan and is evident as unperfused tissue (see Fig 4.12). Its incidence is high in patients who present with three or more poor prognostic signs. It should also be suspected in patients whose pancreatitis fails to settle clinically within a week. Pancreatic necrosis takes 5–10 days to develop so, unless otherwise indicated, a CT scan to establish the presence of necrosis should be performed after the seventh day of the illness, unless otherwise indicated.

4 Acute abdominal pain

53

Table 4.9 Complications of acute pancreatitis Organ system

Complication

Timeframe

Management (prevention*)

Pancreas

Acute fluid collection

1–6 weeks

Observation, drainage if septic

Pseudocyst

6–12 weeks

Drainage if over 5 cm and persistent

Necrosis

1–2 weeks

Close observation ± pancreatic culture Antibiotics

Infected necrosis

2–3 weeks

Operative debridement (often repeated)

Pancreatic ascites

6–12 weeks

Observation initially, ERCP if persistent

Paralytic ileus

From outset

Nasogastric drainage

Stress ulceration

1–3 weeks

Antiulcer therapy

Nutritional

Malnutrition

From outset

Nutritional support, total parenteral nutrition

Renal

Acute renal failure

1–3 days

Adequate fluid resuscitation, dialysis (if becomes established)

Respiratory

Adult respiratory distress syndrome

2–5 days

ICU/ventilation

Pneumonia

2–5 days

Analgesia, antibiotics and physiotherapy

Pleural effusion

2–20 days

Observation, drainage if large

Gastrointestinal

*Preventative measures are shown in italics. ERCP = endoscopic retrograde cholangiopancreatography.

The incidence of the four common major local complications (infected pancreatic necrosis, acute fluid collection, pancreatic pseudocyst and pancreatic abscess) is much higher in patients who have had pancreatic necrosis. These various complications can co-exist. Infected pancreatic necrosis The most life-threatening complication of pancreatic necrosis is infection of the necrotic pancreatic and peripancreatic tissue. This complication should be suspected if clinical signs of sepsis develop, usually beyond the second week after the onset of the illness, or if there is increasing abdominal pain, tenderness and swelling, or if unexplained deterioration occurs in another organ system (e.g. cardiac or respiratory). Previously, a suspicion of infected pancreatic necrosis can be confirmed by a positive culture from a CT-guided pancreatic fine needle aspirate. Infected pancreatic necrosis will usually require surgical intervention to remove the infected necrotic material. Previously, this was done with early and repeated laparotomy and debridement of the pancreas and necrotic retroperitoneal tissue. Currently, the operative intervention is delayed for as long as possible, in order to develop clear delineation between the necrotic tissue and viable tissue. The

intervention is now performed, where possible, using minimally invasive techniques, as opposed to an open laparotomy. If the minimally invasive techniques are unsuccessful a laparotomy may be required to debride the infected necrosis. Acute fluid collection This is a collection of fluid without a fibrous capsule occurring in the lesser sac in the first 6 weeks after the onset of pancreatitis. It is often asymptomatic, being diagnosed by a CT scan (Fig 4.13). It may be associated with slow resolution of the symptoms and signs of acute pancreatitis. It may resolve spontaneously or persist to develop a capsule, when it is defined as a pseudocyst. Alternatively, the collection may become infected, or produce gastric outlet obstruction, in which case it should be drained percutaneously under CT or ultrasound guidance. Otherwise, the collection should be monitored by serial CT or ultrasound scans. Pancreatic pseudocyst This is an acute fluid collection that has developed a fibrous capsule over 6 or more weeks. It may be asymptomatic, or be associated with ongoing abdominal pain, nausea and vomiting. It may be complicated by infection, haemorrhage or rupture. It may be evident as an abdominal mass (see Ch 19). If it is asymptomatic, it can be followed by serial

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Clinical gastroenterology: a practical problem-based approach

Figure 4.12  Dynamic enhanced CT scan showing early pancreatic necrosis (arrow), which is demonstrated as an unperfused portion of the head and neck of the pancreas compared to the perfused portion of the body and tail.

scans (Fig 4.14). Smaller pseudocysts (under 5 cm) may resolve spontaneously; larger pseudocysts (over 5 cm) will persist and eventually need cystenteric drainage. Cyst-enteric drainage is also required for symptomatic pseudocysts (including infected pseudocysts). Cyst-enteric drainage involves draining the pseudocyst into the adjacent gastrointestinal tract lumen. This may be the stomach, duodenum or small bowel. The stomach and duodenum are used when the cyst abuts against these organs. The small bowel is used where the pseudocyst is distant from either the stomach or duodenal walls. Cyst-enteric drainage needs to be continued until the cavity of the collection shrivels. It can be performed percutaneously through the stomach under CT control, endoscopically through the posterior wall of the stomach, or transgastrically at laparoscopic or open operation. Where a pseudocyst cannot be drained into the stomach or adjacent duodenum an open operation is performed, and the pseudocyst joined to a loop of small bowel, in order to achieve cyst-enteric drainage. Pancreatic abscess A pancreatic abscess is a collection of pus in the peripancreatic tissues. It is not an infected pseudocyst. Clinically, the patient is usually septic and has persistent upper abdominal pain and tenderness. Initial treatment is by percutaneous CTguided drainage and broad-spectrum antibiotics.

Figure 4.13  CT scan 4 weeks after an episode of acute pancreatitis. Note that there is an incomplete wall to this collection along the posterior and left sides, differentiating this from an established pseudocyst.

Operative drainage is required if the sepsis does not settle after percutaneous drainage. A pancreatic fistula may develop as a consequence of operative debridement of pancreatic necrosis and the management of such fistulae are described in Chapter 19.

Subsequent management Attention should be directed towards prevention of further attacks of acute pancreatitis. This involves laparoscopic cholecystectomy and operative cholangiography for patients with gallstones. Only

4 Acute abdominal pain

55

Figure 4.14  CT scan demonstrating a large pseudocyst posterior to the stomach. Note that this has a complete wall surrounding the pseudocyst. This pseudocyst is much larger than 5 cm and required surgical intervention.

25% of these cases are found to have persistent stones in the common bile duct (Fig 4.16), which can be removed intraoperatively by exploration of the common bile duct or postoperatively by ERCP. Abstinence from alcohol should be recommended for patients with alcohol abuse and the patient referred to a drug and alcohol specialist for ongoing management. Severe acute pancreatitis with associated pancreatic necrosis may be complicated by the development of diabetes mellitus or malabsorption due to pancreatic endocrine and exocrine insufficiency, respectively (Ch 14).

Figure 4.15  Endoscopic retrograde cholangiopancreatography showing gallstones in the common bile duct.

Right Upper Quadrant Pain Common causes of acute right upper quadrant pain are listed in Box 4.3. Initial assessment involves making a decision about whether the patient has an immediately life-threatening condition. This view would be supported by finding symptoms and signs of systemic sepsis or shock. Such signs might be attributable to gram-negative sepsis from cholangitis or cholecystitis, to haemorrhage from a liver cell adenoma or a hepatocellular carcinoma, or one of the life-threatening problems that more commonly cause epigastric pain, such as a perforated peptic ulcer and pancreatitis. Such patients need to be managed in hospital. Management involves haemodynamic resuscitation and investigation aimed at rapidly identifying the underlying problem. These same investigations are relevant for patients with lifethreatening conditions that cause generalised abdominal or epigastric pain as discussed above. They include plain x-ray examinations of the

Figure 4.16  Abdominal ultrasound demonstrating gallstones in the gall bladder.

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Clinical gastroenterology: a practical problem-based approach Box 4.3  Causes of right upper quadrant pain ll ll ll ll ll ll ll ll ll ll ll ll ll ll ll

No specific cause found Biliary colic* Acute cholecystitis Acute cholangitis Gallbladder dysfunction Sphincter of Oddi dysfunction Metastasis* Abscess* Hepatitis Primary liver tumour Hydatid cyst Other causes of acute liver swelling Peptic ulceration* Acute pancreatitis* Abdominal wall pain

*Conditions that also cause acute epigastric pain.

abdomen and chest, a white cell count, liver function tests and serum amylase and lipase tests. If there are features of gram-negative sepsis, blood cultures should be performed and parenteral broadspectrum antibiotics commenced. The second line of investigation should include an upper abdominal ultrasound looking for cholelithiasis, thickening of the gallbladder wall, dilatation of the biliary tree, air in the wall of the gallbladder or the biliary tree, and intraabdominal fluid. Even though these life-threatening conditions are uncommon, they require prompt, appropriate management. Most patients who present with acute right upper quadrant pain are not systemically ill. They require analgesia (often narcotic) for the relief of pain. If the pain persists, hospitalisation enables the regular administration of narcotic analgesics and intravenous fluids.

Gallstones Gallstones are of two major types: cholesterolcontaining stones and pigment stones. Cholesterol-containing stones are much more common. Cholesterol and mixed stones occur in patients with bile secreted from the liver that is supersaturated with cholesterol. Cholesterolsupersaturated bile results from either enhanced cholesterol secretion (e.g. obesity, pregnancy or fasting) or decreased bile acid secretion (e.g. small bowel disease). Gallbladder hypomotility (e.g. fasting, pregnancy or hyperalimentation) also predisposes to gallstone formation. Pigment stones

occur in patients with excessive haemolysis such as occurs in haemolytic anaemia. Biliary pain (colic) Biliary colic is severe pain of gradual onset, over 5–10 minutes, which reaches a peak that may be sustained for minutes to hours and then resolves slowly. It is more commonly experienced in the epigastrium than in the right upper quadrant, and may be in the lower chest and imitate an acute myocardial infarction type pain. The pain can be severe enough to cause agitation and a secondary tachycardia. It may radiate around the side to the right scapula or through to the back. The pain will often occur in the evening and may wake the patient from sleep. It can be associated with nausea and vomiting. If the patient has had the pain previously, gallstones may already have been demonstrated by upper abdominal ultrasound (Fig 4.16). As well as upper abdominal ultrasound, the following investigations are also performed: ll a white cell count looking for a leucocytosis, which suggests the development of cholecystitis; ll a serum amylase and lipase test so that pancreatitis is not overlooked; and ll liver function tests, looking for evidence of choledocholithiasis. Once the diagnosis of biliary colic is confirmed, initial management depends upon whether the pain is adequately controlled and whether the development of acute cholecystitis or evidence of stones in the common bile duct has complicated the attack of biliary colic. The complications of gallstones are listed in Box 4.4. Acute cholecystitis Obstruction of the outlet of the gallbladder by a gallstone initially causes biliary colic. The obstruction eventually results in chemical inflammation of the gallbladder, which may be complicated by secondary bacterial infection. The pathological process takes about 24 hours to develop. The pain of acute cholecystitis is peritoneal in type. There may be associated fever. Abdominal examination reveals right upper quadrant peritonism. Usually the tenderness is too great to allow detection of a gallbladder mass, even if one is present at this stage. As the attack resolves, and the gallbladder swelling settles, the gallbladder with residual inflammation may be evident as a tender area beneath the costal margin during deep inspiration. This sign is called Murphy's sign. An attack of acute cholecystitis may settle within 24–48 hours. Recovery is assisted by the

4 Acute abdominal pain

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Box 4.4  Complications of gallstones ll ll ll ll ll ll ll ll

Persistent biliary colic Acute cholecystitis Empyema of the gallbladder Mucocoele of the gallbladder Acute cholangitis Obstructive jaundice Acute pancreatitis Gallstone ileus (cholecystoduodenal fistula)

use of broad-spectrum antibiotics administered parenterally. Resolution of the attack is associated with dislodgment of the obstructing gallstone from the gallbladder outlet. The diagnosis of cholecystitis is confirmed, if necessary, by demonstrating a thickwalled gallbladder on ultrasound. Failure of acute cholecystitis to resolve leads to one of five complications: 1. Empyema of the gallbladder is an ‘abscess of the gallbladder’. Clinically, the patient remains septic and has continuing right upper quadrant pain of peritoneal type, tachycardia, high spiking fever, and marked right upper quadrant peritonism, with an underlying grossly thickened, inflamed gallbladder surrounded by an omental phlegmon. The mass may not be evident on clinical examination because of overlying guarding but will be apparent on ultrasound. Antibiotics alone are not enough to produce resolution. Definitive management may be required, with cholecystectomy, which may be done laparoscopically or open. If cholecystectomy is contraindicated or not possible, drainage of the intravesical pus is required either percutaneously under ultrasound (or CT) guidance, or by operative cholecystostomy or cholecystectomy. Clinical neglect may result in perforation of the gallbladder, septicaemia, a right subphrenic, subhepatic abscess or an intrapatic abscess. 2. Gangrenous cholecystitis (Fig 4.17) may be indistinguishable from empyema of the gallbladder on clinical grounds; the pathological diagnosis is made at operation when patchy areas of necrosis are found as the gallbladder is shelled out of its omental phlegmon. The diagnosis may be made radiologically or by ultrasound on the basis of gas in the gallbladder wall from anaerobic organisms. The treatment is as for empyema. Perforation is more common here than with empyema.

Figure 4.17  Operative photograph demonstrating gangrene of the gall bladder.

3. If the gallbladder outlet remains obstructed and the contents do not become infected, a mucocoele of the gallbladder develops over several weeks. The bile is absorbed and the gallbladder distends with mucus secreted by the gallbladder mucosa. Clinically, an avocadosized, slightly tender mass is evident in the right upper quadrant. Ultrasound will reveal a distended, thick-walled gallbladder with a stone impacted in Hartmann's pouch. The treatment is cholecystectomy. 4. The resolution of acute inflammation without the development of an empyema or mucocele results in fibrosis of the gallbladder wall. This produces a thick and contracted gallbladder wall. This may occur after a single or multiple attacks and results in a small, contracted, fibrotic gallbladder with little or no bile in the lumen (chronic cholecystitis). 5. Cholecystoduodenal fistula is recognised only after it has occurred. The fistula forms when a gallstone trapped in the neck of the gallbladder slowly erodes through into the second part of the duodenum. This might be recognised after the event by the presence of air in the biliary tree. It may become evident after a large gallstone impacts in the terminal ileum causing small bowel obstruction (gall stone ileus). Acute acalculous cholecystitis This is a rare form of cholecystitis usually seen in the intensive care unit, where it occurs in debilitated patients, following major trauma, burns, recent major surgery or severe sepsis. Some of these patients are so unwell that they are unable to complain of right upper quadrant pain. If the patient complains of pain, diagnosis is by

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Clinical gastroenterology: a practical problem-based approach

ultrasound. If there are no complaints of pain the diagnosis is made after clinical suspicion, with either ultrasound or CT scan. The alternative way of making a diagnosis is at surgery (when the clinical diagnosis has not been considered) performed as a result of unexplained deterioration thought to have an abdominal cause. Where the diagnosis is suspected and confirmed on ultrasound or CT scan, it may be managed with percutaneous transhepatic cholecystostomy and drainage of the gallbladder. When diagnosed at laparoscopy a cholecystostomy, rather than a cholecystectomy, may be required because of the patient's poor physical state. Definitive management of cholelithiasis The definitive treatment of gallstones is cholecystectomy. If possible, the procedure is performed laparoscopically because this has a lower morbidity and more rapid recovery time than open cholecystectomy. Routine operative cholangiography is performed at the same time to ensure that unsuspected stones are not left behind in the common bile duct and that the common bile duct has not been injured during cholecystectomy. The risk of unsuspected choledocholithiasis at cholecystectomy is 3–7%. This possibility becomes more likely if one or more of the risk factors listed in Box 4.5 are present. In the management of cholecystitis the timing of cholecystectomy has been controversial. Previously, cholecystectomy may have been delayed for 6–12 weeks to allow an acute inflammatory process to resolve, in the belief that the operation can more often be completed laparoscopically without the need to convert to open operation. However, randomised controlled trials have demonstrated that there is no benefit in delaying the operative management in acute cholecystitis. Therefore, unless surgery is contraindicated, acute cholecystitis should be managed with an urgent (within 72 hours) laparoscopic cholecystectomy. Where there is a contraindication to surgical intervention (e.g. a recent myocardial infarction) the episode may be managed non-operatively, with a view to doing elective cholecystectomy when the patient is fit. If the episode of acute cholecystitis were not to resolve in this situation, the gallbladder should be drained with a percutaneous transhepatic cholycystostomy, in a similar fashion to acute acalculus cholecystitis in a sick intensive care patient. Currently, other treatments of cholelithiasis have an extremely limited use. Extracorporeal

Box 4.5  Preoperative risk factors for common bile duct stones ll ll ll ll ll ll

History of obstructive jaundice History of pancreatitis Elevated hepatic transaminases Elevated alkaline phosphatase Elevated bilirubin Dilated common bile duct on ultrasound (over 6 mm)

lithotripsy, even when combined with dissolution therapy (e.g. ursodeoxycholic acid), fails to completely remove stones from the gallbladder in over 50% of patients with asymptomatic gallstones. This therapy is not recommended for symptomatic stones. Dissolution therapy alone will work only in a functioning gallbladder with stones that contain no calcium. It may take several years for successful dissolution. All nonresectional therapies result in recurrent stones, unless the patient is on long-term dissolution therapy, which has its own complications and problems.

Acute right upper quadrant pain and jaundice Most patients with both acute right upper quadrant pain and jaundice have a stone obstructing the common bile duct. If they have pain, jaundice and fever they have biliary obstruction with secondary infection or cholangitis. This triad of symptoms is known as Charcot's triad (Ch 23). Initial management involves resuscitation and treatment of associated gram-negative sepsis. An urgent ultrasound examination should reveal cholelithiasis, a dilated common bile duct and sometimes a stone in the common bile duct. ERCP with sphincterotomy should be performed urgently if the signs of sepsis are severe, or early if they do not settle rapidly with parenteral antibiotics or the jaundice persists. If the jaundice settles promptly, the underlying cause of the jaundice still needs to be treated during that hospital admission. This would be with a laparoscopic cholecystectomy and exploration of the common bile duct. If the ultrasound examination does not demonstrate gallstones, other causes must be sought. In a small subset of patients, as discussed below, the explanation is apparent on the ultrasound of the liver. As mentioned above, normal serum amylase and lipase levels essentially eliminate

4 Acute abdominal pain unsuspected acute pancreatitis. Peptic ulceration is diagnosed by upper gastrointestinal endoscopy. For the remainder, no further investigation is required if the pain resolves without recurrence. If the biliary colic recurs, the ultrasound examination should be repeated because small stones may be missed in up to 5% of cases. If the cause is still not apparent, a cholecystokinindiethyl iminodiacetic acid (CCK-DIDA) test should be performed. This is a test of gallbladder function. Initially, DIDA is taken up by the liver, excreted in the bile and concentrated in the gallbladder. If the gallbladder is non-functional or contains tiny stones, it contracts minimally in response to cholecystokinin. If the cystic duct is obstructed by a small stone, the gallbladder will not be outlined (Ch 26).

Differential diagnosis of biliary colic Occasionally, a patient with a clinical picture suggestive of acute biliary colic has an alternative explanation, which is apparent on ultrasound examination. More usually the pain is less severe in degree and more prolonged in duration. On review, there may be other clinical clues, which are summarised in Table 4.10. Hepatic metastasis Haemorrhage into a liver metastasis, rapid growth or necrosis of a metastasis can produce a dull ache in the right upper quadrant. The primary tumour is usually gastrointestinal and, on questioning, the patient may reveal symptoms attributable to it. Occasionally the primary tumour is in the breast or the lung or is a melanoma. On ultrasound examination, usually multiple solid lesions are found throughout the liver. A CT scan is used to confirm the ultrasound findings and to assess the pancreas. Management of metastatic liver disease is covered in Chapter 26. Hepatic abscess In a patient with a hepatic abscess (Fig 4.18) the symptoms of sepsis (spiking fevers, night sweats, poor appetite and loss of weight) tend to overshadow the right upper quadrant pain. Hepatic abscesses are of two types: amoebic and pyogenic. An amoebic abscess is caused by the protozoan Entamoeba histolytica, which invades the colonic mucosa, and is carried to the liver via the portal circulation. Infestation is rare in Western societies and usually follows a visit to an endemic area. Confirmation that the abscess is amoebic is usually made serologically. Treatment with metronidazole should result in resolution of

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Table 4.10  Causes of right upper quadrant pain other than gallstones found on ultrasound examination Diagnosis

Ultrasound findings

Hepatic metastases

Multiple solid lesions

Previous carcinoma Irregular hepatomegaly

Pyogenic liver abscess

Cystic lesion(s)

Spiking fevers Anorexia Loss of weight Risk factors

Amoebic liver abscess

Cystic lesion(s)

Spiking fevers Anorexia Loss of weight Recent travel to endemic area

Right-sided cardiac failure

Dilated hepatic veins

Pulsatile liver Cardiac symptoms Respiratory disease Peripheral oedema

Hepatic adenoma/ focal nodular hyperplasia

Solitary solid lesion

Young woman Oral contraceptive pill

Hepatocellular carcinoma

Solid lesion Satellite lesions

Risk of hepatitis B or C Known cirrhosis Ascites

Hydatid cyst

Cystic lesion with daughter cysts or calcified wall

Rural exposure

Budd-Chiari syndrome

Caudate lobe hypertrophy Ascites

Ascites

Clinical clues

the abscess. Percutaneous drainage is indicated if the diagnosis is uncertain, the abscess is likely to rupture or there is no clinical improvement after 48 hours. Management of pyogenic abscesses has two components: 1. drainage of the abscess, usually percutaneously, using ultrasound or CT guidance and broadspectrum parenteral antibiotics; 2. elucidation and treatment of the underlying cause. The causes of pyogenic abscesses are listed in Table 4.11.

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Clinical gastroenterology: a practical problem-based approach Table 4.11 Aetiology of pyogenic liver abscesses Mechanism of infection

Figure 4.18  CT scan of a hepatic abscess in a 36-year-old male. This was managed with multiple percutaneous drains. Microbiology examination revealed infection to be due to Streptococcus faecalis. No underlying cause for this abscess was found.

Hepatic adenoma and focal nodular hyperplasia The benign liver tumours, hepatic adenoma and focal nodular hyperplasia, can cause right upper quadrant pain by intraperitoneal rupture, by bleeding into the lesion or expansion of the lesion. Their diagnosis is discussed in Chapter 26. Symptomatic and complicated lesions are usually managed by liver resection. Hepatocellular carcinoma As with hepatic adenoma and focal nodular hyperplasia, hepatocellular carcinoma can cause right upper quadrant pain as a result of rupture, haemorrhage or expansion. The lesion usually arises in a cirrhotic liver, so that the patient may also have signs of chronic liver disease, portal hypertension or ascites. The diagnostic features on scanning are discussed in Chapter 26. Hydatid cyst This lesion may be asymptomatic or cause a dull ache in the right upper quadrant. It is caused by Echinococcus granulosus (rarely Echinococcus multilocularis). The appearance of the liver cyst on ultrasound examination is often diagnostic. In a living cyst, usually there are also daughter cysts. Calcification of the wall of the cyst indicates that the contents are no longer viable (Ch 26). The diagnosis is confirmed serologically, with an enzyme-linked immunosorbent assay (ELISA) and a complement fixation test. Viable cysts need to be removed to prevent complications such as intraperitoneal rupture. Intraperitoneal spillage needs to be avoided during intraoperative

Examples

Cholangitis

Biliary obstruction from stone or malignancy Bile duct instrumentation

Portal pyaemia

Acute/subacute diverticular disease Appendiceal abscess

Direct spread

Penetrating duodenal ulcer

Systemic bacteraemia

Intravenous drug abuse Subacute bacterial endocarditis

Secondary infection of primary liver lesion

Traumatic haematoma Necrotic hepatic metastasis Hydatid cyst Amoebic abscess

clearance of the live cyst contents to avoid the risk of anaphylaxis and intraabdominal seeding with infective material. Preoperative therapy for several weeks with anthelmintics, such as albendazole, reduces the risk of recurrence. Budd-Chiari syndrome Hepatic vein thrombosis or Budd-Chiari syndrome that develops acutely is a rare cause of right upper quadrant pain. Ultrasound examination will show ascites and caudate lobe enlargement. The venous drainage of the caudate lobe is directly into the inferior vena cava, so that this segment hypertrophies as it is not affected by the hepatic vein thrombosis. CT scanning and Doppler flow studies are useful but liver biopsy may be necessary to confirm the diagnosis. Management is by treatment of the underlying cause (e.g. anticoagulation) and usually a portal systemic venous shunt (Ch 24). Right heart failure Severe or acute right heart failure may cause right upper quadrant pain by venous engorgement of the liver and stretching of the capsule. The symptoms and signs of cardiac failure are gross and dominate the clinical picture. Palpation of the liver may show it to be pulsatile.

Right upper quadrant pain after previous cholecystectomy Recurrence of biliary pain after cholecystectomy occurs in 5–20% of patients. The cause may be due to a biliary or a non-biliary cause. Biliary causes include a retained or recurrent stone

4 Acute abdominal pain in the common bile duct or sphincter of Oddi dysfunction. Non-biliary causes include peptic ulceration, pancreatitis, irritable bowel syndrome or non-ulcer (functional) dyspepsia. As discussed above for right upper quadrant pain without prior cholecystectomy, the initial question is whether the patient has an immediately life-threatening illness. Patients with life-threatening conditions such as acute cholangitis are managed along the lines discussed above. Thereafter, investigation is first aimed at exclusion of common duct stones as the cause. The finding of a dilated common bile duct (with or without a stone on ultrasound examination) or abnormal liver function test results supports the diagnosis of choledocholithiasis, which needs to be confirmed or excluded by CT cholangiography or magnetic resonance cholangiopancreatography. Choledocholithiasis after previous cholecystectomy is managed by ERCP and sphincterotomy. If choledocholithiasis is not found, the cause may be sphincter of Oddi dysfunction. This is a syndrome characterised by biliary-type pain following cholecystectomy. There are two types: ll Type 1 is characterised by a demonstrable stricture of the sphincter with a dilated duct on ultrasound examination, elevated liver function test results in association with episodes of pain, and relief of symptoms after endoscopic sphincterotomy in 90–95% of patients; ll Type 2 is characterised by a non-dilated duct, variable abnormalities in liver function test results during episodes of pain and a less certain response to endoscopic sphincterotomy; 60–65% of patients have resolution. Findings of a normal diameter bile duct with normal liver function test results make a biliary cause for right upper quadrant pain less likely.

Right Iliac Fossa Pain The exact cause of acute right iliac fossa pain may remain undetermined. The pain may resolve spontaneously after a short period and does not recur. Patients, on the other hand, have a different perspective. They commonly believe that they have acute appendicitis and require urgent appendicectomy. The causes of right iliac fossa pain are listed in Box 4.6. Differentiation between the various causes is not always possible on clinical grounds, and investigations frequently do not help. Acute appendicitis remains largely a clinical diagnosis; CT scanning is useful where clinical uncertainty

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Box 4.6  Differential diagnosis of right iliac fossa pain Gastrointestinal causes Non-specific right iliac fossa pain ll Acute appendicitis ll Mesenteric adenitis ll Terminal ileitis ll Acute inflammation of a Meckel's diverticulum ll Crohn's disease of the terminal ileum ll Caecal carcinoma ll Inflammatory caecal lesion (e.g. diverticulitis in a solitary caecal diverticulum) ll Inflammatory lesion of the terminal ileum (e.g. foreign body perforation) Non-gastrointestinal causes ll Ruptured ovarian follicle (Mittelschmerz) ll Acute salpingitis (pelvic inflammatory disease) ll Rupture/torsion or haemorrhage of an ovarian cyst ll Endometriosis ll Ectopic pregnancy ll Urinary tract infection ll Renal calculus ll Musculoskeletal causes ll

exists. Right iliac fossa pain seldom represents an intraabdominal catastrophe. The initial aim of the clinician is to determine whether there is sufficient clinical evidence of localised peritonitis to require surgery. A patient with a typical history of periumbilical pain that shifts to the right iliac fossa, together with a low grade temperature, and localised and rebound tenderness maximal over McBurney's point in the right iliac fossa, is likely to have acute appendicitis and should proceed to appendicectomy. Other signs of acute appendicitis are listed in Table 4.12. If the clinical picture is not clearly one of appendicitis, the next priority depends upon the gender of the patient. In women, consideration must be given to possible gynaecological causes of right iliac fossa pain (Box 4.6), some of which require surgical intervention. A history of abnormal or missed periods or a vaginal discharge is sought. A vaginal examination and speculum examination may demonstrate localised tenderness, a mass or a purulent discharge. Relevant investigations include a pregnancy test and pelvic ultrasound. Laparoscopy may be required to confirm a

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Clinical gastroenterology: a practical problem-based approach

Table 4.12 Other signs of acute appendicitis Name

Sign

Jump tenderness

Jumping or hopping induces pain. Useful in children

Cough tenderness

Cough produces localised pain over McBurney's point

Psoas sign

Pain on elevating right leg (due to inflammation adjacent to psoas muscle)

Rovsing's sign

Tenderness felt in the right iliac fossa while palpating the left iliac fossa

Rectal tenderness

Tenderness palpable on the right side accentuated by bimanual palpation

gynaecological diagnosis and/or deliver definitive treatment. Those patients of the cohort without evidence of localised peritonitis are observed and reviewed. Most are afebrile and have a normal white cell count. If the clinical signs progress and become more suggestive of appendicitis, surgery is indicated. If the pain resolves spontaneously, no further investigations or follow-up are required. Other inflammatory conditions of the terminal ileum and caecum may mimic acute appendicitis. Such conditions include mesenteric adenitis or terminal ileitis. These conditions frequently have no clinical clues and are often diagnosed at surgery. Terminal ileitis may be due to Yersinia enterocolitica infection and this is confirmed using acute and convalescent serology. Follow-up of patients with terminal ileitis needs to consider the possibility of Crohn's disease, although this is uncommon. Mesenteric adenitis is common in childhood and adolescence and is a self-limiting illness of probable viral aetiology. Occasionally there are clinical clues that indicate that the localised peritonitis is not due to appendicitis. An elderly patient may have a right iliac fossa mass, suggesting a caecal carcinoma or a complication of a diverticulum. If a mass is found, the presence of tumour or pus within it should be ascertained by CT scanning. An appendix abscess, if diagnosed preoperatively, can be drained percutaneously with ultrasound or CT control, avoiding urgent surgery. The appendix may then be removed electively, after a 3–6 month interval, if the abscess and associated acute inflammation resolve with drainage. A caecal carcinoma is treated by right hemicolectomy. The principles of treatment of right colonic diverticulitis or

caecal diverticulum are the same as for left-sided diverticulitis if the diagnosis is known. Often, however, the diagnosis is established only after the affected colon is removed. A patient with acute right iliac fossa pain and diarrhoea may have acute terminal ileitis. Recurrent right iliac fossa pain and diarrhoea or previous episodes of perianal sepsis may suggest Crohn's disease.

Specific management Acute appendicitis The treatment for acute appendicitis is appendicectomy. Traditionally this is performed open through a muscle-splitting incision. That approach is still best for children. In adults the operation is commonly performed laparoscopically for several reasons: ll The accuracy of the clinical diagnosis is relatively low in adult women (53–78% of cases); it is higher in men (85–90%). The inaccuracy relates to gynaecological diseases that mimic acute appendicitis. ll If the cause is gynaecological, laparoscopy is a more accurate diagnostic tool than laparotomy through an incision in the right iliac fossa. ll Laparoscopic appendicectomy is associated with a more rapid postoperative recovery. Terminal ileitis Some patients with a clinical diagnosis of acute appendicitis are found to have terminal ileitis. Diarrhoea will have been a feature of the disease. The usual cause is Yersinia enterocolitica (Ch 13). This should be confirmed by convalescent serology. Occasionally, terminal ileitis that is not due to a bacterial cause is the first manifestation of Crohn's disease. Mesenteric adenitis Mesenteric adenitis is quite common in children and adolescents. It is presumed to be a viral illness with enlargement of the mesenteric lymph nodes. There is often a preceding history of a viral-like illness. This is a self-limiting condition that resolves without specific therapy. There is no specific test to establish this diagnosis prior to surgery. It presents with a similar clinical picture to acute appendicitis and is often diagnosed at operation. Meckel's diverticulum A Meckel's diverticulum is a congenital remnant of the vitelline duct. It is a true diverticulum that occurs on the antimesenteric border of the terminal

4 Acute abdominal pain ileum, 45–60 cm from the ileocaecal sphincter. It occurs in 2% of the population and complications are unusual. If the base of the diverticulum is narrow, the diverticulum can become obstructed and present with an appendicitis-like illness. Other complications include: ll bleeding from peptic ulceration caused by ectopic gastric mucosa; and ll small bowel obstruction due to a congenital adhesion to the umbilicus. These complications are managed by local resection of the diverticulum. Crohn's disease The management of Crohn's disease diagnosed prior to surgery is covered in Chapter 15. When a segment of Crohn's disease is found at operation for presumed appendicitis, a resection needs to be performed only if there is a local complication (perforation, fistula or obstruction). Caecal carcinoma A caecal carcinoma found at laparotomy is treated by right hemicolectomy and primary anastomosis (Ch 22).

Left Iliac Fossa Pain There are only a limited number of causes of acute left iliac fossa pain. They can be subdivided into gastrointestinal causes (Box 4.7) and the same non-gastrointestinal causes as right iliac fossa pain (Box 4.6). When approaching the patient with acute left iliac fossa pain, the first decision to be made is whether the patient needs an urgent laparotomy. The decision is made on clinical grounds. If there is shock due to sepsis or hypovolaemia, and marked signs of peritonitis, or radiological evidence of bowel perforation, an urgent laparotomy is required. Such presentations are uncommon so that most patients are initially managed non-operatively.

Initially, for those managed non-operatively, investigation is the next step. Age and gender are important pointers. Most gynaecological causes affect women in their reproductive years (15–45) whereas diverticular disease and colonic ischaemia affect older patients of both sexes. Gastrointestinal causes are also associated with disturbances of bowel habit. Acute diverticulitis may be associated with constipation or diarrhoea, whereas ischaemic colitis is often associated with bloody diarrhoea.

Diverticular disease Increasing age is associated with the development of pulsion diverticula of the colon. This process is associated with consumption of a diet low in roughage. Each diverticulum consists of a mucosal pouch with no external muscle. Diverticula are most commonly present in the sigmoid colon (Fig 4.19). They occur with decreasing frequency from sigmoid colon to caecum. They do not occur in the rectum, which has a complete outer longitudinal layer of muscularis propria. There may be hypertrophy of the muscularis propria of the sigmoid colon. Uncomplicated diverticular disease is usually asymptomatic. Treatment of patients with diverticular disease with a long-term high-roughage diet reduces the incidence of the complications of diverticular disease. The infective complications of diverticular disease (acute diverticulitis, abscess, perforation and fistula formation) result when the neck of a diverticulum, which is narrower than the

Box 4.7  Gastrointestinal causes of acute left iliac fossa pain ll

ll ll ll ll ll

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Non-specific left iliac fossa pain including constipation Acute gastroenteritis Acute diverticulitis Colonic carcinoma Colonic ischaemia Localised small bowel perforation Figure 4.19  Diverticulosis on colonoscopy.

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Clinical gastroenterology: a practical problem-based approach

sac, becomes obstructed by faecal material and the contents of the sac become infected. Acute diverticulitis The signs of acute diverticulitis can be remembered as those of ‘left-sided appendicitis’. The usual position of the pain is explained by the fact that it is nearly always the sigmoid colon that is most severely affected by diverticular disease and the sigmoid colon lies most often in the left iliac fossa. Unlike acute appendicitis, the peritoneal pain of acute diverticulitis is usually not preceded by colicky midline pain. Tenderness and guarding in the left iliac fossa are usually seen. A tender mass in the left iliac fossa may be palpable by concurrent abdominal and rectal palpation. A diverticular mass may or may not have a significant amount of pus at its centre. A patient presenting with a clinical diagnosis of acute diverticulitis will have the diagnosis confirmed on CT scanning. CT scanning can grade the severity of diverticulitis and aid in management decisions. Patients with mild tenderness in the left iliac fossa as the only specific sign of flare-up of acute diverticular disease may be treated at home with oral fluids, broad-spectrum oral antibiotics, analgesia and early review. Patient with more severe pain and tenderness, with or without associated evidence of sepsis, require admission to hospital, gut rest and parenteral broad-spectrum antibiotics. Once the flare-up has settled completely, the diagnosis is confirmed with colonoscopy 6–8 weeks after the episode has resolved. A diverticular abscess needs to be drained if there are continuing signs of severe sepsis and left iliac fossa peritonism after 48–72 hours. The drainage may be percutaneous with CT-guided control or by laparotomy to resect the affected colon. Surgical drainage often involves a Hartmann's procedure. Recurrent diverticulitis is an indication for surgical referral. 5-aminosalicylic acid may reduce the risk of recurrence. Complications of diverticular disease The complications of diverticular disease include colovesical fistula, colovaginal fistula, coloenteric fistula, small bowel obstruction (discussed above under ‘Acute abdominal colic’), large bowel obstruction (discussed above under ‘Acute abdominal colic’) and gastrointestinal bleeding (see Ch 10). The outstanding presenting feature of a colovesical fistula is pneumaturia (passage of gas with urine) or faecuria (which is less common).

There may be hypogastric pain due to associated urinary bladder inflammation. The fistula is usually the size of a pinhole. It is unusual to be able to demonstrate the fistula with either a barium enema or cystogram. CT scanning will often demonstrate an inflammatory mass of the colon adjacent to the bladder, with a variable amount of free gas seen within the bladder lumen. This is indicative of the presence of a fistula but the site of the fistula often cannot be determined. The outstanding presenting feature of a colovaginal fistula is a feculent vaginal discharge. A previous hysterectomy has usually been performed as this allows the segment of sigmoid colon to come into contact with the apex of the vagina. The outstanding presenting feature of a coloenteric fistula is profuse diarrhoea and significant weight loss. The treatment of all fistulae is resection of the affected segment of colon and oversewing the defect in the bladder or vagina, or resection of the affected segment of small bowel.

Ischaemic colitis The clinical presentation of ischaemic colitis may be similar to that of acute diverticulitis. Differentiating features include a history of cardiac disease, arrhythmia or other vascular disease, as well as a history of profuse bloody diarrhoea (Ch 10). Ischaemic colitis is managed non-operatively unless there is clinical evidence of sepsis or a progressive deterioration on repeated clinical assessment. The management of ischaemic colitis is discussed earlier in this chapter.

Sigmoid colon cancer Localised perforation of a sigmoid colon cancer can closely mimic acute diverticulitis.

Constipation Constipation may be associated with a dull aching pain in the left iliac fossa. The management of constipation is discussed in Chapter 11.

Key Points ll

ll

ll

The pathological causes of acute abdominal pain are usually one of acute inflammation, acute luminal obstruction or ischaemia to an organ. Key points in the history of acute abdominal pain are its site, nature and onset. Clinical examination in combination with clinical history will establish a short list of differential diagnoses in most cases.

4 Acute abdominal pain ll

ll

ll

Laboratory investigations and imaging are used to support or confirm the clinical diagnosis and plan the appropriate treatment. The overarching principles of treatment include analgesia, fluid resuscitation, fasting and antibiotics (when appropriate). Surgical assessment is essential in all patients with acute abdominal pain.

Further reading Dang C, Aguilera P, Dang A, et al. Acute abdominal pain. Four classifications can guide assessment and management. Geriatrics 2002; 57:30–32, 35–36, 41–42. Korotinski S, Katz A, Malnick SD. Chronic ischaemic bowel diseases in the aged—go with the flow. Age Ageing 2005; 34:10–16. Mackay S, Dillane P. Biliary pain. Aust Fam Physician 2004; 33:977–981.

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Renzulli P, Jakob SM, Tauber M, et al. Severe acute pancreatitis: case-oriented discussion of interdisciplinary management. Pancreatology 2005; 5:145–156. Sajja SB, Schein M. Early postoperative small bowel obstruction. Br J Surg 2004; 91:683–691. Stoker J, van Randen A, Lameris W, Boermeester MA. Imaging patients with acute abdominal pain. Radiology 2009; 253:31–46. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient have acute cholecystitis? J Am Med Assoc 2003; 289:80–86. Wagner JM, McKinney WP, Carpenter JL. Does this patient have appendicitis? J Am Med Assoc 1996; 276:1589–1594. Werner J, Feuerbach S, Uhl W, et al. Management of acute pancreatitis: from surgery to interventional intensive care. Gut 2005; 54:426–436.

5 When to test for Helicobacter pylori and what to do with a positive test

Case A 47-year-old executive consults you because his older brother, aged 61, has recently been diagnosed with gastric cancer. The patient advises you he wants to have testing for the stomach bacteria that causes gastric cancer. The patient is asymptomatic and in particular has no history of epigastric pain, fullness after meals, early satiety, vomiting, weight loss, dysphagia or gastrointestinal bleeding. He is a non-smoker. No other family members have been affected by gastric cancer to his knowledge. The patient was born in Australia to parents of British descent. The patient has been taking low-dose aspirin for cardiovascular health reasons, but has not been taking non-steroidal anti-inflammatory drugs. He has no known drug allergies. Physical examination is completely normal. You counsel the patient that Helicobacter pylori is a known cause of gastric cancer and clusters in families. You further advise him that if testing is performed and infection is found, you would be obliged to advise treatment even though it is not certain in the current clinical situation whether the benefits of treating the infection outweigh the potential risks. You advise the patient the treatment of H. pylori infection can result in serious side effects, including, rarely, pseudomembraneous colitis. After a full discussion, the patient still wishes to go ahead with testing. A 13C urea breath test is performed and the patient returns with a positive result. You advise the patient he does have H. pylori gastritis, which has probably been present since childhood. As there are no alarm features, you do not recommend upper endoscopy although you discuss the pros and cons of the test. The patient is prescribed a course of triple therapy for 7 days (clarithromycin, amoxicillin and omeprazole twice daily). You advise the patient to take all of the medications

66

as prescribed as otherwise treatment may fail, and to call you if he experiences any side effects. You further advise him to undergo a repeat urea breath 1 month after completing treatment to ensure the infection has been eradicated.

Introduction H. pylori is a cause of peptic ulcer disease and gastric cancer, but most people who are infected are unaware of its presence and it usually causes no symptoms. Patients may present to the doctor's office requesting testing for this stomach bacteria even if they have no symptoms. Some patients have a known history of peptic ulcer disease, but have not been tested for H. pylori as far as they know. Other patients present, worried because they have indigestion or one of their close family members has gastric cancer. What to do in these and related situations forms the basis of this chapter.

Pathogenesis H. pylori is a spiral-shaped gram-negative rod with flagella at one end. The organism was first cultured by Barry Marshall after its existence in gastric biopsies was pointed out to him by a pathologist, Robin Warren. These Australians went on to describe the association of H. pylori with histological gastritis and peptic ulcer, and won the Nobel prize for their clinical research. H. pylori is associated with serious upper-gastrointestinal conditions including chronic gastritis, peptic ulcer disease, non-ulcer (functional) dyspepsia, and malignancy (gastric adenocarcinoma and mucosa associated lymphoid tissue—MALT—lymphoma). H. pylori is most often acquired in childhood by close contact with other infected families and, once acquired, persists for life in most cases. The mode of transmission is probably oral (via saliva or vomit) and, in the developing world, faecal

5 When to test for Helicobacter pylori and what to do with a positive test spread. Virtually 100% of infected individuals develop gastritis; the lifetime risk of peptic ulcer disease in those infected is approximately 20%. In Western countries, approximately 20% of the population is infected, with older people and those from lower socioeconomic groups being more often infected. The higher prevalence with age reflects the higher infection rates in the past; the risk of adult acquisition is low (less than 1% per year). In developing countries (and in migrants from these countries), approximately 70% of adults are currently infected. H. pylori is uniquely adapted to the gastric mucosal environment; for example, it produces the enzyme urease in very large amounts. It protects itself from gastric acid produced in the stomach by breaking down endogenous urea using urease to produce a protective ammonia cloud. The infection induces gastric inflammation characterised by mononuclear and polymorphonuclear cell infiltration of the mucosa; the inflammatory products provide nutrients for the bacteria. The stomach is functionally subdivided into the gastric antrum and the gastric body. With H. pylori infection the gastric antrum is predominantly inflamed in well-nourished individuals but the gastritis can involve the gastric body. The distribution of the bacteria determines the physiological effects. Most duodenal ulcer patients (more than 90%) and many gastric ulcer patients (80%) have this infection. H. pylori causes an elevation in serum gastrin (because the antral gastritis reduces the D-cell function in the antrum that produces the inhibitory peptide somatostatin, disinhibiting antral G-cells that then secrete more gastrin). The elevated gastrin increases meal-related acid secretion from the gastric body (unless widespread inflammation in the gastric body impairs the acid output response). These changes in gastrin reverse with cure of the infection. Increased acid secretion damages the mucosa in the first part of the duodenum, leading to areas of gastrictype epithelium in the duodenum (called gastric metaplasia) that can be infected by H. pylori (note that these bacteria can live only on gastric epithelium). The localised inflammation in the duodenum caused by H. pylori (duodenitis) can progress to an ulcer in the presence of acid. A duodenal ulcer will heal with acid suppression but usually recurs in H. pylori-infected patients (the duodenal ulcer diathesis). Cure of the infection leads to resolution of the gastritis (but not gastric metaplasia in the duodenum) and eliminates the ulcer diathesis (in both duodenal

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Box 5.1  Indications for the diagnosis and treatment of H. pylori Well established Active peptic ulcer disease (gastric or duodenal ulcer) ll Confirmed history of peptic ulcer disease (not previously treated for H. pylori) ll Gastric MALT lymphoma (low grade) ll After endoscopic resection of early gastric cancer ll Uninvestigated dyspepsia (‘test and treat strategy’, depending on H. pylori prevalence in the local community) Acceptable ll Functional (non-ulcer) dyspepsia ll Strong family history of gastric adenocarcinoma ll Those newly prescribed chronic nonsteroidal anti-inflammatory drugs, to prevent ulcers ll Unexplained iron deficiency anaemia ll

MALT = mucosa-associated lymphoid tissue

and gastric ulcers) when the ulcer is caused by the infection. Other factors, such as the virulence of H. pylori infection (based on the cytotoxin-associated gene pathogenicity island), smoking and host genetic factors, act as disease modulators.

Management Guidelines Testing for H. pylori infection Testing for H pylori infection should be performed only if the clinician plans to offer treatment to patients with a positive result (Box 5.1). The advantages and disadvantages of tests for H. pylori are summarised in Table 5.1. Non-invasive (non-endoscopic) tests Serology (laboratory enzyme-linked immunosorbent assay [ELISA]) is widely available and relatively inexpensive but is not the test of choice in most circumstances. Serologic testing can determine whether a patient has had H. pylori infection in the past, but cannot definitively identify the presence of current infection. A positive result may be obtained even after the infection has cleared. The sensitivity and specificity are about 80%; consequently, serology risks missing approximately one of every five cases of H. pylori infection or, conversely, administering unnecessary treatment to patients who are no longer infected.

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Table 5.1 Tests for H pylori: advantages and disadvantages Methods

Advantages

Disadvantages

Usefulness

Non-invasive; relatively cheap

Requires validation in local patient population

Initial diagnosis, not follow-up after therapy

Non-invasive Serology C urea breath test

Rapid; allows Involves ingestion of radioactivity. distinction between Otherwise same as 13C current and past infection

Initial diagnosis, follow-up of treatment regimens

13

C urea breath test

No radioactivity

Complex equipment, expensive Useful pre- and post-therapy Reduced sensitivity with acid suppression or antibiotics

Initial diagnosis, follow-up of treatment regimens

Stool antigen test

Allows distinction between current and past infection

Reduced sensitivity with acidsuppressing drugs Monoclonal test appears reliable before/after antibiotic therapy Unpleasantness associated with collecting stool

Initial diagnosis, follow-up of treatment regimens

Rapid urease test

Rapid; inexpensive

Invasive Reduced sensitivity in those on acid suppression or with recent or active bleeding

Initial diagnosis

Histology

Allows assessment of mucosa

Invasive; costly

Assess gastritis, metaplasia and atrophy etc, initial diagnosis

Culture

Specificity: 100%

Invasive; costly; less sensitive

Antimicrobial sensitivities (macrolide resistance 4–12%; metronidazole resistance is common), strain typing

14

Invasive

Urea breath testing is an excellent non-invasive method of assessing the presence of H. pylori via the urease activity of the organism (Fig 5.1). In a patient with infection, the patient ingests urea labelled with either the isotope 13C (which is non-radioactive) or the isotope 14C (using a low dose so there is low radioactivity). If infection is present, there is breakdown of the urea via urease produced by the bacteria; the excessive labelled carbon dioxide produced can be quantified in expired breath. The 14C test is contraindicated in pregnant women and children. This technique offers excellent positive and negative predictive values, regardless of the background prevalence of H. pylori. Moreover, the test is useful both before and after treatment. Accurate results are also more often achieved in the setting of uppergastrointestinal bleeding with this test. Sensitivity is reduced by medications such as proton pump inhibitors, bismuth and antibiotics, which decrease the H. pylori density on which the test

is based. Patients should be off acid suppression medications for at least 1 week before testing by the urea breath test for infection if possible; if the test is negative and the patient is or recently has been on acid suppression drugs, testing with an alternative method or repeating the test later should be considered. The faecal antigen test is excellent (and equivalent in terms of accuracy to the urea breath test). As with other types of testing, the faecal antigen test can produce false-negative results in the presence of proton pump inhibitor therapy. Endoscopic tests H. pylori infection can be diagnosed at endoscopy by a screening test, the rapid urease test, which has a high sensitivity and specificity (over 95%) (Fig 5.2). It involves placing a biopsy in a pH-sensitive medium containing urea. Urease produced by the bacteria splits the urea to ammonia that changes the pH and produces a colour change. The various

5 When to test for Helicobacter pylori and what to do with a positive test

69

10,000 8,000

C=O

Urease H. pylori

Counts/min

NH2 CO2 + NH3

6,000 4,000

Infected

2,000

NH2

0

0

4

Not infected 8 12 16 20 24 28 Time after dose (min)

*C urea

*CO2

H. pylori

*CO2 Blood

Figure 5.1  Schematic representation of the 14C and 13C breath test. After ingestion of labelled urea, urea is metabolised by urease and labelled CO2 is produced. This is exhaled via the lungs and the concentration of labelled carbon atoms can be determined in the exhaled air. The value at 20 or 30 min may be used to define a positive urea breath test (upper curve). An early peak can occur in both Helicobacter pylori-positive and -negative cases from hydrolysis of urea by mouth flora.

Figure 5.2  A rapid urease test—a gastric biopsy is placed in the pH-sensitive medium. Top and bottom tests: no colour change. Middle test: change to magenta within 3 hours, indicating the presence of urease (and hence H. pylori).

commercially available biopsy urease tests have comparable diagnostic accuracy, with excellent specificity (93% to 100%) and very good sensitivity (89–98%). It should be noted, however, that the sensitivity is reduced in patients who have taken

proton pump inhibitors within the preceding 1–2 weeks. In addition, biopsy testing may yield falsenegative results in patients with ulcers that are actively bleeding, and therefore all bleeding ulcer patients should be re-evaluated, preferably using urea breath testing if initially biopsy tests for the infection are negative. Gastric histology offers excellent sensitivity and specificity, but is much more costly than biopsy urease testing. Moreover, the accurate detection of H. pylori depends on the site, number, and size of gastric biopsies. To optimise the diagnostic yield, multiple biopsy samples should be obtained from both the antrum and gastric body. All samples can be placed into a single container to reduce costs. As in the case of biopsy urease testing, the sensitivity of histology is decreased in the presence of proton pump inhibitor therapy such that the diagnosis of H. pylori infection will probably be missed in more than one-third of patients. The main advantages of this technique are its ability to check for pathological changes associated with infection (such as atrophy or intestinal metaplasia) and to diagnose mucosa-associated lymphoid tissue

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Table 5.2 First-line regimens for H. pylori infection Regimen

Duration(d)

Eradication rates (%)

Comments

Standard-dose PPI b.i.d., 7–10–14 clarithromycin 500 mg b.i.d., amoxicillin 1,000 mg b.i.d.

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Consider in patients not allergic to penicillin who have not previously received a macrolide.

Standard-dose PPI b.i.d., 10–14 clarithromycin 500 mg b.i.d., metronidazole 500 mg b.i.d.

70

Consider in penicillin-allergic patients who have not previously received a macrolide or are unable to tolerate bismuth quadruple therapy.

Bismuth subsalicylate 525 mg p.o. q.i.d., metronidazole 250 mg p.o. q.i.d., tetracycline 500 mg p.o. q.i.d., standard-dose PPI q.d. to b.i.d.

10–14

75–90

Consider in patients not allergic to penicillin who have not previously received a macrolide.

PPI + amoxicillin 1,000 mg b.i.d. × 5 d, followed by PPI, clarithromycin 500 mg, tinidazole 500 mg b.i.d. × 5 d

10

> 90

Sequential therapy

b.i.d. = twice daily; q.d. = once daily; q.i.d. = 4 times daily; PPI = proton pump inhibitor.

(MALT) lymphoma. Usually, the gastroenterologist will take samples for histology if there is cause for concern based on the visual findings or if a gastric ulcer is present. Culture is not routinely available, but is valuable for examining patterns of antimicrobial resistance in patients who have failed multiple courses of therapy for H. pylori infection.

Treatment All patients must be tested for H. pylori infection prior to prescribing specific treatment. Suppression of H. pylori is easy with a single antibiotic but unhelpful; eradication (i.e. cure) of infection is essential. Therapy for H. pylori first line consists of acid suppression plus antibiotics in most cases, as this approach is synergistic (Table 5.2). Triple therapy requires that two antibiotics be given along with acid suppression, and is a first-line treatment. Patients who are not allergic to penicillin and have not recently received a macrolide should be considered for treatment with clarithromycin 500 mg twice daily and amoxicillin 1,000 mg twice daily for 7 days, in addition to a proton pump inhibitor (triple therapy). A standard dose of any of the proton pump inhibitors can be used as the acid-suppression component of therapy, as all of these agents have equivalent efficacy. Metronidazole 500 mg twice daily can

be substituted for amoxicillin in patients who are allergic to penicillin. The regimen is associated with eradication rates of about 70%, which means that up to one in three patients will fail treatment. Bismuth quadruple therapy consists of 14 days of treatment with bismuth (e.g. in the US bismuth subsalicylate 525 mg four times daily; an alternative is bismuth subcitrate), metronidazole 250 mg four times daily, and tetracycline 500 mg four times daily, plus a standard-dose proton pump inhibitor either once or twice daily. This is an effective regimen (with eradication rates of 75– 90%) and can be used first line or if clarithromycinbased triple therapy fails. The main limitation is the complexity of the regimen. Sequential therapy incorporates the use of a proton pump inhibitor and amoxicillin (1 g) twice daily for 5 days, followed by a proton pump inhibitor, clarithromycin (500 mg), and tinidazole (500 mg) all twice daily for an additional 5 days. Trials have shown that this approach is associated with higher eradication rates first line than triple therapy. Compliance with treatment is key to success but side effects can limit adherence (Table 5.3). Patients should be warned about potential side effects and to call before stopping therapy. Among the most serious side effects is C. difficile colitis, which is rare.

5 When to test for Helicobacter pylori and what to do with a positive test Table 5.3 Most common side effects related to H. pylori treatments Treatment

Most common side effects

PPIs

Headache, diarrhoea

Clarithromycin

GI upset, diarrhoea, altered taste, C. difficile colitis

Amoxicillin

GI upset, headache, diarrhoea, C. difficile colitis

Metronidazole

Metallic taste, dyspepsia

Tetracycline

GI upset, photosensitivity, tooth discoloration

Bismuth compounds

Darkening of tongue/stool, nausea, GI upset

GI = gastrointestinal; PPI = proton pump inhibitor.

Integrating H. pylori testing and treatment into clinical practice Testing initially Testing for H. pylori should be conducted only if the clinician is planning to offer treatment to all patients who have positive results. Any patient with a history of peptic ulcer or gastric cancer (including MALT lymphoma) must have H. pylori excluded if not already checked. Asymptomatic patients are not usually tested except in special situations. If a patient has a strong family history of gastric cancer, testing can be performed to reassure the patient and treat if infected. Patients about to be started on a long-term non-steroidal anti-inflammatory drug (NSAID) or low-dose aspirin may be offered testing, as eradication of H. pylori in this setting reduces (but does not abolish) the risk of subsequent peptic ulcer. Patients with unexplained documented iron deficiency anaemia after a comprehensive evaluation (to exclude other causes including colonic pathology) may be offered testing and treatment for H. pylori as this can resolve the problem. H. pylori has also been linked to immune thrombocytopenic purpura, so testing in this situation may be considered. H. pylori testing is not recommended for patients with symptoms of gastroesophageal reflux disease (e.g. heartburn) or for oesophagitis. Testing post-therapy Once treatment of H. pylori has been completed, universal testing to confirm eradication (i.e. cure) of the infection is neither cost-effective nor practical. Current guidelines recommend post-treatment

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testing to confirm eradication in specific groups of patients: namely, those with H. pylori–associated peptic ulcer, persistent dyspepsia after treatment (as you need to decide whether to try retreating the infection or offer another empirical treatment approach), those with MALT lymphoma, and those who have undergone endoscopic mucosal resection for early gastric cancer. The urea breath or stool antigen test is recommended in these settings at least 4 weeks after H. pylori therapy has been completed (re-testing earlier gives false negative results). Serology cannot be used to confirm eradication of H. pylori infection. Treatment failure If first-line treatment fails, the infection is usually more difficult to eradicate. The best chance of success is with the first prescription given. Normally if first-line therapy fails a different regimen is prescribed next. The most important predictors of treatment failure are poor adherence to prescribed regimens and antibiotic resistance. Adherence may be limited by the complexity of treatment regimens, the patient's incomplete understanding of the rationale for treatment, the side effects of medications, or the patient's assumption that the medication can be stopped once the symptoms have improved. Promotion of good adherence is critical, as rates of successful eradication of H. pylori are falling. Effective communication with patients is the key to success. The clinician should emphasise that medications must be taken exactly as prescribed to minimise the risk of treatment failure. The patient should also be given an explanation of how non-adherence can lead to the development of antibiotic resistance. Antibiotic resistance is a crucial determinant of treatment outcome. Trends document increasing rates of clarithromycin resistance and relatively stable but high rates of metronidazole resistance. Regardless of the regimen, however, the likelihood of H. pylori resistance is elevated in patients previously treated with either metronidazole or a macrolide. If two attempts to treat the infection fail, specialist consultation is advised. Culture of the organism and testing for antibiotic sensitivities may be considered. Salvage treatment regimens include (1) a 10-day course of a standard dose of proton pump inhibitor, amoxicillin (1 g), and levofloxacin (250 mg), all given twice daily, or (2) a proton pump inhibitor twice daily, rifabutin (300 mg once daily), and amoxicillin (1 g twice daily) for 10 days.

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Summary H. pylori is a prevalent, chronic infection that is linked to the development of dyspeptic symptoms (e.g. epigastric pain and discomfort after meals), and is a significant cause of peptic ulcer disease and gastric malignancy (adenocarcinoma and the rare gastric MALT lymphoma). Most patients with H. pylori infection present to their general practitioner with undiagnosed dyspepsia or a past history of peptic ulcer. If the clinician tests for the infection he or she will be obligated to treat if testing is positive. Non-invasive tests such as the urea breath test and stool antigen test are superior to serology antibody tests. Triple therapy is currently first line but newer sequential regiments may be superior. Post-treatment testing should be performed to document eradication (cure) of infection in patients with a documented ulcer or cancer, but wait at least 4 weeks.

Key Points ll

ll

ll

ll

ll

ll

ll

ll

H. pylori is a cause of peptic ulcer disease and gastric cancer. All patients with a history of H. pylori peptic ulcer (present or past) should be offered eradication treatment. H. pylori is most often acquired in childhood by close contact with other infected family members. Virtually 100% of infected individuals develop chronic gastritis for life unless treated; this can progress to gastric atrophy. Testing for H. pylori should be conducted only if the clinician is planning to offer treatment to the patient who has a positive result. Serology risks missing approximately one of every five cases of true H. pylori infection, and cannot distinguish current from past infection. Urea breath testing and stool antigen testing are excellent non-invasive methods of assessing the current presence of H. pylori. The sensitivity of the urea breath test is reduced by certain medications (proton pump inhibitors, bismuth and antibiotics). Faecal antigen testing can produce false-negative results in the presence of proton pump inhibitor therapy.

ll

ll

ll

ll

Triple therapy for 7 days is first-line treatment. This requires two antibiotics be given along with acid suppression. Metronidazole can be substituted for amoxicillin in patients who are allergic to penicillin. Sequential therapy incorporates the use of a proton pump inhibitor and amoxicillin twice daily for 5 days, followed by a proton pump inhibitor, clarithromycin and tinidazole all twice daily for an additional 5 days. The most important predictor of treatment failure is poor adherence to prescribed regimens. Antibiotic resistance can occur after failed initial therapy and can lead to further difficulty eradicating the infection.

Further reading

Chey WD, Wong BCY, Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007; 102:1808–1825. Ford A, Talley NJ. Does Helicobacter pylori really cause duodenal ulcers? Yes. BMJ 2009; 339:b2784. Laine L, Estrada R, Trujilo M, et al. Effect of protonpump inhibitor therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med 1998; 129:547– 550. Loy CT, Irwig LM, Katelaris PH, et al. Do commercial serological kits for Helicobacter pylori infection differ in accuracy? A meta-analysis. Am J Gastroenterol 1996; 91:1138–1144. Talley NJ, Fock KM, Moayyedi P. Gastric Cancer Consensus conference recommends Helicobacter pylori screening and treatment in asymptomatic persons from high-risk populations to prevent gastric cancer. Am J Gastroenterol 2008; 103:510–514. Zullo A, Gatta L, De Francesco V, et al. High rate of Helicobacter pylori eradication with sequential therapy in elderly patients with peptic ulcer: a prospective controlled study. Aliment Pharmacol Ther 2005; 21:1419–1424.

6 Indigestion (chronic epigastric pain or meal-related discomfort)

Case A 39-year-old female psychologist consults because of problems with indigestion for the past year. She states that after eating a meal she feels very uncomfortable and full. The discomfort she experiences is not at the level of pain, but does interfere with her life. She also feels bloated and is unable to finish normal-sized meals now. She has these symptoms after most meals. She very occasionally will have heartburn (retrosternal burning discomfort in her chest travelling up towards the throat). She never has acid regurgitation and denies dysphagia. She is slightly nauseous at times, but denies vomiting. She has not noticed any change in her bowel habit. Her weight has fluctuated up and down, but overall has been stable. She remembers her mother suffered for years with indigestion problems. She is not taking non-steroidal anti-inflammatory drugs supplied ‘over the counter’. She has already consulted a gastroenterologist who performed an upper endoscopy; she was told the test was normal (no peptic ulcer, no cancer and no reflux oesophagitis), but was given a trial of proton pump inhibitor for 2 months. It did not help her. Physical examination is unremarkable. You order a Helicobacter pylori 13C urea breath test, which comes back negative. In view of the previously negative upper endoscopy and characteristic history, you diagnose functional or non-ulcer dyspepsia (postprandial distress syndrome based on the Rome III criteria). You provide the patient with dietary advice (low fat and small regular meals) and prescribe a prokinetic agent (domperidone, 10 mg before meals). The patient returns a month later and advises you that she has had a good response to this approach. You further reassure her about the benign nature of the condition although you do warn her that while the

symptoms can fluctuate they usually persist long term.

Indigestion and Dyspepsia The terms ‘indigestion’ and ‘dyspepsia’ mean different things to different people. It is therefore important to clarify with a patient what they mean by indigestion. The term is generally used by patients to describe symptoms related to the upper abdomen or chest. ‘Dyspepsia’ is a term usually used only by medical practitioners, and refers to one or more of the following symptoms: chronic or recurrent epigastric pain, epigastric burning, postprandial fullness or early satiation (inability to finish a normal-sized meal). However, many also include classical symptoms of gastrooesophageal reflux (namely heartburn or acid regurgitation) as part of dyspepsia, which has caused confusion; others also include nausea or belching although these symptoms probably have a different pathophysiology (see Ch 1 and Ch 9). The most important underlying causes of dyspepsia are peptic ulcer disease (uncommon), gastro-oesophageal reflux disease (common), cancer (rare) and functional dyspepsia (most common). Despite problems with definitions, there is no doubt that dyspepsia is very common in clinical practice. It is also one of the most common gastrointestinal symptoms in the community, occurring in 25% of the adult population, although only a minority seek medical care.

Mechanisms Underlying Epigastric Pain A diverse range of physiological or pathological mechanisms can result in chronic or recurrent epigastric pain. These include (1) inflammation, not only acute, but also chronic; (2) abnormal motor activity producing distension or excessive

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Clinical gastroenterology: a practical problem-based approach

contraction of hollow organs; (3) hypersensitivity of hollow viscera in the upper gastrointestinal tract; (4) stretching of the capsules of solid viscera, for example the liver; (5) malignant invasion of nerves; and (6) organ-specific responses, such as acid and pepsin acting on nerve fibres in the base of a peptic ulcer. Based on the afferent relays or pathways for pain impulses, activated by these processes, three different types of pain can be appreciated clinically. These types can occur in isolation or together in the one individual. Visceral pain arises from nociceptors situated in the walls of the abdominal viscera, somatic pain from nociceptors situated in the parietal peritoneum and supporting tissues, and referred pain by activation of strong visceral impulses spilling over to the somatic afferent neurones in the same spinal cord segment (Ch 4). Visceral pain tends to be dull, perceived in the midline and poorly localised; it may be described in terms other than ‘pain’, and may be accompanied by symptoms of autonomic disturbance. Somatic pain, like referred pain, tends to be sharp or aching, sustained, lateralised and yet relatively poorly localised; it may be worse on movement. Referred pain tends to be sharp or aching in character, lateral or bilateral and roughly localised to the somatic dermatome. When patients describe pain as superficial, it may arise from lesions in the abdominal wall or hernial sac, but may occasionally also represent referred pain, from disease in intraabdominal or thoracic viscera.

Clinical Assessment Epigastric pain, which is considered to represent a sense of tissue damage, should be distinguished from discomfort; the latter refers to a subjective, negative feeling that does not reach the qualification or intensity level of pain. Discomfort can include a number of other symptoms including early satiation (inability to finish a normal-sized meal), postprandial fullness and nausea (Ch 9). It is useful to determine the major complaint: whether the symptoms are related to meal ingestion or not, and whether they are intermittent (recurrent or cyclical) or continuous. As with any symptom, the other specific features need to be ascertained, including the site, mode of onset, intensity, character, and precipitating and relieving factors (see Ch 7). For the purposes of this discussion, a duration of 3 months or longer is taken as indicating chronicity, which distinguishes dyspepsia from the acute symptoms present in disorders such as perforated peptic ulcer, acute cholecystitis and acute pancreatitis (Ch 4).

Subtypes of dyspepsia Patients with dyspepsia may present with distinct clusters of symptoms. One classification of dyspepsia divides patients into the following subgroups: those patients who have chronic epigastric pain (epigastric pain syndrome or ulcerlike dyspepsia), those who have postprandial symptoms such as postprandial fullness or early satiation (postprandial distress syndrome or dysmotility-like dyspepsia), those with chronic unexplained nausea (chronic idiopathic nausea) or those who have dyspeptic symptoms that do not clearly fall into either grouping (unspecified dyspepsia). However, there is considerable overlap among the subgroups in practice. Also, the groupings appear to correlate poorly with documented disorders such as peptic ulceration, and they do not correlate well with specific pathophysiological disturbances such as delayed gastric emptying or H. pylori gastritis.

Overlap of dyspepsia with other syndromes Symptoms of gastro-oesophageal reflux disease (GORD) and dyspepsia often overlap. Because of the high specificity of the symptoms of GORD, however, if the patient has predominant or frequent symptoms of heartburn or acid regurgitation, as well as upper abdominal pain/ discomfort, the condition should usually be classified as symptomatic GORD, irrespective of the presence or absence of endoscopic oesophagitis (see Ch 1). Likewise, while retrosternal chest pain, and even dysphagia, may be regarded by the patient as indigestion, they should not be classified as dyspepsia. Both cardiac causes (e.g. ischaemic heart disease) and non-cardiac causes (e.g. GORD or oesophageal motility disorders) may be the underlying aetiology in these instances. Upper abdominal complaints also occur frequently in patients with features compatible with other functional gastrointestinal disorders; irritable bowel syndrome is the commonest of these disorders (see Ch 7). Despite this overlap, approximately two-thirds of patients with dyspepsia and no peptic ulcer or other organic disease report a normal bowel habit, which suggests that they constitute a distinct group from irritable bowel syndrome. ‘Aerophagia’ refers to the repetitive pattern of swallowing air and belching to relieve the sensation of abdominal distension or bloating. It is best regarded as a specific functional gastroduodenal disorder and is considered further in Ch 8.

6 Indigestion (chronic epigastric pain or meal-related discomfort)

Differential diagnosis of dyspepsia The differential diagnosis of dyspepsia is extremely wide, including diseases not only of the gastroduodenum, but also all of the other organs situated in the upper abdomen. Therefore, it is crucial to identify the precise symptoms. Leading questions are often required to elicit the complaints that trouble the patient most. Even when a detailed history has been obtained, the exact clinical diagnosis is often difficult— symptoms such as nocturnal waking, or relief or aggravation by eating often fail to discriminate between the different diagnoses. Patients with dyspepsia can, however, be subdivided into two main categories, based on the known or proposed underlying pathophysiology (Table 6.1). Thus dyspeptic symptoms may be ascribed to: 1. various organic diseases (‘organic’ dyspepsia), where there is an identified cause for the symptoms and, if the disorder is improved or eliminated, symptoms also improve; or 2. various functional disorders (‘functional’ or ‘non-ulcer’ dyspepsia), where there is no definite structural or biochemical explanation for the symptoms, although there may be an identifiable pathophysiological or microbiological aberration of uncertain relevance.

Organic dyspepsia In most instances, physical examination of the dyspeptic patient will not reveal any abnormality except deep tenderness in some cases. Evidence of weight loss, dysphagia, vomiting, bleeding, a family history of gastric or oesophageal cancer, anaemia, lymphadenopathy, or an abdominal mass indicates a greater likelihood of an organic

disorder (these are referred to as ‘alarm features’ or ‘red flags’).

Chronic Peptic Ulcer Patients with an uncomplicated peptic ulcer classically describe intermittent symptoms of ‘burning’ or ‘gnawing’ epigastric pain, which they may locate by finger point; the pain tends to be worse before meals and is relieved by taking food or antacids. Epigastric pain may waken the patient at night, commonly at about 2.00 a.m., when it is again relieved by food or antacids. The diagnosis is further strengthened if the history is clearly episodic with symptoms present for a few months at a time, followed by periods of remission (periodicity). The intensity and duration of pain vary from recurrence to recurrence, and the symptom-free intervals vary unpredictably. A history of prompt and good symptomatic relief by a course of H2-receptor antagonists or proton pump inhibitors suggests an acid-related disorder (either peptic ulcer or reflux). There may be associated symptoms of heartburn and occasional vomiting. It is usually not possible to differentiate between gastric and duodenal ulceration by symptoms alone; in gastric ulcer, however, pain relief associated with food may be short-lived and anorexia, nausea and weight loss are more prominent. Unfortunately, classical ulcer-type symptoms also do not discriminate peptic ulcer disease from functional dyspepsia. Chronic peptic ulcer, in most cases, is caused by H. pylori infection (Ch 5) or NSAIDs; an acid hypersecretory state (e.g. the Zollinger-Ellison syndrome due to a gastrin-producing tumour) is a rare but important cause to be aware of in practice.

Table 6.1 Differential diagnosis of epigastric pain or meal-related epigastric discomfort Organic ll ll ll ll ll ll ll ll ll ll ll

Chronic peptic ulcer (gastric ulcer, duodenal ulcer) Gastro-oesophageal reflux disease (with or without oesophagitis) Drugs/medications Symptomatic cholelithiasis Chronic pancreatitis Biliary (sphincter of Oddi) dyskinesia or gallbladder dyskinesia Malignancy (gastric, pancreatic, colonic) Mesenteric vascular insufficiency Metabolic causes (e.g. renal failure, hypercalcaemia, diabetes mellitus with gastroparesis) Abdominal wall pain Ischaemic heart disease (referred pain)

75

Functional dyspepsia ll

ll ll ll

Sensorimotor dysfunction of gastroduodenum: – idiopathic gastroparesis/gastric antral hypomotility; – gastric dysrhythmias; – gastric/duodenal hypersensitivity. H. pylori gastritis but no peptic ulcer Psychosocial factors: chronic life stress, anxiety, depression, somatisation Idiopathic

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Clinical gastroenterology: a practical problem-based approach

Gastric cancer A short history of new onset dyspepsia occurring in a patient over the age of 55 years should raise the suspicion of gastric cancer (Ch 17). Symptoms of pain or discomfort on a daily basis, together with early satiety, increase the probability. Weight loss, anorexia and vomiting are common symptoms, especially when the malignancy is advanced (hence not curable)—these are the alarm features or red flag symptoms. Dysphagia can occur with tumours arising from the cardia or distal oesophagus.

Chronic pancreatitis and pancreatic cancer Chronic pancreatitis is a less common condition that presents as deep, boring upper abdominal pain, often radiating through to the back. There may be other symptoms of pancreatic insufficiency, for example steatorrhoea and possibly diabetes mellitus. Similar symptoms of shorter duration, often with weight loss, may be associated with carcinoma of the pancreas, although this condition can typically present late when the patient is cachectic and jaundiced (Ch 23).

Cholelithiasis ‘Biliary colic’ is associated with the sudden onset of severe or very severe epigastric pain that may pass through or around to the back (Ch 4). Typically there are episodes of pain that occur unpredictably, usually with associated nausea and vomiting. With inflammation of the gall bladder, the pain may shift to the right upper quadrant and become ‘peritoneal’ in type. With biliary colic, movement does not aggravate the pain. The pain is usually not ‘colicky’ but sustained, albeit varying in intensity. Symptoms may be induced by a fatty meal. In the absence of typical biliary pain there appears to be no association between the presence of gallstones in the gall bladder and dyspepsia. If a gallstone enters the common bile duct (choledocholithiasis), there may be associated features of intermittent jaundice, dark urine, pale stools, or with sepsis episodic fever and rigors (see Ch 23).

Other causes Drugs are an important cause of dyspepsia, especially in the elderly. All NSAIDs may be associated with dyspepsia, whether or not there is chronic peptic ulcer. NSAIDs that are cyclooxygenase-2 (COX-2) selective inhibitors can also cause dyspepsia, but ulcers are rare unless aspirin

is being taken concurrently. Traditional NSAIDs inhibit cyclo-oxygenase-1 (COX-1) (involved in gastric cytoprotection) and -2 (expressed with inflammation). A number of antibiotics, digoxin, theophylline, and potassium or iron tablets can induce upper abdominal discomfort. Intestinal ischaemia can sometimes cause dyspepsia. Intestinal or mesenteric angina causes the classical triad of upper abdominal pain induced by eating, a fear of eating (sitophobia), and weight loss (Ch 7). Metabolic causes such as renal failure, hypercalcaemia or thyroid disease can at times present with dyspepsia. Dyspepsia can occur in patients with longstanding diabetes mellitus who have autonomic neuropathy, gastroparesis or diabetic radiculopathy. Other metabolic causes are discussed in Chapter 7. Referred pain from the chest or back may also occasionally cause chronic upper abdominal pain. The abdominal wall is often a source of unexplained upper abdominal pain or discomfort, arising from nerve entrapment or from a previous abdominal wall surgical scar. On physical examination, there is localised tenderness that is not abolished when the abdominal wall muscles are tensed (Carnett's test).

Functional or non-ulcer dyspepsia This category represents the most common cause of dyspepsia in both patient and community populations. The term ‘functional’ implies a true disturbance of function, or an awareness of disturbed function, in the upper abdomen; it is inappropriate to use the term to denote a psychological or psychosomatic disorder. At present, patients with a past history of documented chronic peptic ulcer disease or evidence of pathological gastro-oesophageal reflux should not be classified as having functional dyspepsia.

Management of Dyspepsia A careful history is important to document the symptoms; in particular gastro-oesophageal reflux disease and biliary disease can in most cases be readily suspected from the history and relevant further investigations and treatment undertaken. Otherwise, if there are no symptoms or signs to indicate a higher probability of organic disease, and the patient is under 55 years of age and is not taking regular aspirin or other NSAIDs, then immediate investigation is not warranted (Fig 6.1).

6 Indigestion (chronic epigastric pain or meal-related discomfort)

Dyspepsia (epigastric pain, postprandial fullness, early satiety) Clinical evaluation History Physical examination

Age > 55 years

No clinical evidence of organic disease

or

and

Evidence of organic disease (alarm symptoms or signs, or abnormal blood tests)

Age ≤ 55 years

or

Previously fully investigated (no ulcer or other organic disease diagnosed)

or

Chronic course anticipated or Patient has a strong fear of chronic disease

Endoscopy

Empiric therapy

Reassure and explain Remove any precipitating factors Normal

Other investigations as indicate by clinical evaluation

Organic disease (oesophagitis, peptic ulcer, cancer) Treat appropriately

Exclude irritable bowel syndrome and gastroesophageal reflux disease by history

Treat appropriately

Proton pump inhibitor or H. pylori test and treat

Functional dyspepsia Resolution of symptoms Treat appropriately

Figure 6.1  Management of dyspepsia.

Symptoms not improved in 4–8 weeks

Follow up

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Clinical gastroenterology: a practical problem-based approach

Empiric therapy Depending on the age of the patient, and the duration and severity of symptoms, reassurance regarding the low probability of serious disease, and a full explanation of the mechanisms currently believed to underlie the symptoms may be associated with an improvement in symptoms. A short-term empiric trial of a proton pump inhibitor (or an H2-blocker) for 4–8 weeks is the current standard of care, but patients must be followed up. An alternative approach is to test for H. pylori infection (e.g. a urea breath test) and treat positive cases with specific antibiotic therapy (Ch 5). In late middle-age and elderly patients, the threshold for investigation should be much lower, as organic diseases occur more frequently in this age group. When to investigate further If symptoms are not fully relieved after 8 weeks of empiric drug treatment, investigation of the upper gastrointestinal tract, preferably by endoscopy, is advisable. The aim of endoscopy is to definitely exclude peptic ulcer, reflux oesophagitis, and malignancy. Endoscopy is superior to the doublecontrast barium meal and is now considered the ‘gold standard’ because it allows direct visualisation and biopsy of the oesophagus, stomach and duodenum. Ideally, endoscopy should be performed during a symptomatic phase when the patient is not on potent antisecretory drugs, to help ensure an active ulcer is not missed. All gastric ulcers should be biopsied to exclude gastric cancer (unless there is a strong contraindication, such as active bleeding, use of anticoagulants or known portal hypertension). H. pylori can be accurately detected by histological examination of gastric mucosal biopsies, or by subjecting such biopsies to rapid urease testing. Screening blood tests, such as full blood count and blood film for anaemia, and biochemical testing for glucose intolerance and abnormal liver function are recommended, although these tests generally have a low yield. Urea and electrolyte estimation should be performed in patients with persistent vomiting, as uraemia may present with dyspepsia and vomiting. Hypercalcaemia, usually due to hyperparathyroidism, is an uncommon cause of nausea but may be associated with duodenal ulcer. Serum amylase or lipase levels are usually not helpful in chronic pancreatitis except following an acute exacerbation. Upper abdominal ultrasonography in the absence of symptoms or biochemical test results suggestive of biliary tract or pancreatic disease is not recommended as a routine screening test because outpatient studies

have shown that most dyspeptic patients have no detectable or relevant abnormality. However, if the latter disorders are suspected, ultrasonography should be performed early in the course of investigations. Do not forget that gallstones may be incidentally found on ultrasonography; in the absence of typical biliary pain or alarm features, these can usually be ignored. Barium studies can be useful, especially if mechanical obstruction of the proximal small bowel is suspected. Psychiatric disorders, such as depression, anxiety, somatoform disorder and eating disorders, should be considered in patients with chronic refractory symptoms. The benefit of scintigraphic gastric-emptying studies in routine clinical practice is not established. However, in selected cases with certain symptoms (e.g. severe postprandial fullness or recurrent vomiting) and normal endoscopic findings, documentation of the presence and extent of delayed emptying or abnormal handling of solids (especially with regard to the lag phase and rates of emptying) can improve diagnostic precision and indicate lines of further therapy. A 4-hour gastric emptying test is the preferred technique. Gastric manometric and myoelectrical assessments of gastric and proximal small bowel motility are specialised techniques available in some centres and, at the present time, remain indicated for advanced investigation of severe or unusual cases only. If gastroparesis is identified, systemic disorders such as diabetes mellitus, thyroid disease, and connective tissue diseases, as well as drug side effects and small bowel obstruction, should be excluded. The demonstration of gastroparesis also indicates that particular therapies may need to be pursued more vigorously. Small, frequent low-fat meals combined with a prokinetic (e.g. domperidone) plus, if nausea is prominent, an antiemetic can be helpful in the setting of gastroparesis. Gastric electrical stimulation has been reported to improve symptoms of vomiting without improvement in gastric emptying rate in severe cases, although convincing controlled trials are lacking.

Diseases Associated With Epigastric Pain or Discomfort Chronic peptic ulcer Aetiology and pathophysiology Chronic peptic ulcer can be defined as a break in the mucosa of greater than 5 mm with depth (Figs 6.2 and 6.3). An erosion, on the other hand,

6 Indigestion (chronic epigastric pain or meal-related discomfort)

Figure 6.2  Chronic duodenal ulcer (anterior wall) with clot on the base (at endoscopy). This was caused by H. pylori.

Figure 6.3  Chronic gastric ulcer with no signs of recent haemorrhage (at endoscopy). This was caused by aspirin.

is smaller, lacks depth and is not associated with symptoms. In the general population, a chronic ulcer can be demonstrated in about 20% of patients with dyspepsia who are investigated; the risk is higher in the elderly. Gastric acid secretion (from the parietal cells in the body and fundus of the stomach) is controlled by several interrelated factors in health, but the main stimulus is food. The cephalic phase

79

comprises the acid response to the anticipation of food, or the sight, smell or taste of food, and is mediated by the vagus nerve. The gastric phase comprises acid secretion in response to food (primarily amino acids and amines) via gastrin release from the antral G cells. The intestinal phase occurs in response to food (especially protein) reaching the small bowel. Coffee and alcohol also stimulate acid secretion. A negative feedback loop operates when the gastric pH drops below 3, causing gastrin release to be strongly inhibited, by release of somatostatin from antral D cells. The three main causes of chronic ulcer are H. pylori gastritis, NSAIDs and gastrinoma (the Zollinger-Ellison syndrome). H. pylori is a chronic infection of the stomach that causes chronic histological gastritis and most peptic ulcer disease (see Ch 5). Traditional NSAIDs inhibit the enzyme cyclooxygenase and hence reduce the production of prostaglandins such as PGE2 and PGI2, impairing gastrointestinal mucosal defence. NSAIDs (whether given orally, rectally or systemically) induce subepithelial haemorrhage and erosions in the stomach and/or duodenum in about twothirds of patients. Up to 20% of NSAID users develop chronic gastric ulceration, while perhaps 5–10% develop duodenal ulcers. Chronic NSAID users are at a three- to six-times increased risk of serious gastric and duodenal ulcer complications (bleeding, perforation or death) compared with non-users. Unfortunately, complications are the presenting feature rather than dyspepsia in more than half the patients who develop NSAIDrelated peptic ulceration. NSAID ulcers and ulcer complications occur more commonly in the elderly (those over 60 years of age), with high doses, in those with a prior history of peptic ulcer or bleeding, with multiple NSAID use or steroids, with concurrent use of anticoagulants, and in the presence of other serious illness. Those with H. pylori infection and exposure to NSAIDs may be at higher risk of ulcer than those with just one of these factors, but this is controversial. NSAIDs may also cause small bowel disease (ulceration and perforation) and colonic disease (stricture and colitis). COX-2-selective NSAIDs are associated with significantly less peptic ulceration. Treatment All cases of chronic peptic ulceration associated with H. pylori should be treated with combination antibacterial therapy plus antisecretory therapy (Ch 5). Antisecretory therapy is usually then

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Clinical gastroenterology: a practical problem-based approach

continued for a further 4–6 weeks to ensure ulcer healing although this may not be absolutely necessary. With this type of therapy, successful cure of the infection in over 70% of patients and resolution of the ulcer can be achieved. As well as efficacy, the choice of regimen is dependent on other factors, in particular compliance with the drugs, local resistance patterns of H. pylori, and costs of the therapy. It is recommended that cure of infection be checked by a breath test or stool test (or endoscopic biopsy) at least 1 month after ceasing therapy. If initial therapy fails for H. pylori, a repeat course with different agents can be tried. Gastric ulcers need to be followed up by endoscopy to ensure healing and exclude malignancy. If treatment regimens to eradicate H. pylori fail, then long-term proton pump inhibitor maintenance therapy can be utilised. Ulcers associated with NSAID use are ideally treated by stopping the NSAID—at least while ulcer healing therapy is given. In this situation, any conventional ulcer healing regimen can be employed, such as a proton pump inhibitor, as single therapy. If H. pylori is present, it should also be treated. If traditional NSAID therapy is required long term, the lowest dose of a short-acting and less toxic NSAID (e.g. ibuprofen) should be prescribed. Enteric-coated or rectal NSAIDs do not significantly reduce the risk of ulcer. Co-prescription with a proton pump inhibitor or a prostaglandin analogue such as misoprostol is a reasonable option, and is more effective than prophylaxis with H2-receptor antagonists (which at standard dose reduce duodenal but not gastric ulcer recurrence from NSAIDs). Misoprostol has been shown to reduce the occurrence of gastric and duodenal ulcer by more than 60% over the subsequent months, as well as ulcer complications. Surgery is now rarely indicated for control of peptic ulcer disease as cure is attainable (Fig 6.4). When surgery is required, the surgery is directed at treating the complication (e.g. oversewing the perforation or underrunning the bleeding ulcer). Rarely, a gastric resection will be required if a gastric ulcer is resistant to healing and malignancy cannot be confidently excluded. The ulcer diathesis can be treated by conventional therapy (listed above) after the patient has recovered from the operation. However, many patients in the past underwent gastric surgery for this disease. The complications that may arise in these cases are summarised in Box 6.1.

Zollinger-Ellison (ZE)/syndrome The Zollinger-Ellison syndrome refers to a gastrinoma causing gastric acid hypersecretion and, frequently, peptic ulceration. The tumours producing this syndrome may be found in the pancreas (85%) or the duodenal wall. Twothirds are malignant with metastases. Ulcers in this syndrome may be single or multiple. The increased gastrin may cause gastric hypertrophy with prominent folds. Diarrhoea with or without steatorrhoea occurs in one-third of cases (because the high acid level damages small bowel mucosa, inactivates pancreatic lipase and deconjugates bile salts); in 10% of cases, diarrhoea is the only presenting symptom. The Zollinger-Ellison syndrome can also occur as part of the multipleendocrine neoplasia (MEN) type I syndrome where there is hyperplasia, adenoma or carcinoma of the pancreatic islets, parathyroid and pituitary. This is an autosomal-dominant condition, so there may be a family history of ulcer. In addition to the clinical features found with a gastrinoma, there is usually hypercalcaemia, secondary to parathyroid disease (Ch 26). Serum gastrin levels should be checked to screen for this diagnosis if patients have multiple or refractory ulcers, enlarged gastric folds or a dilated duodenum, an ulcer plus diarrhoea or steatorrhoea, or hypercalcaemia, associated with ulcer disease. A serum gastrin concentration greater than 1000 μg/ mL in patients producing gastric acid (which can be measured by testing the pH of gastric juice at endoscopy or by formal gastric secretory function testing) is virtually diagnostic. Conditions such as pernicious anaemia or postvagotomy surgery can cause a high serum gastrin level, but gastric acid secretion is low. In difficult cases, a secretin test is helpful; gastrinomas cause a paradoxical rise in gastrin in response to a secretin bolus of greater than 100 μg/mL above baseline. Once a diagnosis of Zollinger-Ellison syndrome is made, consideration should be given to whether there is evidence of MEN I (e.g. hyperparathyroidism). Thereafter, evidence of metastatic spread (over 60% are malignant) and tumour localisation is sought by a contrast computed tomography (CT) (5 mm sections). Endoscopic ultrasound may identify small tumours. Imaging may miss up to 30% of tumours in this syndrome. Even if no tumour is found by scanning, it can usually be located by surgery. The tumour should be resected where feasible (liver metastases may also be amenable to resection); otherwise, patients are managed with high dose proton (acid) pump inhibitors to control gastric acid. Approximately 50% of patients who

6 Indigestion (chronic epigastric pain or meal-related discomfort)

81

Bilary duct

Intact stomach Ligament of Treitz

Billroth-II (B-II) Indication: gastric carcinoma peptic ulcer Result: prevention of recurrent ulcer

Billroth-I (B-I) Indication: gastric carcinoma, peptic ulcer Result: prevention of recurrent ulcer “dumping”

Roux-en-Y Indication: disordered gastric emptying after vagotomy duodenal gastric reflux with bilious vomiting after B-I or B-II Result: prevention of bilious vomiting prevention of “dumping” occasional stasis in Roux loop

Figure 6.4  Schematic overview of Billroth-I and B-II partial gastrectomy and Roux-en-Y reconstruction with their indications and their consequences for gastric emptying. Based on Smout AJPM, Akkermans LMA, Reud K. Normal and Disturbed Motility of the Gastrointestinal Tract. Petersfield: Wrightson Biomedical Publishing; 1992, with permission.

cannot be completely resected die from tumour spread in 10 years; newer chemotherapy regimens may reduce disease progression.

Functional (non-ulcer) dyspepsia One in six people report chronic symptoms of dyspepsia if asked, and the majority with no alarm features (e.g. weight loss and vomiting) have no

obvious organic cause found at investigation, leading to a working diagnosis of functional dyspepsia. Pathophysiology Although the pathogenesis of functional dyspepsia remains unknown, a number of physiological factors appear to be associated with the disorder. Most attention has been directed

82

Clinical gastroenterology: a practical problem-based approach Box 6.1  Complications of peptic ulcer surgery ll

ll

ll

ll

ll

ll

ll

Recurrent ulceration. Consider incomplete vagotomy, gastrinoma, retained antrum. Dumping syndrome. Early—30 min after eating due to hyperosmolar contents entering the small bowel. This results in tachycardia, sweating and collapse. Late—90–180 min after eating due to hypoglycaemia (reactive). Malabsorption and diarrhoea. Mild steatorrhoea due to rapid intestinal transit after gastric resection. If the stool fat is unexpectedly high, consider bacterial overgrowth, coeliac disease, gastrojejunocolic fistula or gastroileostomy, and Zollinger-Ellison syndrome. Bile reflux gastritis after partial gastrectomy. This results in early satiety, vomiting and distension. Gastric remnant carcinoma. After partial gastrectomy: risk increases after 15 years. Retained antrum after Billroth-II. This results in gastric hypersecretion. Afferent loop syndrome after Billroth-II. This results in pain relieved by vomiting, bloating and bacterial overgrowth.

towards assessment of upper gut sensorimotor function. In health, the main motor functions of the stomach are temporarily storing ingested food during the process of breakdown of solids, emptying chyme appropriately into the small bowel, and emptying the indigestible solids remaining in the stomach after a meal. During ingestion of a meal, vagally-mediated receptive relaxation of the proximal stomach occurs in response to swallowing. This relaxation prepares the proximal stomach to receive oesophageal contents, and is followed by gastric accommodation, whereby the proximal stomach progressively relaxes to accommodate increasing volumes, while maintaining a relatively constant intragastric pressure. Solid emptying is largely controlled by antral and pyloric motor activity. Phasic contractions (the migrating motor complex) sweep from the midstomach to the pylorus, at a frequency of three per minute, mixing and grinding the food until particles are approximately 1 mm in size. Emptying of liquids is controlled by coordinated motor activity in the fundus, body and antrum. Proximal gastric tone appears to be of particular importance in liquid emptying. The pylorus is an important functional component

of the gastroduodenal region and also regulates solid and liquid emptying. The rate of gastric emptying is regulated by additional factors such as the osmolality and fat content of the meal, the amount of gastric acid secreted and duodenal motility. Liquids empty more rapidly than solids; the time taken for half the gastric contents to empty after ingestion of a standard mixed meal is about 90 minutes for the solid phase, and about 30 minutes for the liquid phase. Delayed gastric emptying, predominantly for solids, but also for liquids, is observed in 25% of patients with functional dyspepsia. Fast gastric emptying occurs uncommonly (10%). Abnormalities in intragastric distribution of the meal can also be documented. Postprandial antral hypomotility is accepted as the cause of delayed gastric emptying in most cases, but alterations in duodenal motility may also play a role. The underlying cause of such motility abnormalities is unknown. The presence of gastric stasis, however, correlates poorly with symptoms in individual patients and, thus, its importance in the syndrome of functional dyspepsia is not established. Failure of the fundus to relax normally after meal ingestion occurs in up to 40% of patients with functional dyspepsia. This can cause the symptom of early satiety in some of these patients. The mechanical accommodation of the stomach to gastric balloon distension (compliance), however, does not appear to be different between patients and control subjects. At least some cases of functional dyspepsia appear to be associated with an enhanced gastroduodenal sensitivity to distension (Fig 6.5). The relationship between this phenomenon and the alterations in upper gut motility described above is not clear, but it is likely that in some cases these may be a consequence of altered visceral afferent function. Gastric volumes required to induce feelings of distension and pain have been shown to be significantly lower in patients with functional dyspepsia than in control subjects. H. pylori gastritis histologically is found in 30% of dyspeptic patients with no evidence of peptic ulcer disease. However, H. pylori gastritis is common in totally asymptomatic subjects. The presence of the gastritis does not appear to have an important influence on the prevalence or type of gastric motor dysfunction. Cure of infection results in symptomatic improvement in a minority long term (with a 10% benefit over placebo). Although acute stress can alter gastrointestinal function and induce symptoms in healthy subjects, the role of life-event stress in the pathogenesis of

6 Indigestion (chronic epigastric pain or meal-related discomfort)

6

Abdominal discomfort (score)

*

FUNCTIONAL DYSPEPSIA

*

HEALTH

5

83

4

*

*

*

3 2 1

0

MDP

+2

+4 +6 +8 Intragastric pressure (mmHg)

+10

+12

+14

Figure 6.5  Heightened gastric sensitivity to balloon distension of the stomach in patients with functional dyspepsia versus control subjects. Note the onset of symptoms at lower pressures in patients with functional dyspepsia. MDP = minimal distending pressure. Based on data from Mearin F, Culcala M, Azpiroz F, et al. The origin of symptoms on the brain-gut axis in functional dyspepsial. Gastroenterology 1991; 101:999–1006, with permission from the American Gastroenterological Society.

chronic functional dyspepsia remains controversial. It appears, however, that life events that are highly threatening or which lead to frustration of goals are associated with functional dyspepsia. It is important to note that no characteristic personality profile is demonstrable in patients with functional dyspepsia. Anxiety but not depression is linked to functional dyspepsia. Psychosocial disturbances such as neuroticism, anxiety and depression probably also influence the decision to seek healthcare. Treatment The approach to treatment is outlined in Box 6.2 and Figure 6.1. Once a positive diagnosis has been made, management of functional dyspepsia is based on reassurance regarding the absence of serious disease, and an explanation of the possible factors producing symptoms. Patients should be advised to avoid specific foods that aggravate their symptoms (such as coffee and alcohol) and also to avoid any medications that may be provoking symptoms. A reduced-fat diet may be beneficial, as fat delays gastric motor function more profoundly than other dietary constituents. For postprandial symptoms, a decrease in meal size with more frequent meals should be tried. The presence of anxiety, depression and chronic stress should be explored and can be addressed from the outset

with simple forms of counselling; untreated anxiety or depression may impair the response to other forms of therapy. An explanation of the ways in which stress can affect upper gut function is often valuable, and is used to emphasise the recurrent or episodic nature of the symptoms. If the dyspeptic symptoms are longstanding, a psychological precipitant (e.g. a stressful life event or fear of organic disease)—rather than the specific gastrointestinal symptoms themselves— may account for the current visit. Recognition of this may avoid multiple visits and extensive gastrointestinal investigations. If symptoms are affecting quality of life significantly, drug therapy should be considered. Medical therapy can usually provide at least partial relief of symptoms; this may be related to the high placebo treatment effect (up to 60% in functional dyspepsia). All H. pylori-positive patients with functional dyspepsia may be offered eradication therapy for dyspeptic symptoms, but many will not benefit. Trials with antisecretory drugs, particularly the proton pump inhibitors, have indicated that these medications are modestly superior to placebo in the therapy of functional dyspepsia; patients with epigastric pain may be more likely to respond. Thus, it is reasonable to suggest that these medications should be first-line medications.

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Clinical gastroenterology: a practical problem-based approach Box 6.2  Key features of functional dyspepsia Clinical features Upper abdominal symptoms (Rome III ­criteria) ll Chronic or recurrent (3 months or more) ll Must be one or more of early satiety, postprandial fullness, epigastric pain, epigastric burning ll No clinical, biochemical, endoscopic or ultrasound evidence of organic disease likely to explain symptoms (not all these tests are necessary to make the diagnosis) Subtypes Epigastric pain syndrome (pain or burning in epigastrium) postprandial distress syndrome (early satiety or postprandial fullness) Management 1. Make a positive clinical diagnosis based on the history and physical examination, and a negative upper endoscopy. 2. Minimise invasive investigations and avoid giving ‘mixed messages’; do not perform repeated testing without substantial indication. 3. Determine the patient's agenda; ask why the patient with chronic symptoms has presented now. 4. Provide education and firm reassurance. 5. Try dietary modification (e.g. low-fat diet and small more frequent meals). 6. Set realistic treatment goals and centre therapy on adjustment to illness and patientbased responsibility for care. 7. Prescribe drugs sparingly targeting the symptoms of most concern to the patient; remember the placebo response: l short-term trial of a proton pump inhibitor or prokinetic agent (e.g. domperidone); l consider combination drug therapy or antidepressants in resistant cases. 8. Consider behavioural treatments or psychotherapy for moderate to severe cases. 9. Organise a continuing care strategy.

If there is no improvement, a prokinetic drug (e.g. domperidone, 10 mg, three times per day) can be tried. The prokinetic drugs have been shown to be effective in improving symptoms in functional dyspepsia. The original agent in this class was metoclopramide, and although early studies suggested symptomatic improvement when compared with placebo, recent assessments are not available. Moreover, the side-effect profile,

especially extrapyramidal reactions, is problematic. Domperidone, a dopamine-receptor antagonist with fewer side-effects than metoclopramide, has been shown to be more effective than placebo in relieving symptoms, although the data in functional dyspepsia are limited. In general, long-term drug treatment should be avoided in most patients with functional dyspepsia. For those patients with frequent relapses, short intermittent treatment courses (for example, 1–2 weeks) may be considered when no other management is successful and symptoms are significantly affecting the patient's quality of life. Antidepressants may have a role in difficult cases, although few studies have addressed the use of psychotropics in functional dyspepsia. Newer medications, such as drugs that modify visceral afferent function, may allow a wider choice of therapeutic agents in the future.

Chronic pancreatitis The most common cause of chronic pancreatitis is alcohol (Box 6.3). Alcohol leads to hypersecretion of a proteinaceous fluid that can precipitate first in the small pancreatic ducts and later in the main pancreatic ducts. These deposits block the ducts and cause dilatation of the ducteals; later, inflammatory infiltrates appear. It is unclear whether or not the normal pancreas secretes a specific protein that inhibits calcium carbonate stone formation (stone-inhibitor protein). Smoking increases the risk of chronic pancreatitis. Clinical presentation While patients with chronic pancreatitis may present with episodes of acute pancreatitis (Ch 4), the common mode of presentation is intermittent abdominal pain, usually in the epigastric region after eating (15–30 minutes) and radiating to the back. It may improve by the patient sitting upright and leaning forward. The pain may also occur in the right or left upper quadrant. It is typically severe and is unrelieved by eating or antacids. Alcohol and fatty meals may make the pain worse. It tends to become more continuous with disease progression. There may be diarrhoea and steatorrhoea as well as weight loss due to pancreatic insufficiency (Ch 14). Commonly these patients have a history of high analgesic use and abuse. The clinical problem may be very difficult to evaluate if the patient has become narcotic-dependent. Thus, it may be hard to be sure which of the symptoms are due to chronic pancreatitis.

6 Indigestion (chronic epigastric pain or meal-related discomfort) Box 6.3  Causes of chronic pancreatitis ll ll ll ll ll ll ll ll ll ll ll

ll

Chronic alcoholism Idiopathic Hypertriglyceridaemia Hypercalcaemia Trauma Hereditary (autosomal-dominant) Cystic fibrosis Tropical (nutritional) Haemochromatosis Prolonged parental hyperalimentation Obstruction: – benign, e.g. pancreas divisum with obstruction of the accessory ampulla; – cancer, e.g. of the ampulla or duct (short history). Autoimmune (may be misdiagnosed as pancreatic cancer)

On physical examination, there may be signs of wasting and malnutrition. Rarely, jaundice is present because of obstruction of the common bile duct. Patients may also have evidence of diabetes mellitus with advanced disease. Other complications of chronic pancreatitis include the development of pseudocysts, which may become infected (Ch 4). Pancreatic ascites can also occur (Ch 20). Clinical evidence of vitamin deficiency is rare (fat-soluble vitamins [A, D, E and K] or B12). Diagnosis Levels of amylase and lipase are unhelpful. A plain abdominal x-ray examination may show pancreatic calcification (in 30% of cases), which is virtually diagnostic. An abdominal CT scan will detect pancreatic calcification more often. A CT or ultrasound scan may also show a shrunken pancreas with dilatation of the main pancreatic duct that is a pointer to the diagnosis. Magnetic resonance cholangiopancreatography (MRCP) is the next test to perform if the diagnosis of chronic pancreatitis is suspected but other tests have been unhelpful. This provides information on the morphology of the ducts. An alternative is endoscopic retrograde cholangiopancreatography (ERCP), but complications (2%) include acute pancreatitis, sepsis and cholangitis. Endoscopic ultrasound is an alternative and may be as useful as ERCP. If patients have diarrhoea or suspected steatorrhoea, a 3-day faecal fat estimation should

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be obtained. A faecal fat excretion of over 40 g per day is usually only seen with pancreatic steatorrhoea (Ch 14). Cystic fibrosis needs to be considered in children or young adults in such cases and a sweat electrolyte test should be obtained. It is also important to check serum calcium and triglyceride levels to exclude these rare causes of chronic pancreatitis. Non-invasive tests of pancreatic function, such as the bentiromide and the pancreolauryl tests, are useful in patients with moderate or severe chronic pancreatitis but both false-positive and false-negative results do occur. Intubation studies, such as the secretin test (which stimulates pancreatic exocrine secretion that is measured by obtaining a duodenal aspirate), are not widely available. The differential diagnosis must include pancreatic cancer, as well as rare diseases such as autoimmune pancreatitis and pancreatic endocrine tumours. Treatment Control of abdominal pain is the main problem in most patients. Narcotic addiction needs to be avoided. Total alcohol absence is essential as this may reduce the pain. Oral pancreatic enzyme preparations reduce pain (because they reduce cholecystokinin secretion, leading to a negative feedback on the pancreas, putting it at rest). Large doses are required with meals. Pancreatic steatorrhoea is also treated with pancreatic enzyme replacement. The usual dose is six to eight tablets, or three capsules of enteric-coated pancreases. One or two tablets should be taken on starting the meal, and during and just after the meal. Small, low-fat meals should be prescribed. If this fails, antisecretory therapy to reduce gastric acid secretion (acid inactivates the enzymes) can be helpful. Pain control may be achieved with a short course of narcotics plus a low-dose tricyclic antidepressant and a NSAID long term. Hospitalisation keeping the patient nil by mouth may be needed until pain control is achieved. The usefulness of octreotide is uncertain, but may be worth a trial. In difficult cases, relief of pancreatic duct obstruction with endoscopic removal of stones or extracorporeal lithotripsy may sometimes be helpful. Temporary insertion of a stent into a proximally obstructed pancreatic duct may be of value. If a pseudocyst is present in a patient with pain, it may respond to drainage, which can be done radiologically, endoscopically or occasionally by surgery. Coeliac axis nerve blocks are worth a trial,

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and bilateral thoracoscopic splanchnicectomy has shown promise. Surgery (e.g. a lateral pancreaticojejunostomy [Puestow] procedure) can alleviate pain when the pancreatic duct or system is dilated. Another approach is lateral pancreaticojejunostomy with saucerisation and drainage of the head of the pancreas (Frey's operation). This procedure is also effective in patients without a dilated main pancreatic duct. Focal disease in the head or tail of the pancreas can be treated by a pyloruspreserving pancreaticojejunostomy or distal pancreatectomy. Resection may also be indicated if carcinoma of the pancreas cannot be excluded; this complication occurs in 5–10% of patients with chronic pancreatitis. Surgery has approximately a 70–90% rate of success.

Key Points ll

ll

ll

ll

ll

ll

ll

The terms ‘indigestion’ and ‘dyspepsia’ describe symptoms related to the upper abdomen. ‘Dyspepsia’ is a term usually used only by medical practitioners, and refers to one or more of chronic or recurrent epigastric pain, epigastric burning, postprandial fullness or early satiation (inability to finish a normalsized meal). Dyspeptic symptoms may be ascribed to various organic diseases (‘organic’ dyspepsia, notably peptic ulcer, gastro-oesophageal reflux, cancer, pancreatico-biliary disease) or various functional (unexplained) disorders (‘functional’ or ‘non-ulcer’ dyspepsia). Weight loss, dysphagia, vomiting, bleeding, a family history of gastric or oesophageal cancer, anaemia, lymphadenopathy, or an abdominal mass indicates a greater likelihood of an organic disorder (these are referred to as ‘alarm features’ or ‘red flags’). Patients with red flags deserve prompt investigation to determine if they have organic dyspepsia. A short history of new onset dyspepsia occurring in a patient over the age of 55 years should raise the suspicion of gastric cancer. Prompt upper endoscopy is advisable. Uncomplicated peptic ulcer classically presents with intermittent symptoms of ‘burning’ or ‘gnawing’ epigastric pain, worse before meals, that may waken the patient from sleep at night, and be relieved by food or antacids. Chronic peptic ulcer, in most cases, is caused by Helicobacter pylori infection or NSAIDs. All NSAIDs may be associated with dyspepsia, whether or not there is chronic peptic ulcer.

ll

ll

ll

ll

ll

ll

In patients with dyspepsia and no red flags, a short-term empiric trial of a proton pump inhibitor for 4–8 weeks is the current standard of care. If symptoms are not fully relieved after 8 weeks of empiric drug treatment, investigation of the upper gastrointestinal tract, preferably by endoscopy, is advised. Zollinger-Ellison syndrome refers to a gastrinoma causing gastric acid hypersecretion and, frequently, peptic ulceration. Diarrhoea with or without steatorrhoea occurs in onethird of cases. Management of functional dyspepsia is based on reassurance regarding the absence of serious disease, and an explanation of the possible factors producing symptoms. Acid-suppressing medications or prokinetics may help relieve symptoms. All H. pylori-positive patients with functional dyspepsia may be offered eradication therapy for dyspeptic symptoms, but many will not benefit. Biliary ‘colic’ is different from peptic ulcer pain: it is of sudden onset, always severe or very severe, localised to the epigastrium or right upper quadrant, may be referred through or around to the back, and occurs very unpredictably. The pain is usually not ‘colicky’ but sustained, albeit varying in intensity. Patients with chronic pancreatitis present with intermittent abdominal pain, usually in the epigastric region after eating (15–30 min) and radiating through to the back. Diarrhoea (from steatorrhoea) may be present.

Further reading Bytzer P. Dyspepsia as an adverse effect of drugs. Best Pract Res Clin Gastroenterol 2010; 24(2):109–120. Ford AC, Moayyedi P. Managing dyspepsia. Curr Gastroenterol Rep 2009; 11:288–294. Kiltz U, Zochling J, Schmidt WE, et al. Use of NSAIDs and infection with Helicobacter pylori—what does the rheumatologist need to know? Rheumatology (Oxford) 2008; 47:1342–1347. Lacy BE, Cash BD. A 32-year-old woman with chronic abdominal pain. JAMA 2008; 299:555–565. Nair RJ, Lawler L, Miller MR. Chronic pancreatitis. Am Fam Physician 2007; 76:1679–1688. Park DH, Kim MH, Chari ST. Recent advances in autoimmune pancreatitis. Gut 2009; 58:1680–1689. Talley NJ. Dyspepsia. Gastroenterology 2003; 125: 1219–1226. Talley NJ, Choung RS. Whither dyspepsia? A historical perspective of functional dyspepsia, and concepts of pathogenesis and therapy in 2009. J Gastroenterol Hepatol 2009; 24(suppl 3):S20–S28.

6 Indigestion (chronic epigastric pain or meal-related discomfort) Talley NJ, Seon Choung R. Functional (non-ulcer) dyspepsia and gastroparesis—differentiating these conditions and practical management approaches. Rev Gastroenterol Disord 2009;9: E48–E53. Talley NJ, Vakil N, Moayyedi P. AGA technical review on the evaluation of dyspepsia. Gastroenterology 2005; 129: 1756–1780.

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Talley NJ, Walker MM, Aro P, et al. Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin Gastroenterol Hepatol 2007; 5(10):1175–1183.

7 Chronic lower abdominal pain or ­discomfort

Case A 35-year-old florist presents to her doctor because of a 6-year history of recurrent episodes of lower abdominal pain associated with an erratic bowel habit. Her symptoms have been present intermittently for this period but over the past 12 months have become more frequent and severe, with pain occurring every few weeks and lasting for 4-5 days. The pain is situated in the left iliac fossa and left hypochondrium, and has a cramping nature. The pain can cause her to cease her current activities. Her bowel habit is characterised by an alternating pattern of loose frequent motions for several days followed by a hard dry motion every few days with associated straining and a sensation of incomplete evacuation. She complains of abdominal bloating, which has become more of a problem recently, and this is often accompanied by visible abdominal distension. She has no ‘alarm’ symptoms, with her appetite and weight wellmaintained and no evidence of blood or mucus in her stools. She has no other significant medical illnesses, is a non-smoker and eats a balanced diet. There is no family history of gastrointestinal disease. Physical examination is normal with no evidence of abdominal tenderness, mass or other abnormality. Rectal examination is normal. The patient had undergone a normal colonoscopy 3 years ago when she had experienced a similar exacerbation of these symptoms. A full blood count, C-reactive protein level, and coeliac serology are normal. The doctor makes the diagnosis of irritable bowel syndrome (IBS) and explains the possible origin of symptoms to the patient. He reassures her that IBS does not lead to more serious disease, although it may have a chronic and relapsing course. The patient has tried various dietary modifications previously without any improvement in her symptoms. She has also used a number of antispasmodic agents,

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both prescription and over-the-counter, with little improvement in her symptoms. She uses an osmotic laxative during the constipation phase and this is of some benefit to her. Her doctor suggests instituting low-dose therapy with a tricyclic antidepressant agent for its potential effects as a ‘visceral analgesic’. After 1 month of this therapy, the patient has noticed a definite improvement in symptoms and is willing to continue the medication in the longer term. The doctor suggests she returns for review in a further 3 months to discuss the ongoing use of this therapy.

Introduction Chronic or recurrent lower abdominal pain is a common symptom and often represents a source of frustration and confusion to both patient and physician. Because the management of the large number of different causes of such pain can be quite specific, it is important to make a positive diagnosis of the cause of the abdominal pain. A precise history is especially important in this respect. The commonest causes are irritable bowel syndrome (IBS) and related functional bowel disorders. The separate entity of functional abdominal pain syndrome accounts for a small but important proportion of cases. These functional gastrointestinal disorders represent a substantial source of morbidity and cost to the community.

History Compared to acute abdominal pain, the origin of chronic abdominal pain is often more difficult to diagnose, because the characteristics of the pain tend to be less specific and can be difficult for patients to describe. For example, even the terms used by patients to describe chronic abdominal pain vary greatly. In particular, some refer to pain, while others to discomfort, fullness or even indigestion. Nevertheless a skilled physician can

7 Chronic lower abdominal pain or discomfort make an accurate diagnosis, or at least narrow the range of possible diagnoses, even before the physical examination. At the outset, it is important to remember that the experience of pain includes several components: (1) nociception, whereby a noxious stimulus conveys an impulsive centrally; (2) conscious perception of this sensation; (3) an affective response such as distress; and (4) a behavioural response. The essential features that need to be elicited in the history are described below.

Site, radiation and referral of pain It is helpful to ask the patient to indicate with his or her hand where the pain is felt; this is best elicited during the physical examination with the patient in the supine position. If the site of the pain is midline, the region on the abdomen can give a clue to the origin. For example, pain from the small bowel tends to be periumbilical, whereas pain from the colon tends to be perceived in the lower abdomen. The more the painful area can be localised (e.g. to a finger-tip point), the more likely it is that the site reflects the origin of the painful stimulus. Radiation of pain can be characteristic of certain organs. For example, pancreatic pain can be referred to the back, whereas radiation to the groin occurs in disorders of the ureter and testicle. However, in functional bowel disorders, such as IBS, the radiation of pain—at least pain arising from the colon—can be not only to any of these sites but also to various extraabdominal areas; it may also shift in location at various times in the one patient.

Character, intensity and duration of pain The nature or character of the pain is important to define, as certain disorders are associated with pain of a particular quality. Thus the pain of intestinal obstruction is usually cramping, whereas pain of inflammatory origin is often continuous in nature. Other descriptions can be suggested to the patient by the examiner, or the patient can be asked to relate the current pain to previous pains he or she may have experienced. The intensity or severity of pain does not always provide reliable information, as individual responses to a given painful stimulus vary: thus, while one patient may describe very severe pain, to another it may be mild in intensity. Moreover, the intensity of pain cannot differentiate between ‘functional’ and ‘organic’ disorders. Sometimes, however, associated signs and the manner in which the patient describes the pain can give clues to the intensity. Asking the patient to rate the pain on a numerical scale from one to ten can be used to compare the intensity

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of recurrent episodes of pain. The mode of onset of pain can be helpful; in general, chronic lower abdominal pain has a gradual onset, with a slow increase in intensity, when compared with the sudden onset of pain from mechanical or vascular causes. Some types of recurrent lower abdominal pain, however, can occur in discrete episodes of sudden onset. The overall duration of pain is often an important indicator of the significance of the disorder causing the pain—thus, continuous pain that has been present for months or years, in a patient not obviously unwell, is usually functional in origin. When pain is recurrent, the timing (frequency and duration, time of day) is important to establish, Pain that wakes the patient from sleep may indicate an organic disorder, although it can occur in the functional bowel syndromes. In this context, it is important to determine whether the patient actually wakes because of pain, or whether other factors initially wake the patient.

Modifying factors Factors that modify the pain are also important. Routinely, the relationship of pain to meals, bowel motions, exertion, menstruation and sexual intercourse should be obtained. A diary of the timing of pain in relation to meals and other activities can help both the patient and the doctor to determine provoking or relieving factors. Patients often state that eating exacerbates the abdominal pain, and in some instances this can provide discrimination, such as mesenteric ischaemia with ‘intestinal angina’. In general, however, the timing of pain in relation to food intake is not of great help in diagnosing disorders causing chronic lower abdominal pain. Similarly, the type of food consumed is often not of great relevance, although excessive ingestion of sugars, such as lactose present in milk products, and fructose and sorbitol present in fruits, some soft drinks and confectionery, can be important. Since fructose is poorly absorbed, large amounts can overwhelm the absorptive capacity of the small intestine, leading to bloating, abdominal discomfort, flatulence and diarrhoea. Relief of pain by bowel movements or by passing flatus is suggestive of a colonic origin for the pain; such relief is usually perceived rapidly, and is often short-lived. The associations of the pain are relevant; for example, colonic pain can be temporally associated with a change in stool form or frequency, a key feature of IBS. Episodes of pain related to menstruation raise the possibility of pelvic inflammatory disease or endometriosis; it should be remembered,

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however, that abdominal discomfort from a wide variety of causes can be aggravated premenstrually, and alterations in stool pattern are also common at this time. Musculoskeletal causes of pain can be exacerbated by different postures or exercise and relieved by rest, although once again this distinction cannot be relied upon. The patient can be asked to demonstrate the postures that can bring on the pain. Pain originating in the anterior abdominal wall is aggravated when the abdominal wall is tensed by, for example, raising the lower limbs in the supine position.

Differential Diagnosis The differential diagnosis of chronic or recurrent lower abdominal pain is wide. Traditionally, the two main categories are various ‘organic’ disorders and various ‘functional’ bowel disorders (Table 7.1). In the case of organic disorders, the cause can be identified and, if improved or eliminated, symptoms improve. In the case of functional disorders, there is no structural or biochemical explanation for the symptoms, although in some there may be an identifiable pathophysiological dysfunction present. The distinction between ‘organic’ and ‘functional’ disorders has become increasingly blurred, however, because of the finding of low-grade intestinal inflammation in some cases of IBS.

‘Organic’ disorders Diverticular disease Uncomplicated diverticular disease of the colon is very common, and is not normally associated with symptoms. A proportion of individuals with diverticulosis, however, experience recurrent lower abdominal pain, predominantly in the left iliac fossa, and occasionally a change in bowel habit. These symptoms are similar to, and indeed can be indistinguishable from, IBS, and it is probable that the symptoms in these instances are due to the presence of concomitant irritable bowel. In severe diverticular disease, in contrast, the colonic lumen can become distorted and narrowed in the sigmoid colon; symptoms of partial bowel obstruction may then develop and produce recurrent lower abdominal, often left iliac fossa, pain. Diverticulitis is discussed in Chapter 4. Lactase deficiency Lactose ingestion in lactase-deficient subjects can be associated with recurrent lower abdominal discomfort and diarrhoea. The prevalence of

Table 7.1  Differential diagnosis of chronic or recurrent lower abdominal pain ‘Organic’ disorders

‘Functional’ disorders

Common Common Diverticulitis, diverticu- ll IBS lar stricture ll Functional abdominal ll Lactase deficiency bloating ll Gynaecological disease Uncommon ll Intestinal obstruction Functional abdominal (partial, subacute) pain syndrome ll Crohn's disease (especially small bowel) Uncommon ll Chronic intestinal pseudo-obstruction ll Mesenteric ischaemia ll Malignancy (e.g. ovarian carcinoma) ll Abdominal wall pain ll Spinal disease ll Testicular disease ll Metabolic disease, e.g. diabetes mellitus, familial Mediterranean fever, C1 esterase deficiency (angioneurotic oedema), porphyria, lead poisoning, tabes dorsalis, renal failure ll

lactose intolerance varies widely according to race, for example 60% in Chinese people, 40% in eastern Mediterranean people and 10% in northwest Europeans. Affected individuals usually need to ingest a significant amount of lactose before noting symptoms. Even then, the symptoms may be more associated with concomitant IBS than lactose intolerance, as they do not necessarily improve with lactose restriction.

Gynaecological disorders Endometriosis Endometriosis may cause recurrent abdominal pain and bowel symptoms in women. Usually patients are under the age of 45 years and two-thirds are nulliparous. Symptoms may sometimes occur with the period (because the endometrial implants are influenced by hormonal changes; at termination of the menstrual cycle, endometrial engorgement and sloughing occurs). However, in many cases symptoms do not coincide with periods. Common symptoms include bloating, abdominal or pelvic pain, constipation or diarrhoea, proctalgia and lower back pain; indeed, irrespective of any bowel involvement, gastrointestinal symptoms have been shown to be nearly as frequent as gynaecological

7 Chronic lower abdominal pain or discomfort symptoms. Thus the gynaecological symptoms usually co-exist with the gastrointestinal symptoms (a clinical clue) and can include menstrual irregularity, dysmenorrhoea and dyspareunia. There may also be a history of infertility. Rectal examination may sometimes detect tender nodules or irregular induration. At sigmoidoscopy or colonoscopy, there may occasionally be findings of a submucosal mass, usually with overlying intact mucosa; biopsy may not be diagnostic because endometriosis is usually in the deeper layers. Barium studies may provide useful indirect evidence of the disease. Laparoscopy, the main diagnostic tool, allows direct visualisation and biopsy of serosal lesions, and also ablative therapy. Recurrence after surgical treatment is common. Hormonal therapy (usually oral contraceptives) may be useful in mild disease. Drugs such as danazol, a synthetic androgen, and antigonadotropins, such as gestrinone, are effective, but have a greater incidence of side effects than hormonal therapy. In cases with complicated bowel disease, surgical resection may be required. In incapacitating cases, a total abdominal hysterectomy and oophorectomy may be considered. Pelvic inflammatory disease Pelvic inflammatory disease, reflecting ascending infection of the endometrium or fallopian tubes, can be due to a number of pathogens including Neisseria gonorrhoeae and Chlamydia trachomatis; however, vaginal flora have also been implicated. With salpingitis, midline lower abdominal pain may be associated with a mucopurulent vaginal discharge and occasionally vaginal bleeding. Right iliac fossa pain and tenderness from periappendicitis can occur. Pelvic tenderness on bimanual pelvic examination is typical (uterine fundal tenderness may be due to endometritis whereas adnexal tenderness may be due to salpingitis, which is frequently bilateral). Gynaecological referral is indicated and laparoscopy is the most definitive method for diagnosis. Adhesive enteropathy Adhesive enteropathy is a controversial condition. The procedure of laparotomy is often followed by the development of some adhesions, and such adhesions are commonly encountered during a second laparotomy for some other reason. On most occasions these patients, when asked after that second operation, have had no symptoms referable to these adhesions. There are, however, a small group of patients who have chronic abdominal

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pain that may be due to the adhesions. The pain described by these patients is not colicky, as occurs in intestinal obstruction; it may be lateralised to one side or other. It tends not to be associated with other features of bowel obstruction, such as vomiting and constipation. Physical examination may reveal deep tenderness over the same area where the patient experiences the pain, and no signs of abdominal wall tenderness. Investigation of these patients is usually not rewarding. Standard haematological and biochemical tests are negative. Intraabdominal imaging with ultrasound and computed tomography (CT) scans is also negative. Colonic imaging with barium enema is negative. A small bowel series or CT enterography is negative or equivocal; some minor irregularity, but short of a definite obstruction, may be found and the clinician can be left wondering whether the symptoms and the radiological abnormality are related. Many patients will have taken or be taking oral or even parenteral analgesics for relief. Most have seen several clinicians for their problems. Some patients will have been thought by their clinician to have a functional problem, not an organic disease. The clinical dilemma is: how much of the problem is organic and how much is functional? Unfortunately, there is no simple way of establishing the relative proportions. It is important that these patients be seen by a limited number of clinicians. It is also important that operation be left as the last resort because: ll dividing adhesions does not cure adhesions— they reform almost as soon as the abdomen is closed; and ll there is a risk of intraoperative perforation during adhesiolysis with possible progression to other infective complications in the postoperative period. ll the procedure is often time-consuming, because of the large number of adhesions that need to be divided. Crohn's disease Crohn's disease of the small intestine may produce recurrent mid to lower abdominal pain from inflammation, or symptoms of intermittent partial bowel obstruction from acute inflammation or stricturing disease (see Ch 15). Localised and minimal disease can be associated with delay before eventual diagnosis. Terminal ileal biopsy at colonoscopy enables confirmation of Crohn's ileitis. Barium follow-through or CT or MRI enteroclysis can reveal evidence of likely small bowel Crohn's disease. Capsule endoscopy of the small bowel

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avoids irradiation but is usually reserved for those where the clinical suspicion of Crohn's disease remains despite negative other investigations. Chronic intestinal pseudo-obstruction This refers to a heterogeneous group of rare disorders affecting the neuromuscular apparatus of the bowel (Box 7.1). Recurrent symptoms of small or large bowel obstruction occur in the absence of luminal or extrinsic causes. Some cases can be associated with the ingestion of certain medications or secondary to rare metabolic or systemic disorders; others are idiopathic. Laparoscopic full-thickness jejunal biopsy is becoming increasingly utilised in order to obtain appropriate tissue for histological examination. Histology can provide clues as to the presence of myopathy, neuropathy or both, but in some cases no specific abnormalities can be demonstrated despite impressive clinical features. Therapies for

the disorder are limited, and include symptomatic treatment, especially analgesia, nutritional support and treatment of complications. Drug therapy with prokinetic agents is not usually effective, especially in visceral myopathy. Antibiotics can be given for small bowel bacterial overgrowth. Surgical therapies include jejunostomy to facilitate enteral nutrition, venting gastrostomy or enterostomy to relieve abdominal distension, and resection of localised disease. Abdominal angina (chronic mesenteric ischaemia) This is an important condition to recognise. Usually this is due to atherosclerosis but the condition can also occur with vasculitis or other lesions of the splanchnic vessels. Abdominal pain occurs 10–30 minutes after eating, gradually increasing in severity and then slowly resolving over 1–3 hours. The pain can occur in the periumbilical

Box 7.1  Chronic intestinal pseudo-obstruction Clinical features Abdominal pain—continuous or episodic ll Bloating and visible distension—continuous or episodic ll Vomiting—continuous or episodic ll Constipation (if predominant colonic involvement) ll Diarrhoea (if bacterial overgrowth from small bowel involvement) ll Dysphagia, chest pain (if oesophageal involvement) ll Weight loss (if reduced food intake or malabsorption) ll Palpable bladder (if megacystitis) ll Symptoms and signs of underlying cause (e.g. neurological, endocrine, connective tissue disease) Diagnosis ll Imaging studies (plain films, barium contrast studies, CT scan, endoscopy), e.g. air/fluid levels, dilated gut segments ll Functional studies (gastric and small bowel transit, oesophageal manometry, gastroduodenal manometry, cystometrogram) ll Diagnostic laparotomy or laparoscopy (plus full-thickness biopsy of intestine) ll Specialised histochemical staining techniques of full-thickness biopsy (enteric nerves and ganglia, interstitial cells of Cajal, smooth muscle layers) ll Evaluate for underlying cause ll

Causes Myenteric plexus disease ll Familial visceral neuropathies ll Sporadic visceral neuropathies, e.g. paraneoplastic (small-cell lung cancer) ll Hirschsprung's disease Smooth muscle disease ll Familial and sporadic visceral myopathies ll Scleroderma ll Polymyositis ll Amyloid Endocrine disease ll Hypothyroidism ll Hypoparathyroidism ll Phaeochromocytoma Drugs E.g. phenothiazines, tricyclic antidepressants, clonidine, vinca alkaloids Neurological disease ll Parkinson's disease ll Progressive muscular dystrophy ll Myotonic dystrophy ll Familial autonomic dysfunction ll Mitochondrial myopathy

7 Chronic lower abdominal pain or discomfort region or in the epigastrium. The patient becomes afraid to eat and reduces the meal size to avoid pain, leading to substantial weight loss. The pain may be due to an increase in gastric blood flow after food enters the stomach, leading to ‘stealing’ of blood from the small intestine. On examination, there may be a systolic bruit in the abdomen, but this is non-diagnostic. Doppler flow studies of the celiac axis and superior mesenteric arteries are useful screening tests. Angiography is helpful to confirm the diagnosis if there is involvement of at least two of the three major arteries. However, as such abnormalities can occur in the absence of symptoms, this entity remains a largely clinical diagnosis. Spinal disease Referred abdominal pain from disorders affecting the spine can also occasionally lead to diagnostic difficulties. The abdominal pain is usually due to root irritation or compression associated with the spinal disease. Coughing, straining or sneezing typically increases the pain. Diabetes mellitus This disorder can cause abdominal pain due to diabetic radiculopathy or diabetic plexus neuropathy involving the thoracic nerve roots. Electromyographic studies of the anterior abdominal wall muscles can assist in making this diagnosis. Familial Mediterranean fever This autosomal-recessive disease is common in Europe and the Near East, and causes recurrent episodes of abdominal pain that may start in one quadrant and spread to involve the entire abdomen (due to peritonitis), associated with fever, There are often episodes of acute pleuritic pain with or without the abdominal pain; some patients have episodes of acute arthritis or painful erythematous areas of swelling, usually on the lower limbs. Leucocytosis and elevated C-reactive protein are characteristic features during attacks. The MEFV (for Mediterranean FeVer) gene responsible for the disease has been identified, and many mutations reported. Renal amyloidosis can complicate this disease. Prophylactic long-term use of colchicine reduces the number of acute attacks, and prevents renal amyloidosis. Angioneurotic oedema This is an autosomal-dominant disease associated with functional C1 esterase deficiency in which there are recurrent attacks of abdominal colic. There are no urticarial skin lesions but there may

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be episodes of laryngeal oedema. The diagnosis is suggested by a family history. In myeloproliferative disorders, an acquired form of C1 esterase deficiency has been reported. Lead poisoning In adults, abdominal pain associated with anaemia, renal disease, peripheral neuropathy, ataxia, memory loss and headache may occur in lead poisoning. Lead lines (a thin blue-black pigmented line along the gingival margin) may be evident. The pain of lead colic, as well as that of porphyria, can be difficult to distinguish from intestinal obstruction. Acute intermittent porphyria This is a rare autosomal-dominant condition. Abdominal pain is the most common symptom and is typically steady and poorly localised although it may be colicky in nature. Other symptoms include nausea and vomiting, constipation, tachycardia and hypertension, mental symptoms, pain in the limbs and elsewhere, sensory loss and muscle weakness, as well as urinary retention. Drugs, infections and surgery can precipitate attacks. Tabes dorsalis Acute attacks of pain may occur in the abdomen, although pain in the legs is more common. Loss of position sense leads to gait ataxia in 50% of patients. Neurological signs in the legs (e.g. loss of reflexes and impaired position and vibratory sense) are usually present.

‘Functional’ bowel disorders These disorders are the most common causes of chronic or recurrent lower abdominal pain or discomfort. Based on characteristic symptom clusters, a number of functional bowel disorders can be recognised. Irritable bowel syndrome This disorder is defined (Rome III diagnostic criteria) as at least 6 months of recurrent abdominal pain or discomfort (≥ 3 days per month), associated with two or more of the following: ll improvement with defecation; and/or ll onset associated with a change in frequency of stool; and/or ll onset associated with a change in form (appearance) of stool. The presence of the following symptoms increases confidence in the diagnosis: abnormal stool frequency; abnormal stool form (lumpy/hard or loose/watery stool); abnormal stool passage

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(straining, urgency of feeling of incomplete evacuation); passage of mucus; and bloating or a feeling of abdominal distension. These symptoms often occur in discrete episodes, varying in frequency and severity, and are present without abnormalities on radiological, endoscopic and laboratory investigations. IBS accounts for 5% or more of attendances to general practitioners and 20–50% of referrals to gastroenterologists. It is twice as common in females as males, and half of the patients are younger than 35 years of age. Functional bloating This disorder is defined (Rome III diagnostic criteria) as at least 3 days per month of symptoms of (1) recurrent feeling of bloating or visible distension; and (2) insufficient criteria for diagnosis of functional dyspepsia, IBS or other functional gastrointestinal disorders. The term ‘bloating’ is used to indicate a sensory or perceptual phenomenon while ‘distension’ is used to denote an actual increase in abdominal girth. The symptoms in this condition are not usually constant or unremitting. Distension may require clothing to be loosened, tends to be minimal on waking and to increase as the day goes on. There may be accompanying increased passage of flatus and, less often, borborygmi. Bloating and/or distension are also common in IBS, but are accompanied by abdominal pain and bowel dysfunction. Functional abdominal pain syndrome This disorder (also known as chronic idiopathic abdominal pain) occurs far less frequently than either of the above disorders. It is defined (Rome III diagnostic criteria) as at least 6 months of (1) continuous or nearly continuous abdominal pain; (2) no or only occasional relationship of pain with physiological events (e.g. eating, defecation, or menses); (3) some loss of daily functioning; (4) the pain is not feigned; and (5) insufficient symptoms to meet criteria for another functional gastrointestinal disorder that would explain the pain. The description of the pain does not fit a recognisable specific disorder, and the nature and site may change with repeated descriptions. During history taking, symptom-reporting behaviours should be noted. These include verbal and non-verbal expression of varying pain intensity, urgent reporting of intense symptoms, minimising or denying a role for psychosocial factors, requesting additional diagnostic studies, focusing attention on complete recovery, seeking health care frequently, taking limited personal

responsibility for self-management, and making requests for narcotic analgesics.

Clinical Evaluation The extent of the evaluation will depend on the age of the patient and the duration and severity of symptoms. Based on a detailed history and general abdominal examination, the organ and disease process most likely to be involved should be defined. In the history, ‘alarm features’ such as the presence of fever, weight loss, rectal bleeding or steatorrhoea are all strong pointers towards the presence of organic disease (Box 7.2). As well as the aspects of the pain discussed earlier, further questions are often required to elicit specific information, such as new exacerbating factors to the pain (e.g. dietary change or change in medication), worry about serious disease (especially cancer), new life stresses, the presence of psychological or psychiatric disorders, or impairment in the patient's daily functioning. The family history can be very relevant. Because the functional bowel disorders cannot be established by any investigation, it is important to take a structured history, noting the features that support these diagnoses (see the definitions earlier), as well as those that suggest another cause for the symptoms. In some of these disorders (e.g. IBS), upper gastrointestinal symptoms, such as heartburn, dyspepsia, nausea and excessive belching, are frequently present, and non-gastrointestinal symptoms such as fatigue, dysmenorrhoea, migraine and symptoms Box 7.2  Clinical features against the diagnosis of a functional bowel disorder ll ll ll

ll ll ll ll ll ll ll ll ll ll ll

ll

First onset of symptoms in an elderly patient Symptoms waking the patient from sleep New symptoms after a prolonged period of stable symptoms Progressive, steady worsening of symptoms Weight loss Dysphagia Evidence of bleeding or dehydration Evidence of steatorrhoea Recurrent vomiting Fever Elevated C-reactive protein Anaemia or leucocytosis Blood, pus or excess fat in stool Hypokalaemia or persistent diarrhoea during fasting Stool weight greater than 350 g/day

7 Chronic lower abdominal pain or discomfort of bladder irritability are also common. Moreover, in IBS for example, the history is often prolonged with symptoms dating from a relatively early age, and the course is characterised by exacerbations and remissions.

Physical examination Abnormal findings, apart from abdominal tenderness, are not common. Tenderness is often present over the colon in IBS, especially the sigmoid, although this region can be palpable and tender in healthy subjects. It is important to consider the abdominal wall as a possible origin of pain, and specifically test for tenderness confined to this region. The presence of an abdominal mass raises the possibility of complicated diverticular disease or Crohn's disease, while an abdominal aortic aneurysm should be palpable. Enlarged lymph nodes (e.g. supraclavicular) may indicate the presence of malignancy. Small bowel malignancies such as lymphoma, although rare, should be considered where appropriate. Rarely, coeliac disease may be associated with abdominal pain. External hernias should be excluded. The testes should be palpated for tenderness and masses. Pelvic masses or tenderness present on rectal examination may indicate a gynaecological cause.

Investigations Investigations are dictated by the findings on history and physical examination, and the age of the patient. These may be performed to exclude or confirm the likely diagnosis and may include colonic investigation with sigmoidoscopy, colonoscopy or barium enema. Abdominal and/ or pelvic ultrasonography, small bowel radiology, CT or MRI enteroclysis, or lactose tolerance testing may also be required. Screening blood tests are often performed, even if there are no specific causes discovered from the history and examination. Haematological tests include full blood count, blood film, C-reactive protein and, if indicated, iron studies, folate and vitamin B12 levels. Biochemical tests include liver function tests, serum albumin, electrolytes and urea— these are usually unhelpful. In cases of suspected IBS, however, coeliac serology, particularly tissue transglutaminase assay, is a recommended screening test. Stool testing for ova, cysts or parasites, and faecal antigens such as for Giardia spp. can be considered in some cases. There is increasing interest in the role of faecal calprotectin as a simple and non-invasive method to indicate the presence of colorectal inflammation, but

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further studies are required. Highly specialised investigations, such as ultrasound with Doppler flow studies and mesenteric angiography, or tests to diagnose the metabolic disorders above, may be warranted. Capsule endoscopy can be considered where a more definitive examination of the small intestine is warranted. If organic colonic disease is suspected, full colonic investigation by colonoscopy or sigmoidoscopy and barium enema or CT colography is indicated. In patients 50 years of age or older, especially in those with a change in preexisting symptoms, or in patients with a family history of colorectal carcinoma or colonic polyps, colonoscopy is the preferred investigation to rule out colorectal neoplasia. Where an abnormality is detected by laboratory or radiological studies, it is always important to consider whether this is likely to be the cause of the patient's symptoms. When functional bowel disease is suspected, a protracted or piecemeal approach to investigation should be avoided, as it is likely to increase patient uncertainty and anxiety. If the diagnosis remains in doubt, it may be useful to see and investigate the patient during an acute exacerbation of pain. Rare causes should be considered and checked at this stage and appropriate other investigations, e.g. abdominal x-ray during an attack of pain, performed if indicated. ‘Diagnostic’ laparotomy is almost invariably non-contributory in cases of chronic abdominal pain already investigated as above. However, laparoscopy may enable the identification of recurrent intestinal obstruction from adhesions, which has escaped identification using other modalities.

Irritable Bowel Syndrome (IBS) Pathophysiology The pathogenesis of IBS is unknown. A number of physiological factors, however, appear to be associated with the disorder. Digestive tract dysmotility and hypersensitivity are likely to underlie the gut symptoms in these disorders. A variety of modulatory factors can affect the degree of digestive tract dysmotility and hypersensitivity. These factors are discussed below and include external factors such as psychosocial distress and local factors such as the intestinal microflora and specific nutrients.

Normal small bowel and colonic motility In the small intestine, intermittent segmenting and propulsive contractions occur after ingestion of food, mixing it with digestive secretions and

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transporting the chyme aborally. Each propagated contraction is preceded by a propagated relaxation, a phenomenon termed the ‘peristaltic reflex’. The overall duration and intensity of postprandial motor activity depends upon the caloric content and the proportion of fat, carbohydrate and protein in the meal. The jejunum acts primarily as a mixing and conduit segment, while the ileum, which has specialised absorptive properties, retains chyme until digestion and absorption are largely complete. The terminal ileum and ileocolonic junction control the rate of emptying of ileal contents into the colon. In between meals, and particularly during sleep, motility in the stomach and small intestine undergoes regular cycles of activity every few hours, termed ‘migrating motor complexes’. These complexes migrate slowly along the small bowel, clearing away residual food and secretions. In the colon, proximal colonic motor activity normally promotes the mixing of contents, absorption of water and electrolytes, and metabolism of colonic contents by bacteria. The rectosigmoid region stores faeces and generates specific motor programs enabling convenient elimination. Contractions in the colon occur at irregular intervals; there are two main types: individual phasic contractions and highamplitude propagated contractions or giant migrating contractions. The latter are the main propulsive motor events in the colon, producing the so-called mass movements. After eating, colonic motor activity and tone increases (the gastrocolic reflex) in both the proximal and distal colon. Intestinal gas originates from three sources: the majority (about 70%) from swallowed air, a proportion from gases (carbon dioxide, hydrogen and methane) produced by bacterial fermentation of incomplete absorbed food and fibre in the colon, and a very small amount in the way of diffusion from the blood. On the average diet, material takes up to 3 days to pass through the colon, accounting for about 90% of whole gut transit time in healthy subjects.

secretion or absorption, resulting in an erratic bowel habit. Exaggerated patterns of contraction, especially postprandially, have been observed in the small and large intestine; the gastrocolic reflex can be delayed and prolonged. Altered motor activity affects gut transit. Thus, delayed transit through the small and large intestine, and increased absorption of water, can lead to symptoms of constipation, while accelerated transit may result in diarrhoea. Uncoordinated or abnormally high pressure contractions may lead to distension of the intestinal lumen, or trap pockets of intestinal gas that distend the bowel and produce abdominal pain. Stools of small or ‘normal’ volume that are passed more frequently may result from the combined effect of rapid small bowel transit, colonic dysmotility and rectal hypersensitivity to distension. In the majority of patients a trigger factor producing gut hypersensitivity is not found. In some patients (up to 25%), IBS symptoms appear to be precipitated by an attack of infective diarrhoea or gastroenteritis, perhaps due to occult damage to the enteric nervous system. Increased numbers of lymphocytes, mast cells and enteroendocrine cells have also been demonstrated in biopsies from the colon in this ‘postinfective’ IBS. Altered permeability in the small intestine can occur. Symptoms in this disorder can persist for months, years or even a lifetime. There is no evidence that colonisation of the intestine with Candida albicans is a cause of IBS.

Gastrointestinal sensorimotor dysfunction

Dietary factors Eating often provokes symptoms in patients with IBS. In general, meals high in fat move slowly through the gut, and in IBS this may exacerbate symptoms such as bloating and constipation. Foods such as baked beans, cabbage and brussels sprouts, and sugars such as fructose and sorbitol, may exacerbate symptoms in patients with complaints of excessive bloating and rectal flatus.

Up-regulation of the sensory pathways travelling from the gut to the central nervous system appears to account for a heightened perception of normal gut sensations arising from intestinal distension and contraction (visceral hypersensitivity). This phenomenon of hypersensitivity may result in abdominal discomfort or pain; it may also trigger disordered gut motility and/or alterations in gut

Behavioural factors No specific personality type has been shown to be at special risk for development of IBS. Psychological stress, especially chronic stress, is associated with the onset and exacerbation of symptoms in some patients. It is unknown, however, whether the common associations of depression and anxiety are cause or effect. Psychological factors are also important because they influence the individual's decision to seek medical attention as well as the ability to cope with the symptoms.

7 Chronic lower abdominal pain or discomfort Patients frequently associate ingestion of specific food items with the development of symptoms. Although this may be a chance association, there is evidence that a non-immunological gut reaction may occur to a variety of foods such as dairy products, caffeine, onions, tomatoes and citrus fruits. Such food intolerance should be distinguished from the rare condition of true food allergy. Only a very small proportion of patients with IBS appear to have true allergic or immunological responses to specific foods.

Box 7.3  Management of IBS ll

ll ll



Treatment Management is outlined in Box 7.3. Therapy begins at the initial consultation, where it is essential to establish rapport with patients and secure their confidence. This is achieved by a process of reassurance regarding the genuine nature of the symptoms. Many patients have been told that they are not suffering from a significant illness; the patient should be reassured that IBS is a well recognised and common, though benign and chronic, clinical entity. The patient should be made aware at the outset that investigations will probably be negative, but that they serve to confirm the initial diagnosis of IBS. An explanation about the possible mechanism of symptoms should be given. This depends on an assessment of the patient's level of sophistication, but always needs to be sympathetic and unhurried. Patient information leaflets and diagrams can be very helpful, but do not substitute for individual explanation and discussion. At the follow-up visit the physician should check how much the patient has really understood. A concise dietary history should focus on fibre intake, fat and specific carbohydrate ingestion, and any possible food intolerances (e.g. dairy products, soft drinks, some ‘diet’ confectionery, gas-producing foods, or other specific foods). The pattern of symptoms in relation to the patient's day, including work, eating, exercise and sleeping habits can then be broadened into a discussion about stresses at work and at home. The presence of psychological disorders and, if possible, their onset in relation to the onset of gastrointestinal symptoms should be ascertained. It is important to consider why the patient is seeking help now. A careful history to identify possible precipitating or contributing factors should lead to advice about simple lifestyle modifications. It is essential for the patient to understand that IBS is generally a chronic condition, in which exacerbations and remissions are often a feature. Notwithstanding this pattern

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ll

ll

ll

Complete history and examination are essential. A positive diagnosis of IBS can be made by history. Avoid protracted investigation. Reassure the patient that: – diagnosis is correct; – symptoms are produced by gut sensorimotor dysfunction; – there is no predisposition to other bowel disorders such as cancer. Use simple dietary modifications and non-drug therapy initially, according to predominant symptoms. Assure the patient that opportunity for review is available during difficult times, or if new symptoms develop. Inform the patient of the likelihood of residual symptoms persisting or recurring from time

of the disorder, the patient should be advised to report any changes in symptoms that develop over the years. A discussion of prognosis is important and is often overlooked; it is important to reassure patients that the condition does not predispose to other gut disorder, particularly malignancy, and to inform them that residual symptoms may persist despite therapy. Diet and the role of fibre Foods and beverages that clearly and consistently provoke symptoms should be avoided. If bloating and flatulence are prominent symptoms, the patient should be advised to eat slowly, to avoid smoking and chewing gum, and to try to avoid excessive air swallowing associated with belching. Although it is controversial whether dietary fibre supplementation is of any greater overall benefit, a stool bulking by a regular increased intake of fibre-rich foods (e.g. cereals, wholemeal bread and unprocessed wheat bran) and/or proprietary bulking agents should be trialled in most patients. Fibre supplementation should be introduced gradually and continued for at least 1 month before its effect is judged. Patients should be made aware that too much fibre can produce excessive intestinal gas and cause bloating and flatus. Proprietary bulking agents (e.g. those containing psyllium or ispaghula) may be less likely to cause this problem than bran. A trial of stool bulking is less likely to be effective in

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patients with diarrhoea-predominant IBS. In selected cases, where there is a high suspicion of food intolerance, a symptom and food diary may enable the patient to recognise specific items more readily. Medications The decision to use a medication in IBS depends on the severity of symptoms and their influence on the quality of life of the patient. The choice of medication depends on the pattern of symptoms. Randomised, placebo-controlled trials of traditional pharmacotherapeutic agents in IBS have generally been disappointing. However, for predominant diarrhoea, antidiarrhoeal drugs such as loperamide have been shown to be effective. For predominant constipation, in addition to a trial of stool bulking, an increase in fluid intake, and regular exercise, osmotic laxatives such as magnesiumcontaining salts (e.g. Epsom salts), polyethylene glycol compounds or lactulose are safe and can be effective. Anticholinergic agents (such as hyoscine butylbromide or hydrobromide, hyoscyamine sulfate or dicyclomine) or antispasmodic agents (such as mebeverine) may be helpful in some individuals with prominent abdominal pain, especially if it is meal-related. However, differentiation from the placebo response is difficult. Ideally, drugs such as those above should be used in the short term only, and the dose adjusted depending on the timing and severity of symptoms. Moreover, it should be appreciated that such medications target only one symptom—abdominal pain, diarrhoea or constipation—and may not improve (indeed in some cases can worsen) other aspects of the symptom complex. A number of complementary medicine compounds have shown promise in the treatment of IBS. These include several types of probiotic agents and herbal preparations. There is evidence that Bifidobacterium infantis 35624 has greater efficacy in reducing abdominal pain, bloating, straining and overall IBS symptoms than other strains. Further studies are required to investigate other such compounds, and to determine the mechanisms of action of those agents exhibiting efficacy. If there is no improvement It is important to assess whether the patient can cope with ongoing symptoms, or still fears that some other underlying diagnosis is being overlooked. In this latter group, continued reassurance may be necessary. It is also important to re-emphasise to the patient the limitations of current therapies and

that treatment strategies are not aimed at a cure, which in most is not achievable. A small (non-antidepressant) dose of tricyclic antidepressant (e.g. amitriptyline 10–25 mg in the evening) has been shown to be useful in some patients with resistant symptoms, probably by influencing central pain perception. When significant symptoms of depression are present, however, adequate therapy with full antidepressant doses should be employed. The selective serotonin reuptake inhibitors are also efficacious in some patients. Minor tranquillisers (e.g. benzodiazepines) are not recommended for use in this chronic condition. There is increasing evidence that non-absorbable antibiotics improve diarrhoea-predominant IBS. If food intolerance is strongly suspected, trials of exclusion diets and blind challenges to identify offending foods and additives have been reported to decrease symptoms in some patients, especially those with predominant diarrhoea. This is rarely necessary, and may be most appropriately carried out in an allergy clinic with a research interest in this field. There is no role for a gluten-free diet in IBS. If coeliac disease is suspected, serological testing and, if positive, small bowel biopsy are indicated. Relaxation therapy may be appropriate for some patients, and individual psychotherapy or hypnotherapy, which have been reported to improve symptoms if other measures have not been helpful, can also be arranged by a psychologist, psychiatrist or interested general practitioner. When to review the diagnosis If new symptoms develop or there is a change in the pattern of existing symptoms, it is important to review the diagnosis carefully or to consider the possibility that an additional problem has arisen. Other disorders that may need to be considered, depending on the individual case, include: ll the development of colon cancer; ll an episode of diverticulitis or an intercurrent gastrointestinal infection; ll symptoms due to gallstones; ll peptic ulceration; ll the development of pancreatic carcinoma; ll the development or exacerbation of a psychological problem, such as depression.

Key Points ll

Chronic or recurrent abdominal pain is a common symptom and is often a source of diagnostic difficulty.

7 Chronic lower abdominal pain or discomfort ll

ll

ll

ll

ll

ll

ll

ll

Organic gastrointestinal disorders (e.g. complicated diverticular disease, gynaecological disorders and Crohn's disease) and functional bowel disorders (e.g. irritable bowel syndrome and functional abdominal pain syndrome) are the two main categories of disorders causing chronic lower abdominal pain. Irritable bowel syndrome is the most common functional bowel disorder. Important features of the history include the site, radiation and referral of the abdominal pain, and also the character, intensity and duration of the pain and any modifying factors. Alarm symptoms such as fever, weight loss, rectal bleeding, steatorrhoea or family history of gastrointestinal carcinoma increase the likelihood of organic disease. The extent of the clinical evaluation depends on the age of the patient and the duration and severity of symptoms. Investigations required may include colonic investigation, abdominal radiology and a range of blood and stool tests. Other specialised tests (e.g. ultrasound of mesenteric vessels) may be indicated. Management of the relevant organic gastrointestinal disorders depends on a precise diagnosis. Management principles of irritable bowel syndrome include education about the mechanisms of symptoms, reassurance regarding the longer term safety of the diagnosis, and use of simple dietary modifications and non-drug therapy.

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Further reading Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based systematic review on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104(suppl 1):S1–S35. Brenner DM, Moeller MJ, Chey WD, et al. The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Am J Gastroenterol 2009;104:1033–1049. Clouse RE, Mayer EA, Aziz Q, et al. Functional abdominal pain syndrome. In: Drossman DA, ed. Rome III: The Functional Gastrointestinal Disorders, 3rd edn. McLean: Degnon Associates; 2006. Ford AC, Chey WD, Talley NJ, et al. Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis. Arch Intern Med 2009; 169:651–658. Kellow JE, Azpiroz F, Delvaux M, et al. Principles of applied neurogastroenterology: physiology/motility sensation. In: Drossman DA, ed. Rome III: The Functional Gastrointestinal Disorders, 3rd edn. McLean: Degnon Associates; 2006:40–63. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006; 130:1480–1491. Shepherd SJ, Parker FC, Muir JG, et al. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence, Clin Gastroenterol Hepatol 2008; 6:765–771. Spiegel BM, Chey WD, Chang L. Bacterial overgrowth and irritable bowel syndrome: unifying hypothesis or a spurious consequence of proton pump inhibitors? Am J Gastroenterol 2008; 103:2972–2976. Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology 2003; 124:1662–1671. Talley NJ, Spiller R. Irritable bowel syndrome: a little understood organic bowel disease? Lancet 2002; 360:555–564.

8 Wind and gas

Case

History

A student aged 23 years was born and educated in India and attended an Australian university for postgraduate studies. Shortly after arrival he began to experience abdominal discomfort, bloating and occasional bouts of loose bowel habit. Routine blood tests (blood count and chemistry) were normal. An upper gastrointestinal endoscopy was performed. The examination was normal and the rapid urease test for Helicobacter pylori was negative. Small bowel biopsies showed a normal duodenal mucosa, but the lactase level was reduced to 2 U/g protein (normal 20–120). Other disaccharidase levels were normal. Symptoms were attributed to lactose intolerance secondary to the increased intake of lactosecontaining foods since arrival in Australia. At a follow-up consultation he was improved, but still had some abdominal discomfort, bloating and increased flatus. The high dietary intake of lentils was discussed and his diet modified, with symptomatic benefit.

An accurate history is essential. Determine if the problem is excessive belching (usually due to air swallowing), abdominal bloating or distention, or excessive flatus. Check for evidence of irritable bowel syndrome (IBS), which is characterised by abdominal pain and discomfort with altered bowel habit, a sensation of incomplete rectal evacuation and bloating which is often present in the afternoon. Enquire about the presence of alarm symptoms such as vomiting, bleeding or weight loss and investigate these symptoms if they are present. An adequate dietary history is required. In adults, lactose intolerance is the usual status for non-Caucasians. In general, origin from Northern Europe usually indicates normal lactase levels.

Introduction Many patients present complaining of ‘excessive gas’, which can indicate excessive passage of wind through the mouth or anus, abdominal bloating or audible bowel sounds (borborygmi). In population studies about 20% of individuals report abdominal bloating. The causes of a sensation of excess gas include air swallowing or ingestion of poorly absorbed but fermentable foods such as baked beans, bran or brassica vegetables. Other causes include lactose intolerance (due to lactase deficiency; see Ch 18) or malabsorption (e.g. due to coeliac disease, giardiasis or bacterial overgrowth). Functional gastrointestinal disease can also produce a sensation of excessive gas.

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Physical Examination Observe the patient during the interview. You may observe gulping of air and repetitive belching in the patient with aerophagia. An abdominal examination is required to exclude abdominal masses or evidence of intestinal obstruction. In most patients with a complaint of bloating the examination is normal.

Investigations X-ray and endoscopy A plain abdominal x-ray is not normally required. Most patients with bloating and abdominal distention have a normal x-ray. The aim of the x-ray is to confirm the possibility of intestinal obstruction. An upper gastrointestinal endoscopy is required if there are alarm features such as vomiting and weight loss. Mucosal biopsies could be considered to exclude giardiasis or coeliac disease. The lactase level can be quantified on small bowel biopsy specimens.

8 Wind and gas

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BREATH H2 PRODUCTION

CHO

CHO

Coliforms Anaerobes

Degradation

H2 15%

Absorbed Breath, 5 min

Figure 8.1  Schematic diagram showing arrival in the colon of carbohydrate (CHO) that has escaped digestion in the small intestine.

Breath hydrogen testing for lactose intolerance Gas production in the human gut is determined by two factors: first, the amount of fermentable substrate that evades digestion in the small bowel and reaches the colon (Fig 8.1); and, secondly, by the individual characteristics of the colonic flora. Lactose intolerance is due to a deficiency of the enzyme lactase in the brush-border membrane of the intestinal villous cell and is manifested by abdominal cramps, borborygmi, bloating, excessive flatus (bacterial fermentation) and diarrhoea (osmotic effect) following milk ingestion. Primary lactase deficiency is genetically determined and lactose intolerance occurs from late childhood in populations who are not of northern European ancestry. The breath hydrogen (H2) test following a 50 g lactose challenge is a non-invasive, sensitive and specific method to identify subjects with lactase deficiency (Fig 8.2). The subject is prepared by an overnight fast following a meal of meat and rice and avoidance of foods rich in starch and fibre (to reduce baseline H2 levels): smoking is prohibited. A baseline breath test is obtained and then a 50g test load of lactose is administered. Breath samples are obtained at half-hourly intervals for 4 hours. An abnormal result is characterised by breath hydrogen exceeding 20 parts per million over the baseline. Lactose-intolerant patients may experience the usual symptoms listed above. The majority of patients with lactase deficiency have adjusted their diet and generally avoid symptoms associated with lactose-containing

foods. Management is by the use of commercial milk products containing lactase, hard and mature cheeses (minimal residual lactose) and yoghurt (auto-digesting).

Breath hydrogen testing for bacterial overgrowth of the small intestine The syndrome of bacterial overgrowth of the small intestine is characterised by the presence of diarrhoea, malabsorption and weight loss. Potential causes include altered anatomy (e.g. a blind loop associated with a Billroth II gastrectomy) and altered motility (e.g. scleroderma or intestinal pseudo-obstruction). Confirmation of the diagnosis is by demonstration of increased microbial numbers (over 105 organisms/ mL) in the proximal small intestine. Alternative, non-invasive techniques use the metabolic action of the bacteria. These indirect diagnostic tests include measurement of the production of H2 after exposure of a fermentable substrate (e.g. glucose or rice flour) to pathologically high levels of intestinal bacteria. A positive test is characterised by a high fasting breath H2 level after dietary preparation as mentioned above and the finding of a rise in breath hydrogen of at least 12 ppm within 2 hours of a 50 g glucose challenge (Fig 8.3).

Incompletely absorbed dietary carbohydrates Fructose is a monosaccharide present in fruits (juices and dried fruits), honey and table sugar. Sorbitol is a sugar found naturally in various fruits, for example apples, pears and prunes.

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120

Hypolactasia (n = 10)

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Breath H2 (ppm)

80

60

40

20 Normal lactase (n = 12) 0 Lactose 50 g

1

2

3

4

Time (h)

Figure 8.2  The lactose breath H2 test.

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Breath H2 (ppm)

100 80 60 40 Normal range

20 0 0 Glucose 50 g

30

60

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120

Time (minutes)

Figure 8.3  The 2-hour glucose breath H2 test. In this patient with scleroderma and bacterial overgrowth, the basal breath H2 is elevated and rises further after exposure to glucose.

Both fructose and sorbitol are used as artificial sweeteners in many sugar-free mints and gums. Incomplete absorption can result in fermentation in the colon with resulting abdominal discomfort, bloating and diarrhoea.

Laboratory Tests These tests are rarely required. If organic disease is suspected check the haemoglobin, iron, red cell folate and vitamin B12 levels. Check the serum albumen level for evidence of malabsorption. The

8 Wind and gas tissue transglutaminase (TTG IgA) antibody is a sensitive and specific test for coeliac disease.

Physiology of Gas The limited available information about the content, composition and role of intestinal gases is due in part to the difficulties of obtaining data in humans. The information on intestinal gas is based on (1) the ‘wash out technique’ (of Levitt and colleagues) in which an inert gas (argon) is infused rapidly into the jejunum and gases are collected with a rectal tube for analysis; (2) analysis of colonic gas collected via a rectal tube; and (3) scattered observations have been obtained by sampling gases at various levels of the gastro-intestinal tract. Based on the ‘wash out technique’ the normal gastrointestinal tract contains about 100 mL of gas. The passage of gas per rectum ranges from 200 to 3,000 mL (mean 700 mL) per 24 hours. Based on observations in young healthy subjects, the normal frequency of passage of flatus is 13.6 ± 6 times a day. The volume of flatus increases dramatically after ingestion of poorly absorbed carbohydrates such as baked beans or brassica vegetables.

Composition The composition of gases in the gut varies with the site of sampling. For example, nitrogen concentration in the human stomach approaches atmospheric, suggesting that it originates from swallowed air. The five gases nitrogen (N2), oxygen (O2), carbon dioxide (CO2), hydrogen (H2) and methane (CH4) comprise about 99% of intestinal gas (Table 8.1, Figure 8.4). Nitrogen is the predominant gas and O2 is present in low concentrations. Carbon dioxide in the upper small bowel reflects the interaction of gastric acid and bicarbonate secretion from the pancreas, biliary tree and small intestine. Most of the small bowel CO2 appears to be absorbed. Carbon dioxide in the lower small bowel results from the interaction of bicarbonate and organic acids. Breath CO2 can be studied by the use of isotopic labelling of the carbon atoms. Three gases (CO2, H2 and CH4) are produced in the gut by bacterial action on unabsorbed carbohydrate. Hydrogen production is usually limited to the colon and is dependent on the ingestion of fermentable substrates, which escape absorption in the small intestine (Fig 8.1). In general, about 90% of most staple carbohydrate is absorbed in the small bowel but 10% escapes absorption and passes to the colon. Baked beans contain unabsorbable oligosaccharides such as stachyose and raffinose and these produce large quantities of gas after

103

Table 8.1 Gastrointestinal gas Gas* N2 O2 CO2 H2 CH4

Origin Swallowed air, diffusion from blood Secretion, diffusion, bacterial metabolism Bacterial metabolism

*Plus traces of odiferous gases that are socially significant.

interaction with colonic bacteria. About 15% of hydrogen production in the colon is absorbed into the circulation and expired from the lungs. About 30% of normal individuals produce significant amounts of CH4. The production is constant and unrelated to food intake. All of the five major gases are odourless. The odour of flatus is due to trace quantities of other gases produced by colonic bacteria. Ammonia is due to urea breakdown; indoles and skatoles are produced by protein breakdown; and hydrogen sulphide (H2S) and methanethiol result from amino acids with sulfur content. There are few published data on these odiferous gases.

Symptoms Associated with Intestinal Gas Swallowed air (O2 + N2) is the main source of gas in the upper gastrointestinal tract. Some gas is swallowed during regular meals and this is intensified by gulping when excited. At times patients with troublesome, frequent and noisy belching are encountered. There is usually no detectable underlying pathology and the situation probably represents an acquired habit. Although this area has not been well studied, the likely explanation is that air is sucked back into the oesophagus during each act of belching. The most useful therapeutic option is to concentrate on avoiding the next belch. Aerophagia refers to the unconscious habit of swallowing air. The subject needs to avoid smoking, chewing gum and carbonated beverages. The origin of odoriferous gases after garlic ingestion has been studied by Suarez and colleagues from Minneapolis. The halitosis initially originates from the mouth and subsequently from the gut (metabolism in the colon causing large concentration in alveolar air). Oral hygiene may reduce the halitosis from the mouth and manipulation of the diet may limit gas production from the gut flora.

104

Clinical gastroenterology: a practical problem-based approach Swallowed air

2

1

Eructation O2 + N2 3

8

9

Trace gas CO2 H2 CH4 7

HC H+ +

N2

H2 O2

10

N2

5

O– 3

4

Consumed by bacteria

CO2

6

Bacteria

11

N2, O2, CO2, H2, CH4, + trace volatiles

Figure 8.4  Mechanisms influencing rate of accumulation of gas in the gastrointestinal tract. Air is swallowed (1) and a sizeable fraction is then eructated (2). The O2 of gastric air diffuses into the blood draining the stomach (3). The reaction of H+ and HCO3– yields CO2 (4), which rapidly diffuses into the blood (5) while N2 (6) diffuses into the lumen down a gradient established by the CO2 production. In the colon (7), bacteria produce CO2, H2 and CH4, which diffuse into the blood perfusing the colon (8). Bacteria also consume O2 and H2 (10). N2 diffuses into the colon (9) down a gradient established by bacterial production of CO2, H2 and CH4. The net result of all these processes determines the composition and rate of passage of gas per rectum (11). From Dr Michael Levitt, in Johnson LR, ed. Physiology of the gastrointestinal tract. 3rd edn. New York: Raven Press; 2004, with permission.

A sensation of abdominal bloating, sometimes accompanied by an increase in girth (distention), is a common and frustrating symptom in patients with IBS. Abdominal x-rays generally show normal quantities of gas in the intestines. A washout technique by Lasser et al. has been applied to quantify intestinal gas volume and composition in patients with IBS using normal healthy subjects as controls. Collection of gas at the rectum demonstrated similar volumes and composition of gas in the two groups. The patients with IBS experienced increased symptoms in response to the infusion of gas and there was increased retrograde flow of gas as determined by aspiration via a gastric tube. This experiment supports the view that abnormal gut sensation occurs in some patients with IBS, and this may explain the sensation of bloating. Visible abdominal distension can occur in patients with IBS. This has been studied by

Accarino and colleagues from the Barcelona group of researchers. They studied morphovolumetric differences between computerised scans obtained before and during a severe bloating episode. The symptom was due to the descent of the diaphragm and protrusion of the anterior abdominal wall. The buoyancy of stool is determined by the content of gas within the stool and not the content of fat. In the laboratory, stools must contain gas to float. Floating stools sink when their gas volume is compressed by positive pressure. The floating stool should not be considered a sign of steatorrhoea. Based on observations in healthy young students the frequency of passage of flatus is 14 per day. The frequency and volume of flatus varies widely, and depends on the composition of the colonic flora. Maximum gas production occurs after poorly digested food such as baked beans and brassica vegetables (cabbage, brussels sprouts and

8 Wind and gas broccoli), which should be avoided by patients with excessive flatus. Least rectal gas follows ingestion of carbohydrates such as rice flour, which is fully absorbed in the small intestine. The addition of fibre in patients with IBS is an important therapeutic option but can temporarily aggravate abdominal discomfort and bloating for 2–3 weeks. Hydrogen and methane may reach combustible concentrations in the colon (greater than 4%). It is for this reason that the use of electrocautery to remove colonic polyps is restricted to the prepared colon. Fermentable substrates such as lactulose are best avoided in bowel preparation before electrocautery. The offensive odour in flatus is due to sulfurcontaining compounds. These include hydrogen sulfide, methanethiol, dimethylsulfide, shortchain fatty acids, skatoles, indoles, volatile amines and ammonia. Various approaches have been evaluated to minimise problems with odoriferous rectal gases. The only product that absorbed virtually all of the sulfide gases was briefs constructed from an activated carbon fibre fabric. Charcoal-containing pads worn inside the underwear were less effective and their role is limited by incomplete exposure of the activated carbon to the gases.

Key Points ll

ll ll

ll

ll

A complaint of ‘excessive gas’ requires clarification about the presence of excessive belching, increase flatus production, the presence of bloating or abdominal distension, or the symptom of borborygmi. The human gut contains about 100 mL of gas. Healthy individuals pass flatus about 10–20 times per day with a mean daily volume of 700 mL. The volume of flatus increases after ingestion of poorly absorbed carbohydrate such as baked beans or brassica vegetables. Nitrogen (N2) is the predominant gas. Three gases (CO2, H2, CH4) are produced in the gut by bacterial breakdown of unabsorbed carbohydrate.

ll

ll

ll

ll

ll

ll

105

The five major gases (N2, O2, CO2, H2, CH4) are odourless. The odour of flatus is due to trace quantities of sulfur-containing compounds. Breath H2 testing can be used clinically to diagnose conditions such as lactose intolerance and bacterial overgrowth of the small intestine. The buoyancy of stool is determined by the content of gas within the stool and not the content of fat. Excessive belching can become a ‘habit’ in which air is sucked back into the oesophagus after each belch (aerophagia). Halitosis originates from the mouth and subsequently from excretion via the lung of products of colonic metabolism. Fructose and sorbitol are used as artificial sweeteners. Incomplete absorption can result in colonic fermentation with abdominal discomfort, bloating and diarrhoea.

Further reading Accarino A, Perez F, Azpiroz F, et al. Abdominal distention results from caudo-ventral redistribution of contents. Gastroenterology 2009; 136(5):1544–1551. Anderson IH, Levitt AS, Levitt MD. Incomplete absorption of the carbohydrate in all purpose wheat flour. N. Engl J Med 1981; 304:891–892. Azpiroz F, Malagelada JR. Abdominal bloating. Gastroenterology 2005; 129(3):1060–1078. Kerlin P, Phillips SF. Differential transit of liquids and solid residues through the ileum of man. Am J Physiol 1983; 245:G38–G43. Kerlin P, Wong L, Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988; 95:982–988. Kerlin P, Wong L, Harris B, et al. Rice flour, breath hydrogen and malabsorption. Gastroenterology 1984; 87:578–585. Lasser RB, Bond JH, Levitt MD. The role of intestinal gas in functional abdominal pain. N Engl J Med 1975; 293:524–556. Ohge H, Furne JK, Springfield J, et al. Effectiveness of devices perported to reduce flatus odour. Am J Gastroenterol 2005; 100(2):397–400. Suarez F, Springfield J, Furne J, et al. Differentation of mouth versus gut as site of origin of odiferous breath gases after garlic ingestion. Am J Physiol 1999; 276:G425–G430.

9 Nausea and vomiting

Case A 21-year-old university student consults because of episodic nausea and vomiting. In between attacks, he is well. However, approximately every 2 months he will experience worsening nausea preceding violent vomiting episodes that can last for 3–5 days. The vomiting has been so severe that he has presented to casualty where intravenous injections of antiemetics have been given. There is mild abdominal pain associated with the nausea and vomiting at times. His bowel habit has been normal. He denies any neurological symptoms. He has had a history of occasional migraine-type headaches, but has otherwise been in excellent health. He has not been taking any regular medications. He has already seen a gastroenterologist who performed an upper endoscopy that was normal and a small bowel x-ray that was normal. Screening blood tests (including electrolytes, liver function tests and a blood count) have all been normal. You ask him two specific questions. First, you ask whether he feels the compulsion to take a hot bath or shower during an episode; while the patient is surprised by the question he acknowledges this is true and this seems to help. You also ask him whether he has ever used marijuana. The patient admits he has from time to time smoked marijuana to try to prevent his symptoms. Physical examination is completely unremark­ ably, including a full neurological examination and fundoscopy. You make an astute diagnosis of cyclic vomiting syndrome secondary to cannabis use. You explain to the patient that in some cases vomiting can be precipitated by use of marijuana. You strongly encourage him to cease all marijuana use. A prescription for a tricyclic antidepressant (desipramine) is subsequently given because the

106

attacks do continue off cannabis. The dose is slowly titrated up, and the patient has an excellent response with a substantial reduction in the number of vomiting episodes over the subsequent 6 months.

Definition Nausea and vomiting are common symptoms. Nausea is best considered a painless, unpleasant, subjective feeling of wanting to vomit. Vomiting, on the other hand, is the forceful expulsion of gastric or intestinal contents through the mouth, secondary to a pre-programmed series of motor and autonomic responses. Vomiting is not retching; ‘retching’ describes contractions of the abdominal muscles that typically precede vomiting, associated with laboured, rhythmic respiration, not the expulsion of the contents through the mouth. Vomiting must be distinguished from regurgitation, which is an effortless movement of gastric material into the mouth. Clinically, it is key to distinguish vomiting from rumination, as management is totally different. In the rumination syndrome, there is effortless regurgitation of recently ingested food into the mouth that is not preceded by nausea or abdominal muscular contractions. The food tastes like it has not been eaten. Often the patient will re-chew or spit the food out, but this does not always occur. Rumination typically occurs within minutes of a meal and is almost always repetitive.

Physiology of Vomiting With the onset of nausea, there will be accompanying autonomic discharge of variable severity. This results in intense salivation, bradycardia, sweating, pallor and hypotension. The normal electrical activity of the stomach may become slow, fast or fluctuate wildly with nausea. It is unclear whether the same neural pathways that mediate vomiting also mediate nausea.

9 Nausea and vomiting Just prior to vomiting, a large amplitude contraction in the small bowel is propagated retrogradely. Moderate amplitude phasic contractions may also occur in the small intestine, with these motor activities probably being mediated by the vagus nerve. These motor changes result in the small bowel contents entering the relaxed stomach where closure of the pylorus then occurs with contraction of the abdominal muscles, causing respiration to be suspended. Gastric contents are then forced against a contracted diaphragm, the lower oesophageal sphincter relaxes and the cardia elevates. Gastric contents are forced into the oesophagus, which dilates. Protection of the airway occurs via the glottis closing and the soft palate rising, and then the vomitus is forcibly ejected from the mouth. The vomiting centre is located in the dorsal portion of the medulla. The vomiting centre has afferent inputs via vagal fibres, which are rich in 5-hydroxytryptamine type 3 (5-HT3) receptors. There is afferent input from sympathetic nerves. There is also input from the vestibular system, which is rich in histamine H1 and muscarinic cholinergic fibres. The chemoreceptor trigger zone is in the area postrema in the floor of the fourth ventricle. This area, when stimulated, will activate the vomiting centre, and is responsive to drugs, hypoxia, toxins and acidosis; it is rich in dopamine D2 and 5-HT3 receptors. The presence of these receptor subtypes forms the rationale for drugs used to treat nausea and vomiting. Other trigger areas include the pharynx, coronary vessels, peritoneum and bile ducts, cortex, thalamus and hypothalamus, and the vestibular apparatus (motion sickness).

History Nausea and vomiting are non-specific symptoms and may occur in many diseases. Box 9.1 lists the important causes of nausea and vomiting. When taking the targeted history, it is key to differentiate between vomiting, regurgitation and rumination. It is very helpful to determine the duration, frequency and intensity of nausea and vomiting, and its relationship to eating. Self-limiting symptoms will often occur with an acute infectious gastroenteritis, with inflammatory disease such as cholecystitis or pancreatitis, or from drugs. Gastroenteritis is usually associated with headache, myalgias and diarrhoea and will settle within 5 days, so a longer duration of symptoms should raise the suspicion of another cause. An insidious onset of nausea without vomiting can occur with functional dyspepsia, gastroparesis, medication use, gastro-oesophageal

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Box 9.1  Common causes of nausea and vomiting Intestinal obstruction Anatomic: – small bowel obstruction, e.g. adhesions; – gastric outlet obstruction, e.g. pyloric ulcer. ll Functional: – diabetic gastroparesis; – idiopathic gastroparesis; – chronic intestinal pseudo-obstruction. Infections ll Food poisoning ll Viral or bacterial diarrhoea ll Acute viral hepatitis Central nervous system disorders ll Migraine ll Meningitis ll Increased intracranial pressure ll Ménière's disease ll Motion sickness Metabolic disorders ll Renal failure ll Diabetic ketoacidosis ll Adrenal insufficiency (Addison's disease) ll Hyperthyroidism Visceral pain ll Peritonitis ll Cholecystitis ll Pancreatitis Drugs Psychiatric disorders ll Anorexia or bulimia nervosa ll Panic attacks Other ll Pregnancy ll Conditioned reflexes ll Cyclical vomiting ll Functional vomiting ll

reflux disease, pregnancy and metabolic disorders. Vomiting on waking in the morning may occur from excess alcohol use the night before. Early morning vomiting can also occur with pregnancy, renal failure and raised intracranial pressure. The character of the vomit is useful to document. Undigested food in the vomit may occur from oesophageal disorders (e.g. achalasia or Zenker's diverticulum). Gastric outlet obstruction may result in partially digested food, free of bile. In small bowel obstruction, the vomitus is usually

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Clinical gastroenterology: a practical problem-based approach

bile stained. Faecal vomiting indicates distal small bowel obstruction or a gastrocolonic fistula. The presence of other gastrointestinal symptoms such as abdominal pain or diarrhoea suggests a primary gastrointestinal disease. In the presence of significant weight loss with nausea and vomiting, consideration needs to be given to a gastrointestinal tract malignancy, intestinal obstruction or an eating disorder. An adolescent female with a history of repeated bouts of vomiting immediately after meals, particularly after binge eating, may have anorexia nervosa or bulimia nervosa; accompanying weight loss, fear of gaining weight, impaired body image, amenorrhoea and binge eating should be asked about. The vomiting is generally self-induced; laxatives, diuretics and vigorous exercise may also be used to prevent weight gain (Ch 17). Diseases of the central nervous system can present with vomiting. This may manifest as sudden projectile vomiting without nausea. Emesis may also be triggered by an abrupt change in body position. It is unusual for a patient with a brain tumour to present with vomiting in the absence of other neurological symptoms such as headache, vertigo, deafness, tinnitus or visual impairment. If the patient describes acute episodes of nausea and vomiting separated by intervening totally asymptomatic periods, this is suggestive of cyclical vomiting, which can occur in adults but is much more common in children; a history of migraine may be present. Symptoms of systemic diseases that may cause nausea and vomiting, including diabetes mellitus, renal failure, hypercalcaemia and hyperthyroidism, should be actively sought. Gastro-oesophageal reflux disease can present with recurrent vomiting in the absence of heartburn and acid regurgitation. Chronic nausea with little or no vomiting, and not accompanied by other symptoms or signs, presents a diagnostic challenge. Organic diseases rarely cause chronic persistent nausea alone. In the first trimester of pregnancy, nausea and vomiting are common. All women of childbearing age should have pregnancy excluded as a cause.

Physical Examination An abdominal examination may reveal evidence of obstruction, malignancy or peritoneal signs, but is usually negative in the patient with chronic symptoms. Scars from previous surgery should be noted. Assessment of hydration status (skin turgor, mucous membranes, pulse, and blood pressure lying and standing) is important in terms

of management decisions. The pigmentation of Addison's disease should be looked for. Evidence of fever should be sought. Chronic vomiting can also cause dental erosions and caries. Selfinduced vomiting can cause calluses or ulcers on the dorsum of the hand and dental erosions (from acid) and hypertrophied salivary glands. Pinheadsized red macules on the face and upper neck may occur with recurrent vomiting. A careful neurological examination should be conducted. Evidence of nystagmus may occur in labyrinthitis. Focal neurological signs are usually present if there is a central nervous system cause for the nausea and vomiting, although the changes may be relatively subtle. Look in the fundi for evidence of raised intracranial pressure.

Investigation Investigation is undertaken to: 1. define any derangements that may result from the loss of fluid and electrolytes during vomiting; and 2. determine the diagnosis of the underlying cause. The investigations need to be guided by the initial history and physical examination. Serum electrolytes will exclude hypokalaemia, renal failure and metabolic alkalosis due to chronic loss of gastric contents. Serum albumin levels, if low, would suggest a chronic disease or malnutrition. Anaemia would suggest colonic or small bowel disease, whereas leucocytosis would suggest an inflammatory process. If there is upper abdominal pain, pancreatic and liver enzymes can be useful. Peripherally, eosinophilia can occur in eosinophilic gastroenteritis, which can present with recurrent vomiting. Pregnancy testing is mandatory before radiographic testing in any woman of reproductive age with new-onset nausea and vomiting. A suggested management algorithm for chronic nausea and vomiting is shown in Figure 9.1. Supine and upright abdominal x-rays will document small bowel obstruction, although in 20% of cases partial small bowel obstruction can be missed with plain films. Upper endoscopy will exclude gastric outlet obstruction and significant gastroduodenal disease, such as peptic ulcer. If small-bowel follow-through fails to reveal evidence of obstruction, which can occur with a partial lesion, an enteroclysis (where barium and methylcellulose are infused into the proximal intestine via a nasojejunal tube in order to provide double-contrast pictures) or computed tomography enterography can be useful. If there is

NAUSEA OR VOMITING Exclude pregnancy, localised pain, drugs

History/physical examination Acute

Chronic

Not toxic

Febrile, dehydrated

After meal

Viral gastroenteritis

Abdominal X-rays

Peptic ulcer Gastric malignancy

Distended bowel/ feculent vomitus

Oral fluids, anti-emetics

Gastric outlet obstruction Gastroscopy Normal

Structural lesion

Multiple air fluid levels Persists

Investigate as chronic

Several hours after meal

Symptoms persist Treat

Yes

No

Bowel obstruction

Observe and rehydrate

Persists Investigate as chronic

Figure 9.1  Diagnostic algorithm for nausea and vomiting.

Exclude secondary causes

Impaired gastric emptying Treat

Normal gastric emptying Exclude psychiatric or CNS disease

9 Nausea and vomiting

Resolves

Further tests

109

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Clinical gastroenterology: a practical problem-based approach

any suggestion of lower bowel obstruction, barium enema or colonoscopy should be undertaken. Endocrine disease may present with chronic vomiting and, therefore, testing should be done to exclude diabetes mellitus, hypothyroidism and, in particular, Addison's disease. If the patient has normal structural evaluations and continues to be symptomatic, gastric emptying testing can be undertaken. An alternative is 13 C octanoic acid breath testing, which is nonradioactive and can be used in children or pregnant women. However, symptom improvement on prokinetics correlates poorly with changes in gastric emptying, and abnormal emptying is not a reliable way to direct management of nausea and vomiting. Another controversial test is electrogastrography. Cutaneous electrodes can measure the gastric slow wave activity. In the setting of vomiting, there may be slow (bradygastria) or fast (tachygastria) myoelectric rhythms, but this has not been established to be useful for directing treatment of chronic nausea or vomiting. Antroduodenal manometry is valuable in specialised centres. Approximately 40% of patients with unexplained nausea and vomiting have normal results, and the test alters management in only about 10% of cases. It is useful to consider this test when symptoms continue to be very troublesome; normal results of antroduodenal manometry should direct evaluation outside the gastrointestinal tract, which is of value.

Consequences of Nausea and Vomiting The main complications with acute vomiting include trauma to the distal oesophagus as well as severe fluid and electrolyte disturbances. Recurrent vomiting may result in laceration of the oesophageal mucosa at the gastrooesophageal junction, and a small amount of blood may streak the vomitus, typically following repeated vomiting. Haemorrhaging may occur as a consequence of a laceration to the mucosa into the submucosa, termed a Mallory-Weiss tear. If the laceration extends through the submucosa and the serosa to result in an oesophageal perforation, this is called Boerhaave's syndrome. This perforation typically enters the left chest cavity, producing intense pain. Acute severe vomiting, particularly in patients with neurological defects or impaired consciousness from alcohol intoxication, may result in aspiration of vomitus into the lungs. Recurrent vomiting in young and elderly people, particularly, may result in severe fluid

and electrolyte disturbances. Most of these losses occur from the vomited secretions of the stomach and upper small intestine. As hydrogen, sodium, potassium and chloride irons are lost from gastric secretions, prolonged vomiting results in metabolic alkalosis, hypokalaemia and dehydration. Occasionally, a patient who is vomiting will conceal it and present with unexplained hypochloraemic hypokalaemic metabolic alkalosis. Here, the differential diagnosis includes surreptitious diuretic use, primary hyperaldosteronism and Bartter's syndrome. The urine chloride is typically low with vomiting (or diuretics). Chronic nausea and vomiting significantly impair quality of life, and warrants appropriate therapy.

Important Diseases that may cause Nausea and Vomiting Gastric and intestinal obstruction The nature of vomiting and associated symptoms caused by intestinal obstruction depends on the level of the gut involved as well as the rapidity with which the obstruction occurs (Ch 4). Acute small bowel obstruction is more likely to be associated with severe pain compared with obstruction of a more insidious onset. Bile is almost always present in the vomitus when the obstruction is below the duodenal ampulla. The vomiting of partially digested food one to several hours after eating would suggest obstruction at the pylorus. Malignant obstruction of any form is usually accompanied by anorexia and weight loss. Complete obstruction of the stomach or duodenum usually results in the loss of large volumes of fluid in the vomitus (Ch 4). Functional obstruction, as seen in diabetic gastroparesis or postvagotomy, differs from mechanical gastric obstruction in that intense nausea and anorexia are more common; signs of peripheral and autonomic neuropathy are usually present if diabetes mellitus is the cause. Postprandial fullness and early satiety are common symptoms with diabetic gastroparesis. Physical examination of the abdomen varies depending upon the cause of the obstruction. In pyloric obstruction, upper abdominal distension and a succussion splash may be observed. Generalised abdominal discomfort may be noted. Distended loops of bowel are observed with peristaltic rushes early in intestinal obstruction, but absent bowel sounds are noted later.

9 Nausea and vomiting

111

Infection

Visceral pain

Acute viral gastroenteritis may result in vomiting. Bacterial gastroenteritis induces vomiting usually accompanied by fever and diarrhoea (see Ch 13). Nausea and vomiting, which occasionally may be prolonged and result in dehydration, may be prominent characteristics of acute viral hepatitis (Ch 24).

Vigorous stimulation of visceral afferent fibres either due to direct external pressure on certain organs such as the kidney and the testis or via unusual distension, as in obstruction of the intestine, ureter, cystic duct or common bile duct, results in nausea and vomiting. In addition, local inflammation in any of the above organs is frequently accompanied by nausea and vomiting (e.g. with mumps, orchitis, cholecystitis or ascending cholangitis). Nausea and vomiting also occur with acute pancreatitis. Infiltration of the gastrointestinal tract (e.g. eosinophils in eosinophilic gastroenteritis, amyloid in amyloidosis or malignant cells in carcinoma or lymphoma) may be associated with vomiting. Severe pain in other areas outside the abdomen may also be accompanied by nausea and vomiting (e.g. acute myocardial infarction).

Central nervous system disorders Space-occupying lesions with increased intracranial pressure are a cause of vomiting often without associated anorexia or nausea. The vomiting may be sudden and projectile in nature, and may occur early in the morning or with a sudden change in body position. Signs of raised intracranial pressure such as papilloedema on fundoscopy may not always be present. Radiological investigations, including magnetic resonance imaging of the brain, are important to perform if persistent or recurrent vomiting of unknown cause is being investigated. Nausea and vomiting due to diseases of the vestibular apparatus are accompanied by vertigo and nystagmus. Tinnitus also accompanies Ménière's disease. Migraine headaches that are often unilateral and may be accompanied by a prodrome of visual disturbances are characteristically associated with nausea and vomiting.

Psychiatric disease Nausea and vomiting are prominent symptoms in eating disorders, including anorexia nervosa and bulimia nervosa (Ch 17). Panic attacks can also cause nausea. If nausea is not accompanied by anorexia or is associated with weight gain, an organic cause is rarely observed.

Metabolic disorders

Pregnancy

In certain metabolic disorders, vomiting is invariably present, such as in untreated renal failure and in diabetic ketoacidosis. Nausea and sometimes vomiting may accompany hypoadrenalism (Addison's disease) and less commonly hyperthyroidism.

In any woman of childbearing age who describes nausea of recent onset, a pregnancy test should be considered. Morning sickness may also occur in susceptible women who use oral contraceptives. Morning nausea during the first 12 weeks of pregnancy is common and occurs in up to 90% of normal pregnancies. Accompanying vomiting, however, occurs in only 25–50%. The nausea usually resolves spontaneously as the day progresses, with the appetite returning to normal in the afternoon and evening. In the majority of pregnant subjects, nausea and vomiting is self-limiting and disappears spontaneously in the first trimester. If vomiting is severe and is associated with dehydration or electrolyte disturbances, it is termed ‘hyperemesis gravidarum’. The cause is unknown. This state can potentially threaten the fetus and mother because of electrolyte disturbances and nutritional deficiencies.

Drugs The potent emetic agent Ipecac is given as a therapeutic agent to induce vomiting. Morphine and opiate derivatives produce nausea and vomiting in some people when given in therapeutic doses, and in most patients when given in large doses. Non-steroidal anti-inflammatory drugs may be associated with nausea and sometimes vomiting in susceptible individuals with or without accompanying peptic ulcer disease. Other gastric irritants such as iron preparations can also cause nausea. Erythromycin, despite its prokinetic actions, often induces nausea. Both digitalis and theophylline preparations may cause insidious nausea and occasionally vomiting; they may have been taken for months or years before symptoms occur because of a narrow margin between toxic and therapeutic levels.

Conditioned reflexes An offensive sight (e.g. blood) or unpleasant smell may result in immediate nausea and sometimes vomiting in susceptible people. Conditioning may

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Clinical gastroenterology: a practical problem-based approach

occur in response to such sights or smells, so that nausea and vomiting is more easily precipitated by the same circumstances in the future. Such conditioning also applies to motion sickness and the vomiting induced by chemotherapy.

Medical therapy

Motion sickness is treated with anticholinergic agents such as scopolamine. This can be given as a transdermal patch. Sometimes this will also help gastrointestinal causes of nausea and vomiting. H1-receptor antagonists such as promethazine (25 mg four times a day) or diphenhydramine (25– 50 mg three to four times a day) can be helpful in vestibular disturbances and motion sickness, and sometimes improve gastrointestinal-related nausea. 5-HT3 antagonists (e.g. ondansetron, granisetron and dolasetron) are useful in postoperative vomiting, in prevention of chemotherapy-induced emesis and after radiation therapy, but appear to produce relatively little improvement in other forms of vomiting. Tetrahydrocannabinol and nabilone have proven useful in chemotherapyinduced emesis. These cannabinoids can produce drowsiness, orthostatic hypotension, dry mouth and tachycardia, as well as anxiety, depression and visual hallucinations. The neurokinin-1 antagonist aprepitant is indicated for chemotherapy-induced nausea and vomiting. It is given orally (80–125 mg) and side effects include somnolence, fatigue and hiccups. Talnetant and osanetant are other neurokinin antagonists. Any benefit in gastrointestinal disease is uncertain.

Antiemetics Neuroleptic agents such as prochlorperazine, chlorpromazine or haloperidol have both anticholinergic and antihistamine effects as well as blocking dopamine D2 receptors in the chemoreceptor trigger zone. Sedation, blood dyscrasias, dystonia and jaundice are potential side effects. Prochlorperazine (5–10 mg three times a day) is most widely used and can be given orally, rectally or parenterally.

Prokinetic agents Metoclopramide (5–20 mg four times a day) is a substituted benzamide, and is a dopamine D2receptor antagonist. It has central antidopaminergic effects and stimulates cholinergic actions locally in the gut. It is associated with side effects including drowsiness, dystonia, parkinsonism and, rarely, cardiac arrhythmias or tardive dyskinesia (which can be irreversible despite ceasing the medication, particularly in the elderly). Metoclopramide

Principles of Treatment Treatment involves successfully correcting any dehydration and electrolyte abnormalities. Malnutrition should also be corrected, if present. If clinically necessary, intravenous fluids (normal saline with potassium) should be given and a nasogastric tube put in place; the output, which should be replaced intravenously, should be measured. Dietary modification is particularly important if there is evidence of gastroparesis. Frequent small meals (six per day), a low-fat diet, avoidance of indigestible material to reduce the chance of bezoar formation and reduced fibre intake can all be useful. Splitting the ingestion of liquids and solids may reduce symptoms. Liquids are generally tolerated better than solids in this setting, and so the use of a blender or liquid formulas can be helpful. Medical therapy (Table 9.1) may be necessary.

Table 9.1 Examples of drugs to control nausea and vomiting Drug

Site of action

Administration

Comment

Diphenhydramine

Antihistamine (H1-blocker)

Oral/parenteral (25–50 mg × 3–4)

Sedative Motion sickness

Prochlorperazine

Phenothiazine

Oral/parenteral/rectal (5–10 mg × 3)

Extrapyramidal side effects

Hyoscine

Anticholinergic

Transdermal

Motion sickness

Metoclopramide

Dopamine D2 antagonist

Oral/parenteral (5–20 mg × 4)

Neurological side effects

Domperidone

Dopamine D2 antagonist

Oral (10 mg × 4)

No neurological side effects

Ondansetron

Serotonin receptor 5-HT3 antagonist

Oral/parenteral (8 mg × 3)

Cancer chemotherapy

9 Nausea and vomiting is available both orally and parenterally. Domperidone is another substituted benzamide that poorly penetrates the central nervous system and so has fewer central side effects. It can cause cardiac arrhythmias and gynaecomastia (5%). Erythromycin is a macrolide antibiotic that, through motilin receptors, accelerates gastric emptying. However, it has a very narrow therapeutic window and high doses induce nausea. While the drug may accelerate emptying, it usually does not relieve symptoms when taken orally for nausea and vomiting. Other motilin agonists have proven disappointing in clinical studies of functional dyspepsia. Benzodiazepines Lorazepam and other benzodiazepines can reduce anticipatory nausea and vomiting prior to chemotherapy, although any benefit in other causes of nausea and vomiting is unclear. They may be a useful adjunctive treatment in combination with other therapy. Tricyclic antidepressants Limited data from primarily retrospective analyses suggest that low-dose tricyclics will reduce chronic nausea and vomiting in up to 80% of patients with functional bowel disease. Botulinum toxin injection Patients with gastroparesis may have temporary symptom reduction after injection of botulinum toxin into the pylorus, although data are limited. Gastric electrical stimulation Gastric electrical stimulation is emerging as a potentially useful therapy for refractory gastroparesis with nausea and vomiting. Applying stimulation parameters at four times the basal rate (12 cycles per minute), symptoms, but not gastric emptying, have been reported to improve. The neurostimulators are placed in the subcutaneous pouch and the electrodes are placed along the greater gastric curvature at laparotomy or laparoscopy. High-frequency gastric electrical stimulation is approved for patients with chronic intractable nausea and vomiting due to idiopathic or diabetic gastroparesis. Alternative treatments Acupressure or acupuncture, ginger, hypnosis, transcutaneous electrical nerve stimulation, behaviour modification treatments and psychological therapies are of some efficacy in selected clinical settings, but data remain limited, particularly in terms of idiopathic nausea and vomiting.

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Specific Clinical Scenarios Gastroparesis Start with an antiemetic and prokinetic agent in combination. Combination therapy tends to be more useful than in the clinical setting. If maximal medical therapy fails, options include gastric electrical stimulation, endoscopic placement of a percutaneous endoscopic gastrostomy, jejunostomy or a subtotal gastrectomy in extreme cases. Gastric bypass procedures and less extensive gastric resection should be avoided as they give much poorer results.

Cyclical vomiting syndrome This is a condition characterised by discrete acute episodes of nausea and vomiting with completely asymptomatic intervening periods. Migraine headaches, motion sickness and atopy may be positive on history taking. While primarily a condition of childhood, there are reports in adults. Typically in adults, the episodes of nausea and vomiting last for 3–6 days. Cyclical vomiting is often associated with abdominal pain (in twothirds of patients) and psychiatric diagnoses are uncommon (in one-fifth). In children, an association with mitochondrial DNA mutations has been described. Tricyclic antidepressants appear to be useful for this syndrome. Antimigraine therapy (e.g. beta-blockers or sumatriptan) may also be of some value, particularly if there is a family history of migraine. Cannabis hyperemesis can mimic cyclic vomiting syndrome; compulsive bathing to relieve symptoms is a characteristic feature.

Functional vomiting This is a rare condition that has been defined by the Rome Foundation Committee (Box 9.2). If gastric emptying is delayed, it is important to exclude chronic intestinal pseudo-obstruction as well as mechanical intestinal obstruction. No medications have established efficacy in this group, but anecdotally, tricyclic antidepressants seem to be of value and can be tried at a low dose, but may require full dose to be efficacious.

Key Points ll

ll

Nausea is a painless, unpleasant, subjective feeling of wanting to vomit, while vomiting is the forceful expulsion of gastric or intestinal contents through the mouth. ‘Retching’ describes contractions of the abdominal muscles that typically precede vomiting.

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Box 9.2  Functional vomiting diagnostic criteria ll

ll

ll

ll

Frequent episodes of vomiting, occurring on at least 1 separate day in a week over 3 months Absence of criteria for an eating disorder, rumination or significant psychiatric disease Absence of self-induced and medicationinduced vomiting Absence of abnormalities in the gut or central nervous system, and metabolic diseases to explain the recurrent vomiting

From Rome III. The functional gastrointestinal disorders. 3rd edn. 2006:331, with permission. http://www.romecriteria.org

ll

ll

ll

ll

Regurgitation is an effortless movement of gastric material into the mouth. Rumination syndrome is the effortless regurgitation of recently ingested food back into the mouth and is not preceded by nausea; patients may say they are ‘vomiting’. All women of childbearing age must have pregnancy excluded as a cause of nausea or vomiting. Chronic nausea without vomiting can be caused by functional dyspepsia, gastroparesis, medication use, gastro-oesophageal reflux disease, pregnancy and metabolic disorders. Early morning vomiting occurs in pregnancy, in renal failure and with raised intracranial pressure.

ll

ll

ll

ll

Self-induced vomiting (bulimia) can cause calluses or ulcers on the dorsum of the hand and dental erosions (from acid). Haemorrhaging may occur as a consequence of vomiting from a laceration to the mucosa into the submucosa—a Mallory-Weiss tear. If there is vomiting, any dehydration and electrolyte abnormalities must always be checked and corrected. Dietary modification is important if there is evidence of gastroparesis. Antiemetic and prokinetic therapy is helpful in combination for this syndrome.

Further reading Abell TL, Bernstein RK, Cutts T et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil 2006; 18:263–283. Bai Y, Xu MJ, Yang X, et al. A systematic review on intrapyloric botulinum toxin injection for gastroparesis. Digestion 2010; 81(1):27–34. Ma J, Rayner CK, Jones KL, et al. Diabetic gastroparesis: diagnosis and management. Drugs 2009; 69(8): 971–986. Parkman HP, Camilleri M, Farrugia G, et al. Gastroparesis and functional dyspepsia: excerpts from the AGA/ ANMS meeting. Neurogastroenterol Motil 2010; 22(2):113–133. Quigley EMM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology 2001; 120:263–286. Soffer E, Abell T, Lin Z, et al. Review article: gastric electrical stimulation for gastroparesis— physiological foundations, technical aspects and clinical implications. Aliment Pharmacol Ther 2009; 30(7):681–694.

10 Vomiting blood, black stools, blood per rectum, occult bleeding

Case A 67-year-old male presents to the emergency department with a history of a massive haematemesis (fresh blood) over 12 hours. He was unwell and also complained of syncopal episodes. He had no previous episodes. There was a past history of hepatitis C infection. Alcohol consumption was 120 g/day, which he ceased 2 years back. Examination revealed a pale man, with a pulse of 110/min and a blood pressure of 90/65 on admission (10 mmHg postural drop). There were no signs of chronic liver disease. Assessment: Haematemesis likely reflecting upper gastrointestinal bleeding complicated by hypovolaemic shock. Differential diagnosis included bleeding peptic ulcer and bleeding oesophageal varices. Management: Intravenous fluids—haemacell as a volume expander. Urgent full blood count revealed a haemoglobin level of 65 g/L. Four units packed cells were transfused. Intravenous esomeprazole was initiated together with an octreotide infusion. Subsequent management: Gastroscopy in theatre with intubated patient as there was a risk of aspiration (blood). Findings: Altered blood in the stomach with blood clots, but cherry red spot on one of three oesophageal varices. The varices were banded. Subsequent management: Over the next 8 hours the blood pressure returned to 120/70 and pulse to 88/min. Esomeprazole and octreotide infusion ceased as patient made a good recovery and was discharged on day 5. Ultrasound of the abdomen suggests cirrhotic liver with portal hypertension, enlarged spleen and splenic varices. Further elective banding planned as well as the introduction of propanolol. Patient had already ceased alcohol consumption, but abstinence

further reinforced. Further plans were made to review as an outpatient to evaluate and possibly treat the chronic hepatitis C infection.

Introduction Assessment and management of gastrointestinal bleeding is at times a challenging area of clinical practice. The problem is common and very diverse in its presentation, ranging from occult microscopic bleeding to massive, life-threatening haemorrhage from an ulcer or bleeding oesophageal varices. Patients who present with gastrointestinal bleeding often require a multidisciplinary approach encompassing a variety of skills. Patients with severe bleeding often require urgent attention from emergency medicine doctors who are well-versed in resuscitation principles and a gastroenterologist with a good knowledge of the causes of gastrointestinal bleeding and understanding of the appropriate investigations and treatments. It is commonplace for the gastroenterologists to work in a team that includes a surgeon and interventional radiologist. Five different clinical situations are commonly encountered: 1. vomiting bright red blood or altered ‘coffee grounds’ blood. There may also be associated melaena or passage of tarry black bowel motions; 2. passage of melaena alone without any vomiting; 3. passage of bright red blood per rectum—this may range from a trace on the toilet paper to a life-threatening massive bleed; 4. iron-deficiency anaemia without any visible blood loss from the gastrointestinal tract (occult bleeding); and 5. blood loss detected on screening by a faecal occult test. The approach to management of these clinical situations forms the basis of this chapter.

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Definitions Haematemesis means vomiting blood, whether it is bright red, dark and clotted, or ‘coffee grounds’. Haematemesis indicates that bleeding originates from a site proximal to the ligament of Treitz. A history of fresh haematemesis usually implies a significant bleed. ‘Coffee ground’ vomiting may arise from altered black blood. Coffee grounds emesis often indicates that active bleeding may have ceased. The ‘coffee grounds’ appearance is due to gastric acid breaking down the haemoglobin in red blood cells to form haematin. If the patient vomits ‘coffee grounds’, he or she may not recognise that this is due to internal bleeding and a delay in presentation to the doctor may occur. Melaena is the passage of black tarry stool. It occurs when haemoglobin is converted to haematin by bacterial degradation. Ingestion of as little as 200 mL of blood can produce melaenic stool. Although melaena generally implies bleeding proximal to the ligament of Treitz, bleeding from the small bowel or proximal colon may also cause melaena, especially when colonic transit is slow. Hematochezia is the passage of pure red blood or blood mixed with stool. It usually occurs when bleeding comes from the lower gastrointestinal tract. It can also present in a massive upper gastrointestinal bleeding (in 10–15%) when there is rapid intestinal transit.

Vomiting Blood Haematemesis is a common clinical problem. More than 50% of these patients are over 60 years of age, many have other medical problems and management is both urgent and complex. The overall mortality from haematemesis is of the order of 10%, though there are certain high-risk groups (e.g. patients over the age of 60 years) that can be identified and targeted for more aggressive management. The main causes of haematemesis are listed in Box 10.1. So how do these patients present? They may feel nauseous and even continue to vomit during the initial assessment or have symptoms related to blood loss including sweating, dizziness and confusion.

Management The first goal in managing a patient with haematemesis is to resuscitate him or her and ensure that the haemodynamic state is stable. Limited time is available for detailed history taking and physical examination. The most important initial steps are as follows:

Box 10.1  Causes of haematemesis Very Common Gastric or duodenal ulcer or gastric erosions Common ll Mallory-Weiss tear (a laceration at the gastro-oesophageal junction) ll Ulcerative oesophagitis ll Oesophageal or gastric varices ll Portal hypertensive gastropathy Uncommon ll Vascular malformations, angiodysplasia and vascular ectasia ll Ulcerated gastrointestinal stromal tumour ll Carcinoma of oesophagus, stomach or duodenum ll Aortoenteric fistula ll

Ensure that the patient's airway is clear. Check for shock and hypotension and organise blood or fluid replacement. ll Check if the patient is still actively bleeding. ll Look for clues as to the source of bleeding. These important steps will be considered in more detail below. Delays in assessment and the institution of proper management may prove fatal. ll ll

Airway The mental state should be noted carefully because a drowsy or comatose patient is at high risk of aspiration if he or she continues to vomit blood. The mental state may be impaired by a number of factors, including: ll severe, acute blood loss leading to cerebral hypoperfusion; ll concomitant chronic liver disease or renal failure leading to encephalopathy; and ll alcohol or drug intoxication or overdose. If the patient is unconscious or has an impaired gag reflex, the airway must be protected, especially if vomiting continues. The patient should be kept flat on his or her side. A cuffed endotracheal tube may need to be inserted. Such patients should be managed in an intensive care facility. Hypotension and shock Assessment of hypovolaemia involves simple bedside clinical observations. The patient may be clammy and sweaty with cold peripheries and a fast thready pulse. There may be associated

10 Vomiting blood, black stools, blood per rectum, occult bleeding confusion. The blood pressure will be low, often under 90 mmHg systolic. If any of these signs are seen, resuscitation should commence immediately. At least two large-bore intravenous cannulae should be inserted into large peripheral veins. A central venous line should be placed in high-risk cases (see below). Rapid infusion of isotonic saline followed by a plasma expander such as Haemaccel® should be commenced and blood samples should be drawn urgently for full blood count, coagulation screen, blood group and cross-matching of four to six units of packed cells, and urea, electrolytes and liver function tests. As a rule of thumb, patients who have obvious signs of shock, with clammy peripheries and low blood pressure, may have lost up to 50% of their circulating blood volume. If these signs are not present, the patient may be sat up carefully and a check made for a postural drop in blood pressure. If this is present, it is likely that 10– 20% of blood volume has been lost. Remember that with haemoconcentration immediately after a bleed, the haemoglobin may initially be near normal despite the loss of a considerable amount of blood. Patients with a gastrointestinal bleed have lost ‘whole blood’ and there is, therefore, logic in transfusing them with whole blood (Box 10.2). In practice, however, donated blood is separated into packed cells and other products, such as platelets and plasma, which may be used in different clinical situations. Thus, in current clinical practice, patients with a significant bleed are given packed cells alternating with a plasma expander such as Haemaccel if they are hypovolaemic and packed cells alone if they are normovolaemic but anaemic. The aim of transfusion is to restore circulating blood volume so that the blood pressure is normal and to correct anaemia so that the oxygen carrying capacity of the blood is satisfactory. This generally means maintaining a haemoglobin level of approximately 100 g/L. One

Box 10.2  Indications for blood transfusion in patients with gastrointestinal bleeding Consider transfusing if: blood pressure < 110 mmHg or ll postural hypotension (> 10 mmHg) or ll pulse > 110/min or ll haemoglobin < 70 g/L* ll

*May be a normal haemoglobin level with severe bleeds initially.

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unit of packed cells will increase the haemoglobin level by 10 g/L (haematocrit by 3%). In hypovolaemic patients, packed cells are transfused rapidly until the patient is haemodynamically stable. Rarely, group-specific uncross-matched blood or O rhesus-negative blood will be required. In haemodynamically stable patients, packed cells are transfused slowly, approximately one unit every 2 hours. If the patient is coagulopathic or needs more than four units of packed cells, fresh frozen plasma (two units initially) should also be given to provide clotting factors. Active bleeding As resuscitation is proceeding, it is important to consider whether bleeding is still active. This assessment is straightforward if the patient continues to vomit bright red blood or if the blood pressure keeps falling. Passing melaena does not necessarily signify active bleeding; it may simply be old blood that has worked itself through the bowel. However, if the patient starts to pass more ‘fresh’ melaena, which is maroon-coloured or even bright red with visible clots, active bleeding is likely. Source of the bleed A targeted history should be obtained if possible from the patient or from the family. Particular attention should be given to: ll the amount of blood vomited and any obvious precipitant; violent retching before the haematemesis suggests that bleeding may be from a traumatised oesophagogastric junction such as a Mallory-Weiss tear; ll a history of dyspepsia (often absent in older patients who have non-steroidal antiinflammatory [NSAID]-induced ulceration) or previous peptic ulcer, liver disease, oesophageal varices or previous bleeds; and ll recent ingestion of aspirin, NSAIDs, warfarin, alcohol or selective serotonin reuptake inhibitors (SSRIs). The patient should be assessed, focusing on the following points: ll close and repeated monitoring of haemodynamic state with pulse and blood pressure measurements—hourly initially; central venous pressure monitoring may also be used, especially in high-risk, unstable patients and those with a history of cardiac failure for whom the problem of fluid overload from overenthusiastic transfusion is nearly as much a concern as under-transfusion;

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Figure 10.1  Arterial spurting from a gastric ulcer. ll

ll

ll

Figure 10.2  Gastric varices.

signs of chronic liver disease (e.g. spider naevi or palmar erythema) and, in particular, portal hypertension; splenomegaly in a patient with signs of liver disease or a history of alcohol abuse suggests that portal hypertension may be present and that bleeding may be from varices; consideration of some rare causes of bleeding— for example, signs of cutaneous or buccal telangiectasia, which may be a marker for hereditary haemorrhagic telangiectasia (OslerWeber-Rendu syndrome), should be checked for; this condition is rare and associated with gastrointestinal bleeding from telangiectasia in the stomach or small or large intestine; and a baseline haemoglobin measurement should be obtained and then measured twice daily, initially, in more severe cases.

Endoscopy Even if the history points to a likely diagnosis (e.g. past history of duodenal ulcer), the cause of bleeding may be different on this occasion. Studies have shown that the clinical diagnosis as to the most likely cause of an upper gastrointestinal bleed is correct in only 60% of cases. Thus, investigation is necessary to establish a correct diagnosis. Upper gastrointestinal endoscopy is the single most useful test. If performed within 24 hours of presentation, the cause of bleeding will be found in 90–95% of patients (Figs 10.1 to 10.3). Furthermore, it may permit the endoscopist to perform therapeutic interventions that in turn may arrest the bleeding or minimise the chance of

Figure 10.3  Gastric arteriovenous malformation.

further bleeding. It requires considerable expertise, especially in the situation of an actively bleeding lesion, and is not without some risk. So who should be endoscoped and when should it be done? This decision is more easily made if consideration is given to why the endoscopy is being done. First, the aim is to make an accurate diagnosis. Secondly, a prognosis for further bleeding may be given, based on the endoscopic findings. Finally, a bleeding lesion or one at high risk of re-bleeding may be able

10 Vomiting blood, black stools, blood per rectum, occult bleeding

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Box 10.3  High risk features in patients with haematemesis ll ll

ll ll

ll ll

Older age (over 60 years old) Associated serious medical conditions (e.g. chronic lung disease, cerebrovascular disease, recent myocardial infarction) Coagulopathy Magnitude of bleed (patients presenting with hypotension or shock are a high-risk group—this includes those patients with syncope, systolic blood pressure below 100 mmHg and if more than four units of blood are required over a 12-hour period) Re-bleeding after the initial bleed Endoscopic findings (variceal bleeding, peptic ulcer with arterial spurting, oozing, visible vessel or clot in the ulcer base)

to be treated. However, if the patient is not in a high-risk category, it may not be necessary to do an emergency procedure. In general terms, endoscopy should always be done within 24 hours but, for patients considered being at ‘high risk’, particularly if there is a possibility of oesophageal varices, emergency endoscopy should be arranged once the patient has been adequately resuscitated. Risk factors for greater morbidity and mortality from haematemesis are now well known and are listed in Box 10.3. These patients should be targeted for the most aggressive management with emergency endoscopy. Endoscopy for acute haematemesis requires a high level of skill and experience. The main risk to the patient is of aspiration of blood, especially if sedation is used, and all staff must be aware of the need to protect the patient's airway with a cuffed endotracheal tube, if necessary. There is some evidence to support the administration of intravenous erythromycin (approximately 250 mg) prior to endoscopy. The prokinetic effect of this drug clears blood from the stomach, thereby potentially improving visualisation of bleeding lesions and probably also reducing aspiration risk. It should be noted that in about 80% of patients bleeding has stopped spontaneously upon presentation. In the remaining 20% of patients, bleeding persists or recurs during their period of hospitalisation. The mortality in this group increases as much as eightfold compared to those without further bleeding.

Figure 10.4  Injection sclerotherapy equipment for variceal bleeding.

Common causes of haematemesis Oesophageal varices Oesophageal varices are dilated submucosal veins forming a portal systemic circulation anastomosis in patients with portal hypertension. They look like large varicose veins and bulge into the oesophageal lumen. Arising from these veins are very thin-walled vascular channels, lined only by endothelium, extending into the squamous epithelium of the oesophagus. These have a high risk of rupture, which is considered to be mainly precipitated by sudden pressure rises. About 50% of patients with cirrhosis of the liver have oesophageal varices, and 30% of these varices bleed within 2 years of their diagnosis. After bleeding, the risk of further bleeding is very high—about 70% over the ensuing 2 years. The mortality rate from bleeding oesophageal varices ranges from 40% to 70%. Predictors of haemorrhage include the presence of very large varices and varices with ‘cherry red spots’. These red spots represent the intraepithelial vascular channels arising from the varices. Ongoing alcohol ingestion, thrombocytopenia and poor liver synthetic function are also predictors of variceal bleeding. If bleeding oesophageal varices are found during endoscopy, rubber band ligation is the current treatment of choice. Bleeding can be controlled in 80–90% of cases with a relatively low risk of complications. If passage of the rubber band ligating device mounted on the tip of the endoscope is not feasible or if equipment and expertise for rubber band ligation are not available, injection sclerotherapy may be performed (Fig 10.4). This involves direct injection of a sclerosant such as ethanolamine oleate or sodium tetradecyl sulfate into the varices. Injection sclerotherapy has a very high success rate

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in controlling the bleeding, although with a greater risk of complications including sepsis, oesophageal stricture and mediastinitis. Pharmacological treatment is frequently used in the control of variceal bleeding. The most widely used drug in this situation is intravenous octreotide, which is an analogue of somatostatin. It can be given acutely in the emergency room if there is a high index of suspicion that varices are the cause of the bleed, even before endoscopic confirmation. It is given by an initial bolus injection of approximately 25–50 mcg, followed by an infusion of 25–50 mcg octreotide per hour in 5% dextrose. An octreotide infusion is regarded as part of the resuscitation process. It works by decreasing portal venous blood flow and has been shown to control variceal bleeding in over 70% of cases. Octreotide is a safe and effective vasoactive agent. The benefit is more prominent if octreotide is prescribed early, even before endoscopy. Octreotide has also been shown to be effective when used as an adjuvant therapy in combination with endoscopic therapy. Recurrent bleeding episodes and hence requirement of transfusion are significantly reduced. Sometimes, the above approaches fail and the patient continues to bleed. This is a very high-risk situation and a long-term management plan must be prepared. Important questions are: ll What other methods of bleeding control are available? ll Is the patient suitable for an urgent liver transplant? ll Is the patient's general condition so poor and the severity of underlying liver disease so advanced that ongoing resuscitation is inappropriate? If ongoing aggressive management is decided upon, the next step should be to insert a Minnesota or Sengstaken-Blakemore tube (balloon tamponade) into the oesophagus and stomach (Fig 10.5). This can be passed through the nose, preferably with the patient anaesthetised, though in practice the tube is often inserted in an emergency situation without a general anaesthetic. Once the position of the tube has been confirmed by x-ray examination to be in the stomach, the gastric balloon is inflated to 300 mL with air or with water and the tube withdrawn so that the gastric balloon is snug against the cardia. This can be maintained in position by gentle traction using a weight of approximately 0.5 kg. Most variceal bleeding will stop since the oesophageal varices are ‘fed’ from veins passing up across the cardia and these are compressed by the gastric

Figure 10.5  Sengstaken-Blakemore tube.

balloon. If bleeding continues, the oesophageal balloon should be inflated to a pressure of 30–40 mmHg using a sphygmomanometer to monitor the pressure achieved. Patients who have a Minnesota or SengstakenBlakemore tube in situ need special monitoring in an intensive care environment and have a nurse dedicated to the care of the tube. It is imperative that the nurse watch carefully for displacement of the tube and regularly check the pressure in the oesophageal balloon. This technique may stabilise the patient until alternative treatments can be given. A further attempt at endoscopic sclerotherapy or rubber band ligation is the next step. If this fails to control the bleeding, other strategies must be considered. TIPS (transjugular intrahepatic portal systemic stent) is a radiological procedure that involves the creation of a fistula within the liver substance between the hepatic and portal veins, followed by insertion of an expandable metal stent. This forms a portal systemic shunt and lowers the pressure in the portal venous system. The technique is being increasingly used after failed banding or sclerotherapy and buys time for definitive longterm management such as liver transplantation. It certainly requires the presence of a highly experienced interventional radiologist. Mortality from bleeding oesophageal varices is still very high despite the advances in endoscopic and radiological management. The severity of the underlying liver disease is the main determinant of outcome. For those patients who do respond well to the initial banding or sclerotherapy, careful follow-up is required with ongoing endoscopic treatment at 1–3 weekly intervals until the varices are obliterated. These treatments can be given on a day-case basis. This treatment approach should be supplemented by a beta-blocking agent such as propranolol.

10 Vomiting blood, black stools, blood per rectum, occult bleeding Bleeding from gastric varices is a less frequent event. Injection therapy with cyanoacrylate (‘glue’) is frequently used.

Gastric or duodenal ulceration Ulcers bleed when an artery or other vessels in the base of the ulcer are eroded. If the bleeding is arterial in origin, it may be very brisk and rapidly lead to shock. In a young patient, there is good arterial contractility, which can cause spasm of the damaged vessel and bleeding may cease spontaneously. In an elderly patient with atherosclerotic arteries, this ability to induce arterial spasm is impaired and bleeding is more likely to continue. Endoscopic interventions may be used if a gastric or duodenal ulcer is found at endoscopy. These are particularly appropriate if there is active bleeding with oozing or arterial spurting, or an adherent blood clot, or a flat pigmented spot on the ulcer base or if there is a visible blood vessel in the base of the ulcer crater. These are stigmata, which predict a high risk of ongoing or recurrent bleeding. Several studies support aggressive management combining adrenaline injection therapy, clot removal and thermal ablation using a heater probe and haemostatic clips. The most widely used agent for injection is 1:10,000 adrenaline, which probably works by causing spasm of any feeding arteriole or artery and encourages platelet plugging and thrombosis. For actively spurting vessels or visible vessels in a peptic ulcer, thermal ablation therapy using a heater probe or bipolar electrocoagulation probe, often in combination with adrenaline injection and/or endoclips, is now the most widely utilised technique. If there is an index of suspicion of a bleeding peptic ulcer, an intravenous proton pump inhibitor infusion is usually initiated in the emergency department while waiting for an endoscopic diagnosis. Many studies have shown a clear reduction in the risk of re-bleeding when a proton pump inhibitor is used as primary therapy for bleeding ulcers without concomitant endoscopic therapy. Best results appear to occur with highdose infusion (e.g. omeprazole 8 mg per hour) over a period of 3–5 days. There is also theoretical evidence to support high-dose intravenous infusions, which elevate gastric juice pH to above 6, a level at which fibrinolysis of adherent clots is inhibited. Both regular and high-dose intravenous infusions of omeprazole have been shown to be effective at preventing re-bleeding in patients whose peptic ulcers have been treated initially by endoscopic therapy.

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Since there is a high risk of re-bleeding it is common practice in some centres to have a ‘second-look’ endoscopy 24 hours after the first endoscopic intervention. After bleeding has stabilised, definitive ulcer healing treatment is introduced; this comprises avoidance of ulcerogenic medications, such as aspirin or NSAIDS, administration of oral proton pump inhibitor therapy at standard dosage and eradication of Helicobacter pylori if identified on initial assessment (but note active bleeding can cause false negative testing). An endoscopy to document healing is often performed 4–6 weeks after treatment has been given, especially in a high-risk patient whose ulcer has bled without warning symptoms. The discovery that most peptic ulcers are caused by an infection in the stomach, courtesy of the bacterium H. pylori, has led to the frequent adoption of antibacterial therapy (Ch 5). Treatment of H. pylori in patients with peptic ulcer markedly reduces the risk of subsequent ulcer relapse and associated bleeding, without the need for long-term maintenance drug treatment. The current regimens will work in up to 80% of patients, eradicating the infection, healing the ulcer and markedly reducing the risk of ulcer recurrence. In the immediate aftermath of a haematemesis, clinicians may choose to use the simpler drug regimen of an H2-receptor antagonist or proton pump inhibitor alone to heal the ulcer and then, when the patient has stabilised and out of hospital, follow on with H. pylori eradication, or treat the infection as soon as the patient can eat at the same time as giving acid suppression drug therapy. The success of the treatment can be documented in the patient with a bleeding ulcer by taking gastric biopsies to look for the organism during a subsequent endoscopy 4 or more weeks after stopping therapy. Alternatively, a 14C or 13C urea breath test or stool antigen can be done. If a peptic ulcer is found in a patient receiving NSAID therapy, these drugs should be discontinued at least in the short term and, ideally, long term. Ulcer healing can then proceed along the lines outlined above. Some patients cannot manage without regular NSAIDs and, in that case, longterm prophylactic treatment with a proton pump inhibitor should be considered. Misoprostol can also be used to protect against recurrent gastric ulceration in a patient on NSAIDs. The COX-2 inhibitors can be used in these patients in place of traditional NSAIDs, but the risk of further bleeding is only reduced, not abolished, by this substitution

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and ideally these patients should also remain on a proton pump inhibitor. Other causes of haematemesis Acute gastric erosions and a Mallory-Weiss tear are usually self-limiting lesions that will heal fully over a matter of days. In the case of erosions, withdrawal of gastric irritants such as aspirin or NSAIDs should be done. A short course of a proton pump inhibitor is often prescribed. Ulcerative oesophagitis that bleeds sufficiently to cause an overt haematemesis is usually severe and requires aggressive acid suppression. Rarely, a chronic ulcer in a Barrett's oesophagus may bleed (Ch 1). By far the most effective treatment for oesophageal ulceration is with the proton pump inhibitors such as omeprazole, esomeprazole, rabeprazole or pantoprazole. Long-term therapy is likely to be needed. Laparoscopic fundoplication may also be considered as an alternative to longterm medical treatment.

Role of surgery in bleeding peptic ulcers Modern endoscopic treatments have reduced the need for surgical intervention in bleeding peptic ulcers. Nonetheless, some patients will be bleeding so massively at presentation that endoscopic therapy cannot be applied due to poor visualisation of the lesion, or endoscopic interventions fail to control the bleeding. A major arterial bleed (e.g. from the gastroduodenal artery in a posterior wall duodenal ulcer) is unlikely to respond to endoscopic therapy. Therefore, it is imperative that all high-risk patients be assessed early by a gastrointestinal surgeon. For patients with uncontrollable massive bleeding, emergency surgery can be life-saving and the decision to operate is usually straightforward. For patients whose bleeding continues at a slower rate or who have episodic re-bleeds despite initial endoscopic treatment, the timing of surgical intervention is more difficult and requires careful consideration of the risks of ongoing conservative management and blood transfusion balanced against the risks of an anaesthetic and operation. An experienced surgeon can give far better input to this decision if he or she has been reviewing the patient from admission rather than being called in at the last moment. Often the ultimate decision regarding surgical intervention depends on the expertise of the endoscopist, the endoscopy facilities and the experience of the surgeon and gastroenterologist. The choice of operation will vary according to the clinical circumstances. In most instances,

an oversewing of the bleeding artery is all that is performed since it is assumed that medical therapy afterwards will deal with the ulcer effectively. In some instances, especially if there is a history of recurrent bleeding or ulceration despite medical therapy, a more definitive operation will be performed, such as a partial gastrectomy for a gastric ulcer (Ch 6).

Discharge from hospital As a general rule, patients with bleeding should be admitted to hospital. There is a growing body of literature supporting same-day discharge in carefully selected patients following clinical and endoscopic evaluation. This would be an appropriate strategy for young, otherwise healthy individuals with clinically small bleeds in whom endoscopy shows minor erosive gastritis, mild oesophagitis or peptic ulceration without any high-risk stigmata. These patients can resume eating normally after the endoscopy. A long-term management strategy should be instituted. Patients with bleeding varices comprise the highest risk group and these patients should remain in hospital for up to a week, during which time the risk of massive re-bleeding is highest. Treatment also has to be directed to the underlying liver disease and its complications (Ch 24). Patients with high-risk peptic ulcers are at increased risk of re-bleeding for at least 72 hours after the initial bleed. Discharge from hospital is reasonable after 4–5 days if the patient's course in hospital has been uncomplicated.

Passing Melaena Alone This is a common clinical situation, sometimes badly managed, because the patient or the doctor underestimates the seriousness of the complaint. The patient may blame the colour of the motions on something eaten and not appreciate that the black colour is due to altered blood. The characteristic strong odour of melaena should help the clinician distinguish it from other causes of black-coloured motions (e.g. the use of iron supplements, bismuth or liquorice). Most cases of melaena are due to bleeding from the upper gastrointestinal tract, mainly from peptic ulceration. Oesophageal varices rarely present in this way, because they bleed so briskly that bright red haematemesis occurs long before melaena is seen. However, some patients with portal hypertension ooze blood more slowly from dilated blood vessels in the stomach (portal gastropathy, Fig 10.2) or intestine (portal enteropathy), and melaena may be the first sign.

10 Vomiting blood, black stools, blood per rectum, occult bleeding Therefore, all patients with active melaena should be assumed to have an upper gastrointestinal cause and be managed in exactly the same way as the patient who presents with haematemesis (including appropriate resuscitation as described above). Admission to hospital is warranted, even if the patient is haemodynamically stable, since the melaena from a mild initial bleed may herald a more severe life-threatening bleed to follow. If the melaena has been transient and is over a week old, it may be safe to investigate on an outpatient basis, though endoscopic evaluation should be done promptly, within a few days, so that an accurate diagnosis can be made and definitive treatment started. Some patients with melaena will not be bleeding from the upper gastrointestinal tract and the endoscopy will fail to show a lesion. Blood loss from the right colon or the small intestine may also present as melaena. Colonic lesions such as polyps, cancer, angiodysplasia and diverticula are much more common than small bowel lesions and the next step should, therefore, be a colonoscopy. If polyps are found, these can be removed by polypectomy during the examination. Bleeding angiodysplastic lesions can be treated by argon plasma coagulation or by injection sclerotherapy. If no abnormality is found on upper endoscopy and colonoscopy, a decision to investigate the small bowel has to be made. If there are any associated small bowel symptoms, small bowel evaluation with double or single balloon enteroscopy or capsule endoscopy should be considered. These tests can identify vascular lesions and angiodysplasia, small bowel tumours and inflammatory bowel disease. In some cases, more extensive evaluation with enteroclysis, Meckel's scanning and angiography will be required. This will be discussed further in the next section. If patients with melaena have associated iron deficiency anaemia secondary to chronic blood loss, iron replacement therapy may be necessary. It is important to warn the patient that oral iron will colour the motions black and mimic the appearances of melaena. Iron-containing stools, though black in colour, do not have the characteristic odour of melaena and most patients will be able to distinguish at least a more severe melaena stool from the effects of iron tablets. If the patient is severely iron-deficient, an intravenous iron infusion may be more beneficial.

Bright Red Blood Per Rectum This is also an extremely common clinical complaint affecting patients of all ages. In the vast majority of cases, the bleeding is trivial in quantity,

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Box 10.4  Causes of rectal bleeding In patients under 40 years old Very common ll Haemorrhoids ll Anal fissure ll Inflammatory bowel disease (mainly proctitis) Less common ll Polyps (hamartomatous or adenomatous) ll Infective colitis ll Meckel's diverticulum ll Intussusception Rare ll Colorectal cancer In patients over 40 years old ll Haemorrhoids ll Anal fissure ll Colorectal cancer ll Colorectal polyps (mostly adenomas) ll Angiodysplasia ll Diverticular disease ll Inflammatory bowel disease ll Ischaemic colitis ll Radiation colitis ll Infective colitis

although in some patients a large volume of blood is passed and, rarely, the bleeding is massive and associated with hypotension or shock. Causes of rectal bleeding in patients under the age of 40 years are listed in Box 10.4. In older patients, the differential diagnosis is wider, and more serious conditions such as colorectal cancer are much more prevalent (Box 10.4). A careful history should be taken, focusing on the following points: ll amount of bleeding and colour of blood; ll blood on toilet paper only (suggesting anal pathology) or blood mixed in with the stool; ll associated perianal pain suggesting local anal pathology; ll pattern of bowel habit—constipation and straining at stool point towards haemorrhoids or anal fissure; diarrhoea and mucus per rectum suggest ulcerative colitis ll family history of colorectal diseases such as carcinoma. Examination should include a check for an abdominal mass arising from the colon and a careful inspection of the anal area to look for any signs

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of an anal fissure. A rectal examination should be done, feeling with the finger for any palpable lumps and any local tenderness. A proctoscopy and/ or rigid or flexible sigmoidoscopy should follow. This is an extremely useful test in this situation, especially if done acutely. If a bleeding source is clearly identified, such as bleeding haemorrhoids or fissure, further immediate investigation may be avoided. If no lesion is found or if a possible source is seen but with no evidence of recent bleeding (e.g. non-bleeding haemorrhoids), further investigation will be necessary in most instances. Remember that haemorrhoids are common and it is dangerous to assume that they are the source of the bleeding, especially in a more elderly patient, if no evidence of recent bleeding is seen at the time of the examination. For patients over the age of 40 years, a colonoscopy should be arranged if the initial local inspection and sigmoidoscopy have not clearly identified the source of bleeding. A barium enema is not an appropriate investigation in this situation. It is less accurate than colonoscopy, especially in the detection of vascular lesions such as angiodysplasia. Barium also obscures the views if subsequent colonoscopy or angiography is required, and therapeutic interventions, such as polypectomy, cannot be performed. For younger patients, discretion and clinical judgment are needed if the initial work-up is negative. The yield from colonoscopy in this group is small and serious pathology, such as colorectal cancer, is very rare. If the bleeding is persistent or recurrent, a colonoscopy is clearly warranted.

Causes of rectal bleeding Specific points related to the individual causes of rectal bleeding are given below. Haemorrhoids These are particularly associated with constipation and straining at stool. They are vascular cushions that form in the venous plexuses at the anorectal junction. Bleeding is typically intermittent. Blood is seen on the toilet paper, as a splash in the toilet bowl or on the outside of the stools. For minor bleeding, reassurance is all that is necessary after the clinical evaluation has been performed. Attention to diet and treatment of associated constipation is appropriate. If bleeding is more persistent or recurrent, local treatment of the haemorrhoids can be given. The most common interventions include injection of the haemorrhoids with sclerosant, and rubber band ligation. For more severe prolapsing haemorrhoids, haemorrhoidectomy is appropriate (Ch 12).

Anal fissure Treatment again is directed towards the underlying constipation. Fibre supplements and stool softeners are used and the patient is encouraged to avoid straining at stool. Glyceryl trinitrate ointment will relax anal spasm and allow some fissures to heal. This conservative approach will work in many cases but for more chronic recurrent fissures, surgical intervention is necessary (Ch 12). Rectal polyps If these are seen at sigmoidoscopy, the patient should be fully prepared for a colonoscopy so that a search for more proximal polyps can be made. Most polyps can be removed at colonoscopy using a snare or biopsy forceps. Since approximately 90% of colorectal cancers arise from preexisting adenomatous polyps, the rationale for polyp excision is not only control of the rectal bleeding but also cancer prevention. If the polyps are found at histology to be adenomatous, colonoscopic surveillance is warranted, especially in patients with multiple polyps or large polyps, as there is an increased risk of new polyp formation and colorectal cancer. Repeat examinations should be done at 3- to 5-yearly intervals in most cases (Ch 22). Angiodysplasia or vascular ectasia of the bowel These vascular lesions are increasingly common with advancing age. About 25% of patients over the age of 60 years have angiodysplasia but only a small proportion bleed. Vascular lesions are most commonly found in the right colon, but are occasionally found in the small intestine or left colon. They may present with occult bleeding leading to iron deficiency anaemia or with more brisk bleeding leading to moderate or even massive rectal bleeding. The cause of these lesions is unclear. They are dilated, thinwalled vascular lesions in the submucosa of the colon and may develop in response to chronic pressure changes, especially in the right colon. Bleeding is typically intermittent and ceases spontaneously, only to recur at a later date in most patients. Sometimes the bleeding is torrential and emergency intervention is required. If detected at colonoscopy, argon plasma coagulation, injection therapy or laser may be used to stop the bleeding. At angiography, injection of vasopressin or embolisation techniques may be used successfully. In some patients, surgical intervention, often a right hemicolectomy, may prove necessary. Delineation of the extent of angiodysplasia by investigation, such as capsule endoscopy for small

10 Vomiting blood, black stools, blood per rectum, occult bleeding

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bowel involvement, is appropriate before surgical intervention is planned. Diverticulosis This is a condition with pseudodiverticula or mucosal herniations through the colonic wall, at sites of relative weakness caused by penetrating blood vessels. They become increasingly common with age; 5% of 50-year-old people and more than 50% of 90-year-old people have colonic diverticula. It is widely believed that the Western refined diet, low in fibre, is a significant predisposing cause for diverticula formation. They develop most commonly in the sigmoid colon although, for reasons that are not understood, bleeding is more commonly seen with right colonic diverticula. In the vast majority of patients, bleeding settles spontaneously and management is conservative. Fewer than 25% of patients will have further episodes of bleeding, although those patients that do have further episodes tend to continue with bleeding and require surgical resection. Diagnosis is usually presumptive, made at colonoscopy when other colonic causes have been excluded. Active bleeding is rarely seen at colonoscopy; it can be treated using thermal ablation or injection therapy. Inflammatory bowel disease Ulcerative proctitis may present as rectal bleeding without any associated change in bowel habit, though most patients also have diarrhoea. The condition may be due to ulcerative colitis or Crohn's disease and is easily diagnosed by sigmoidoscopy (Ch 15). If there are other symptoms suggesting the presence of more proximal disease, the patient may need a colonoscopy. Local treatment of proctitis with steroid enemas, 5-aminosalicylic acid enemas or oral sulfasalazine treatment works well in most patients. Resistant cases need more aggressive immunosuppression with high-dose oral steroids. Ischaemic colitis This usually occurs in the setting of widespread peripheral vascular disease or cardiac disease. The rectal bleeding is often associated with mild lower abdominal cramps. Characteristic changes are seen on colonoscopy or barium enema usually at the level of the splenic flexure and descending colon because this is a watershed area in the blood supply to the colon (Fig 10.6). Treatment is conservative and the condition settles spontaneously in most cases. Some patients develop a stricture at the site of the ischaemia, which rarely requires subsequent excision (Ch 4).

Figure 10.6  Ischaemic colitis of the splenic flexure on barium enema.

Massive rectal bleeding This is a relatively uncommon clinical problem. The clinical management is more complex and acute. The patient may be hypotensive or in shock and require urgent resuscitation, as has been described above for patients with haematemesis. The most frequent cause of this clinical presentation is massive bleeding from colonic diverticula or angiodysplasia. However, the site of bleeding may be virtually anywhere in the gastrointestinal tract since massive bleeding even from the stomach or duodenum may pass rapidly to the rectum without becoming discoloured to form melaena. History taking should focus not only on colorectal symptoms, but also on any symptoms that might suggest an upper gastrointestinal origin for the bleeding. A rectal examination and sigmoidoscopy should start the diagnostic work-up because occasionally a local perianal cause will be found. If the findings are negative, it is appropriate to proceed to an upper gastrointestinal endoscopy so that a gastroduodenal cause is fully excluded. This can be accomplished quickly and prepares the way for

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more complex and invasive investigation of the small and large intestine. Colonoscopy (after rapid colon cleansing in 12 hours), radiolabelled red cell scan, selective mesenteric angiography and computed tomogram angiography can all be used to try to identify the site of bleeding. Red cell scan and angiography can localise the site of bleeding if it is faster than 0.5–1 mL/minute. Colonoscopic intervention or angiographic embolisation can be used to stop bleeding if an active site is identified. Recent studies have demonstrated that it is safe to give these patients bowel preparation and to proceed to emergency or urgent colonoscopy within 12–24 hours. Since most colonic lesions will stop bleeding spontaneously, there is still debate about the appropriateness of emergency, as opposed to urgent, colonoscopy. If a bleeding lesion is identified during emergency colonoscopy, it can be treated using similar techniques to those described for upper endoscopy. Adrenaline injections, argon plasma coagulation, thermal probes and endoscopic clips all have a role. The next step in the work-up depends on the clinical condition. If the patient is haemodynamically stable and colonoscopy fails to identify the source of bleeding, a technetiumlabelled red cell scan is often performed. In this test, a sample of the patient's blood is taken and labelled with a radioisotope before being injected back into the patient's bloodstream. Abdominal scans can then be taken at intervals, looking for extravasation of radiolabelled blood into the bowel. The technique can detect bleeding at rates as low as 0.5 mL per minute. If bleeding is intermittent, the patient can be sent for repeated scans over the next 24–48 hours in the hope of catching a fresh bleed. The object is to localise the source of bleeding to the small or large bowel and give some indication to the surgeon of the precise site in the event of surgery being necessary. The accuracy of the test has been questioned by some clinicians and false localisation of the site of bleeding is a problem in some cases. A Meckel's scan (99Tc pertechnetate) should be considered in young patients with massive rectal bleeding. The 99Tc is taken up by the ectopic acid-secreting gastric mucosa of a Meckel's diverticulum, which rarely ulcerates and bleeds. A positive red cell scan may lead to a mesenteric angiogram, which may be both diagnostic and therapeutic. The radiologist may identify not only the site of bleeding but also the cause. Vascular lesions such as angiodysplasia may be seen. An abnormal tumour circulation may be identified.

Active bleeding may be controlled by a vasopressin or terlipressin infusion into the appropriate feeding artery, or by embolisation, and thus avoid the need for surgery. Growing experience with capsule endoscopy has highlighted a beneficial role for this procedure in patients with large-volume rectal bleeds who are relatively stable. The capsule test provides the best mucosal imaging of the small intestine and is particularly useful for the detection of vascular lesions such as angiodysplasia. A capsule endoscopy study takes many hours to perform and then report. Accordingly, the patient must be in a stable condition to allow the procedure to be performed. Small bowel endoscopy can now be performed by using a colonoscope (push enteroscopy) or special small bowel scopes (e.g. double-balloon enteroscope). If the above techniques identify the lesion but fail to control the bleeding, an operation will be necessary. In some instances, a laparotomy is combined with an on-table endoscopy or colonoscopy, as the endoscopist may be able to assist the surgeon in the precise localisation of a small bleeding point, particularly in the case of angiodysplasia.

Iron Deficiency Anaemia In all patients over the age of 40 years, iron deficiency anaemia should be assumed to be due to gastrointestinal bleeding. Investigation gives a high yield of gastrointestinal lesions in this age group, even if the anaemia is not associated with any gastrointestinal symptoms. Young menstruating women, however, have a very high incidence of iron deficiency and pathology in the gastrointestinal tract is rarely found. Thus, empirical treatment of the anaemia without full investigation in the absence of gastrointestinal symptoms is usually appropriate. The presentation may be vague with illdefined symptoms, such as lethargy, dizziness or depression. Some patients will present with shortness of breath or angina. A careful search for signs of anaemia is warranted although often none is found. The skin creases, buccal mucosa and conjunctivae should be examined for pallor. There may rarely be spooning of the fingernails present (koilonychia) if the condition is chronic. Blood tests confirm the presence of anaemia and show that the blood is iron-deficient. The key elements are: ll microcytic hypochromic anaemia; and ll low serum iron and serum ferritin with decreased transferrin saturation.

10 Vomiting blood, black stools, blood per rectum, occult bleeding Box 10.5  Aetiology of occult gastrointestinal bleeding Oesophagus Cameron erosions Stomach ll Portal hypertensive gastropathy ll Dieulafoy's disease ll Gastric antral vascular ectasia (watermelon stomach) ll Arteriovascular malformation (angiodysplasia) Biliary tree ll Haemobilia (trauma or stone) Pancreas ll Aneurysm (haemosuccus pancreaticus) Small intestine ll Portal hypertensive intestinal vasculopathy ll Neoplasia (GIST, carcinoma) ll Crohn's disease ll Arteriovenous malformation (angiodysplasia) ll Aortoenteric fistula ll Radiation ileitis ll Meckel's diverticulum ll Polyposis and Peutz-Jeghers syndrome ll Medication-induced mucosal lesions (NSAIDs) ll Jejunal diverticula ll Carcinoma ll Carcinoid tumour Colon Arteriovascular malformation (angiodysplasia) ll

Sometimes a high platelet count occurs in patients with chronic active blood loss. A wide range of gastrointestinal lesions (see Box 10.5) may be responsible for the anaemia, from ulcerative oesophagitis to colonic angiodysplasia. A great concern in elderly patients is the possibility of a caecal carcinoma. Usually, distal colonic lesions or oesophageal lesions present with overt blood loss from respective ends of the gastrointestinal tract leading to haematemesis or rectal bleeding and are uncommon causes of isolated iron-deficiency anaemia. Nonbleeding lesions should also be considered. Malabsorption of iron in patients with coeliac disease, previous gastrectomy or atrophic gastritis may occur. Unless there are specific symptoms pointing to a particular region of the gastrointestinal tract, investigation should focus initially on the large

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intestine and, in most instances, also include an upper gastrointestinal evaluation. If the findings are negative, most clinicians would treat the anaemia with oral iron and, if more severe, with an intravenous iron infusion and observe the response. If the haemoglobin fails to rise or if anaemia recurs, more detailed investigation should be considered. Enteroclysis (small bowel enema) was the preferred next step in the past but, today, capsule endoscopy and/or enteroscopy should be performed. These endoscopic techniques will identify vascular lesions that cannot be detected by enteroclysis and are also more sensitive at detecting benign and malignant tumours of the small intestine. Other tests that may help in some cases include a Meckel's scan in younger patients and angiography of the mesenteric vessels.

Positive Faecal Occult Blood Test Faecal occult blood testing is recommended only in the context of population screening for colon cancer. It is not an appropriate test for the assessment of patients with colonic symptoms such as rectal bleeding or anaemia. These patients are symptomatic and should have more definitive investigations performed (such as colonoscopy). The most widely used occult blood test is the haemoccult test. This is a guaiac test, which detects the pseudoperoxidase activity of haeme. It is generally recommended that three spontaneously passed stools are tested twice to give a total of six possible reactions. A positive reaction is seen as a blue colour on any one of the specimens and is interpreted as a positive test result for the battery. This implies blood loss from the colon of the order of 1–2 mL/day or blood loss from the stomach of 10–20 mL/day. This test will probably detect 40–80% of asymptomatic colorectal cancers and 30–40% of large colorectal adenomas. False positive results can be caused by the presence of peroxidase activity in certain foods or from the haemoglobin content of red meat. Antioxidants such as vitamin C may produce a false negative result. Aspirin and NSAIDs may cause excessive bleeding from the gastrointestinal tract, causing a true but unrelated positive result. Thus, the following conditions should apply when performing occult blood testing with the haemoccult test: ll

ll

dietary restrictions for 3 days before and during the testing; no red meat;

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no high peroxidase-containing vegetables such as cantaloupe (rockmelon) and other melons, raw radishes, turnips, horseradish, broccoli or cauliflower; and ll no vitamin C and NSAIDs. Newer occult blood tests are also available. These include more sensitive versions of the guaiac test such as Hemoccult® SENSA® and immunological tests that utilise antibodies to human haemoglobin. Occult blood tests have been used in a number of major population trials in an attempt to diminish the mortality from colorectal cancer in the screened population. The tests have been offered to asymptomatic people over the age of 50 years in most of these studies. When positive results were obtained, the subjects were offered colonoscopy and, if appropriate, polypectomy. These studies have shown a 20–33% reduction in mortality from colorectal cancer in the screened population when compared with the control group. In these programs, about 60% of the subjects accepted the invitation to do the test and about 2% had a positive result. When these were investigated, 3–5% of the positive results were found to be associated with a colorectal cancer and 30–45% with an adenoma. The other positive results may have reflected bleeding from a wide range of gastrointestinal tract lesions or false positive reactions from peroxidase-containing foodstuffs. If the tests are done correctly with appropriate dietary restrictions, high specificity is achieved with 98–99% of healthy subjects being occultblood negative. Thus, if an asymptomatic patient, aged 40 years or more, is found to have a positive occult blood test, he or she should be referred for a colonoscopy. If polyps are found, these should be removed at the time of the colonoscopy. Any cancer found should be biopsied and the patient referred on for surgical resection. If the colonoscopy findings are negative, investigation of the upper gastrointestinal tract by upper endoscopy should be considered. In practice, the yield from this is very small except in patients with upper gastrointestinal symptoms, such as dyspepsia, or in patients with frank iron deficiency anaemia. When should occult blood testing be performed? At present, in Australia, faecal occult blood testing is offered to all people on their 50th, 55th and 65th birthdays. Others support annual occult blood testing for all asymptomatic people over the age of 50 years. In the USA and many European countries, annual occult blood testing ll

has been endorsed as one of a number of bowelcancer-prevention strategies that can be offered to asymptomatic people aged 50 years and over. More invasive screening with colonoscopy may be appropriate if there is a strong family history of bowel cancer. One first-degree relative in the family with bowel cancer under the age of 55 years or two first-degree relatives with bowel cancer at any age increases the chance of the patient getting bowel cancer by three- or fourfold, compared with the general population. A colonoscopy in those with a strong family history is recommended every 5 years from the age of 40 years, or from the age of onset of the cancer in the family member less 10 years (Ch 22).

Key Points ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

Haematemesis means vomiting blood and usually means bleeding from the oesophagus, stomach or duodenum. Melaena is the passage of black tarry stool and usually represents upper gastrointestinal bleeding, but at times may represent bleeding from the small intestine or proximal colon. Hematochaezia is the passage of pure red blood or blood mixed with stool and usually represents lower gastrointestinal bleeding. Patients may present with gastrointestinal bleeding and are otherwise well, but may also present in hypovolaemic shock. Resuscitation of those patients with significant blood loss should be the first priority and blood transfusion is often required quite urgently. A targeted history and clinical examination may assist with the diagnosis. After resuscitation, gastrointestinal bleeding always warrants a prompt endoscopic investigation to assist with both a diagnosis and therapeutic intervention. Common causes of major blood loss presenting with haematemesis and melaena include gastric and duodenal ulceration, bleeding oesophageal varices and portal hypertensive gastropathy. Common causes of haematochezia include haemorrhoids, anal fissures, inflammatory bowel disease and, in those over 40 years of age, colon cancer. A surgical opinion is necessary for those patients with uncontrolled gastrointestinal bleeding. Iron deficiency anaemia in a patient over 40 years of age should always be initially attributed to gastrointestinal blood loss.

10 Vomiting blood, black stools, blood per rectum, occult bleeding ll

ll

ll

In patients presenting with iron deficiency anaemia, unless there are specific symptoms pointing to a particular region of the gastrointestinal tract, investigation should focus initially on the colon. In patients with persistent unexplained iron deficiency anaemia, small bowel investigations with capsule endoscopy are usually warranted. A faecal occult blood test is recommended only for population screening for colon cancer. It is not useful as a test for patients who are symptomatic.

Further reading Bleau BL, Gostout CJ, Sherman KE, et al. Recurrent bleeding from peptic ulcer associated with adherent clot: a randomised study comparing endoscopic treatment with medical therapy. Gastrointest Endosc 2002; 56:1–6. Burling D, East JE, Taylor SA. Investigating rectal bleeding. BMJ 2007; 15:335(7632):1260–1262. D'Amico G, Garcia-Pagan JC, Luca A, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006; 131(5):1611–1624. Frossard JL, Spahr L, Queneau PE et al. Erythromycin intravenous bolus infusion in acute upper gastrointestinal bleeding: a randomised controlled double blind trial. Gastroenterology 2002; 123:17–23. Hadithi M, Heine GD, Jacobs MA et al. A prospective study comparing video capsule endoscopy with double-balloon enteroscopy in patients with obscure gastrointestinal bleeding. Am J Gastroenterol 2006; 101:52–57.

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Kravetz D. Prevention of recurrent esophageal variceal hemorrhage: review and current recommendations. J Clin Gastroenterol 2007;41(suppl 3):S318–S322. Lau JY, Sung JJ, Lee KK et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000; 343:310–316. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev 2006; (1):CD002094. Manning-Dimmitt LL, Dimmitt SG, et al. Diagnosis of gastrointestinal bleeding in adults. Am Fam Physician. 2005; 71(7):1339–1346. McCormick PA, Burroughs AK, McIntyre N. How to insert a Sengstaken Blakemore tube. Br J Hosp Med 1990; 43:274–277. Peter S, Wilcox CM. Modern endoscopic therapy of peptic ulcer bleeding. Dig Dis 2008; 26(4):291–299. Young GP, St John DJ, Winawer SJ et al. Choice of fecal occult blood tests for colorectal cancer screening; recommendations based on performance characteristics in population studies: a WHO (World Health Organization) and OMED (World Organisation for Digestive Endoscopy) report. Am J Gastroenterol 2002; 97:2499–2507. Zhu A, Kaneshiro M, Kaunitz JD. Evaluation and treatment of iron deficiency anemia: a gastroenterological perspective. Dig Dis Sci 2010; 55(3):548–559.

11 Constipation

Case A 33-year-old female accountant consults because of worsening constipation. She describes on specific questioning passing a bowel movement every 2 days. She strains excessively to pass the bowel movement, and the stools feel hard. She has a sensation of incomplete emptying after she has a bowel movement, and she finds this troubling. Occasionally, she will press around the anal area to help hard stool evacuate. She remembers being constipated as a child and all her life. She has not seen any mucus or blood in the stools, and she has no history of weight loss, vomiting or any alarm symptoms. She describes mild abdominal discomfort at times; this is usually present before she passes stools, but she denies pain relief with defecation or a change in her stools when pain begins. She has been regulating her bowels by taking over-the-counter laxatives, but has found that these have not been very helpful. She never has diarrhoeal symptoms. She has otherwise been in excellent health. She takes no other regular medications. There is no family history of colon cancer, inflammatory bowel disease or other gastrointestinal diseases. Abdominal examination is unremarkable with no evidence of any organomegaly or distension. Bowel sounds are normal. Rectal examination is abnormal. While anal sphincter tone felt normal, on straining there was paradoxical contraction of the anal musculature felt around the finger. There was also increased perineal descent seen on straining. There were no masses palpable and no blood on the glove. The remainder of the physical examination was non-contributory. Because of the history of life-long constipation, further investigations were ordered. An anorectal manometry was undertaken to exclude Hirschsprung's disease and determine whether there is pelvic floor dysfunction. Anorectal

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manometry showed the patient had paradoxical contractions with straining, confirming the rectal examination findings. Furthermore, she was unable to expel a 50 mL warm-water-containing balloon in two minutes, sitting on the commode. There was a normal rectal inhibitory reflex ruling out Hirschsprung's disease. In view of the absence of any alarm features, further evaluation of the colon was not ordered. The patient was advised that she has pelvic floor incoordination and this is the most likely explanation for her constipation. She was further advised that laxatives are often unhelpful. She was given the option of trying suppositories as needed. She was referred for biofeedback training and advised there was a 70% chance that biofeedback training would result in long-term resolution of her constipation.

Introduction Constipation is a very common symptom. When patients present with constipation, they must be asked what they mean by this term. They may mean that they have a decreased bowel frequency, hard stools or some difficulty or pain with bowel evacuation. In surveys of the general population not seeking healthcare, 10–17% of people strain at stool on more than a quarter of occasions, but only between 1% and 4% report bowel frequency of fewer than two stools per week. Constipation is often dismissed as a minor symptom by doctors, although for some patients it can be the source of considerable anxiety and disability, and is frequently associated with general malaise and a sense of poor health. A list of the causes of chronic constipation is presented in Box 11.1. While the majority of patients who complain of constipation have a benign disorder of colorectal function associated with faulty diet, drugs or bowel habit, called simple constipation,

11 Constipation Box 11.1  Classification of constipation in adults No gross structural abnormality Inadequate fibre intake ll Irritable bowel syndrome (associated with abdominal pain) or functional constipation ll Idiopathic slow-transit constipation (colonic inertia) ll ‘Obstructed defecation’—pelvic floor dysfunction (pelvic floor dyssynergia or anismus) Structural disorders ll Anal fissure, infection or stenosis ll Colon cancer or stricture ll Aganglionosis and/or abnormal myenteric plexus: Hirschsprung’s disease, Chagas’ disease, neuropathic pseudo-obstruction ll Abnormal colonic muscle: myopathy, dystrophia myotonica, systemic sclerosis ll Idiopathic megarectum and/or megacolon ll Proximal megacolon Neurological causes ll Diabetic autonomic neuropathy ll Damage to the sacral parasympathetic outflow ll Spinal cord damage or disease, e.g. multiple sclerosis ll Parkinson's disease ll Blunting of consciousness, mental retardation, psychosis ll Pain induced by straining, e.g. sciatic nerve compression Endocrine or metabolic causes ll Hypothyroidism ll Hypercalcaemia ll Porphyria ll Pregnancy Psychological disorders ll Depression ll Anorexia nervosa ll Denied bowel habit ll

Drug side effects

it should always be remembered that constipation may be the presenting symptom of a serious colonic disorder, such as carcinoma, or a generalised metabolic disorder, such as hypothyroidism or hypercalcaemia. Chronic constipation can occur in the absence of structural or metabolic disorders because of abnormally slow colonic transit (slow transit constipation), obstructed defecation (pelvic

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floor dysfunction), or both. The irritable bowel syndrome, characterised by abdominal pain and a variable bowel habit, is also an important cause of constipation (Ch 7). A careful history and examination to ascertain the likely mechanism producing constipation allows investigations to be correctly chosen, which in turn should determine management.

Clinical Approach to Patients with Constipation History First, the history should be taken. If the problem is a chronic one, ask why the patient has sought help on this occasion. He or she may have fears about the possibility of malignancy or the chronic use of laxative drugs. Details of bowel frequency, stool consistency and colour, presence of blood or mucus and accompanying features such as abdominal pain, bloating or weight loss are therefore relevant. Stools that feel hard to the patient usually are not when objectively tested! The onset of the complaint should be ascertained. Constipation dating from the neonatal period may suggest Hirschsprung's disease (congenital aganglionosis causing absent peristalsis in a part of the rectum or colon), whereas symptoms dating from the time of toilet training or early childhood may suggest childhood megarectum or stool withholding (often with soiling and overflow). Severe constipation (with a defecation frequency of less than once a week off laxatives) in young women dating from adolescence or following pelvic surgery may indicate colonic inertia (slow transit constipation); these patients typically lack the urge to defecate. In older patients, progressive constipation may indicate a colorectal neoplasm or diverticular stricture. Some patients with a disorder of pelvic floor function complain of a sense of difficulty with evacuation and feeling of anal blockage or obstruction; they may manually disimpact themselves by pressing in or around the rectum or vagina. A history of obstetric trauma in such patients may be relevant. However, symptoms cannot distinguish pelvic floor dysfunction with sufficient accuracy from irritable bowel syndrome or functional constipation. Constipation may be induced by certain drugs, such as narcotics, antihypertensives or antidepressants. Thus, it is very important to ask about the use of drugs and whether their introduction corresponded to recent alterations in bowel habit. A lack of dietary fibre is a common

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cause of constipation and a full dietary history should be taken. Slow transit constipation, and occasionally simple constipation, may run in families and a history of other family members being similarly affected may provide useful information. If the problem is chronic, it is important to find out whether previous investigations have been performed and what previous treatment regimes have been employed, including alternative medicine treatments.

Physical examination An important part of the assessment of patients with chronic constipation is the physical examination. The general demeanour of the patient may give information regarding anxiety or depression. Signs of neurological or endocrine diseases, such as hypothyroidism or Parkinson's disease, should be looked for. Abdominal palpation may reveal faecal masses in young patients with rectal impaction or a tender spastic colon in a young anxious patient with irritable bowel syndrome. A craggy abdominal mass may indicate a colonic neoplasm. A rectal examination is important. The perineum should be inspected for painful anal fissures, fistulae, abscesses or local neoplasm. The patient should be asked to bear down to demonstrate perineal descent due to pelvic floor weakness, haemorrhoidal prolapse or the formation in women of a rectocoele or uterine prolapse. Occasionally, rectal mucosal or full-thickness prolapse may be seen (Ch 22). An anal fissure will be very painful on trying to put your finger in the anal canal. Obvious fistula suggests Crohn's disease. A rectal examination can detect if there is any evidence of anal canal stenosis. An obvious rectal mass may represent a cancer. Obvious faecal impaction may be present in very severe constipation, particularly in the elderly. To complete the rectal examination, the patient should be asked to try to push the examiner's finger out by straining. If the puborectalis and anal sphincter contract and increase pressure in the anal canal rather than relaxing to widen the canal, this suggests (but is not diagnostic of) pelvic outlet obstruction. Next, turn your finger to the anterior position. Try to feel if there is any evidence of a rectocoele, which pushes through the anterior rectal wall when straining. Sigmoidoscopy should be performed if adequate rectal emptying can be achieved.

Investigations Generally, types of constipation can be divided into those with no apparent structural abnormality of the anus, rectum or colon and those with

recognised structural disease such as cancer, a stricture or megacolon. A third group of patients have generalised metabolic, neurological or endocrine diseases, which may produce constipation as a secondary event (Box 11.1). The extent of investigations for the individual patient with constipation depends very much on the clinical assessment (Fig 11.1). In young patients in whom suspicion of serious underlying disease such as colon cancer is low, a trial of therapy without investigation is reasonable. In most other patients it is logical to first assess that the colon is structurally normal. In those patients who do not respond to initial simple therapy, further investigations may be necessary.

Haematology and biochemistry It is reasonable to check for anaemia (especially iron deficiency) and a raised erythrocyte sedimentation rate or C-reactive protein result. Biochemical tests to check thyroid function and serum calcium levels may also be performed.

Colonoscopy Colonoscopy is the test of choice to exclude significant structural colonic disease. It is an alternative to sigmoidoscopy and barium enema. Melanosis coli may be evident in patients who use laxatives regularly (Fig 11.2). Colonic stricture and neoplasm can usually be effectively diagnosed by this technique.

Radiology A plain abdominal x-ray examination often gives useful information about colonic loading and the presence of distended loops or fluid levels if obstruction is a possibility. The plain x-ray examination is also often helpful in children in whom megarectum is suspected. The rectum or colon is of increased diameter in adult patients with megacolon (due to Hirschsprung's disease or chronic idiopathic intestinal pseudo-obstruction). An unprepared barium enema is useful to assess the size, shape and configuration of the distal colon, especially in cases where rectal impaction or Hirschsprung's disease is suspected. A double-contrast barium enema after bowel preparation can assess a structural disorder, such as stricture, volvulus or megacolon. Virtual colonoscopy (CT colonoscopy) is a radiological technique that provides a threedimensional reconstruction of the colon; it can accurately detect large colonic polyps (1 cm and over) or cancer. A bowel preparation is required. Extra colonic findings are seen commonly; one in

11 Constipation

133

History of constipation

Diet/medications

Physical examination Proctoscopy/sigmoidoscopy Cause identified

Blood tests Cause identified

Barium enema and/or colonoscopy Cause identified

Colonic transit Pelvic floor studies

Slow transit constipation

Pelvic floor dysfunction

Both slow transit and pelvic floor dysfunction

Normal findings (functional bowel disease)

Figure 11.1  Diagnostic approach to chronic constipation.

10 is sent for additional testing but this is of little benefit in the majority.

Colonic transit studies

Figure 11.2  Melanosis coli.

Firmer stool consistency is correlated with slower colonic transit. Total gut transit time (to which the colonic transit time is the greatest contributor) may be simply measured by giving radio-opaque shapes by mouth and recording their course through the colon by abdominal x-ray or stool collection. It is known that normal subjects pass 80% of administered shapes by 5 days. One clinically useful quantitative test is to give 24 radio-opaque markers by mouth on 3 consecutive days and obtain a plain abdominal x-ray examination on day 4; the number of markers is counted to calculate total and regional colonic transit times (Fig 11.3A and B). A transit time of 70 hours or longer is abnormally slow. Laxatives should be stopped 2 days prior to the test and a high-fibre diet should be continued throughout. Patients should be off opioid painkillers.

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A

The recto-sphincteric reflex may be elicited by rectal distension with simultaneous recording of anal pressure. A positive reflex consists of a relaxation of the internal anal sphincter (lowered resting anal tone) following rectal distension (Fig 11.4). The reflex is mediated by the myenteric plexus and is characteristically absent in those with Hirschsprung's disease (because of congenital aganglionosis). Rectal sensation can be tested by inflating a rectal balloon with increments of air, noting the onset of initial sensation and the maximum tolerated volume. Using more sophisticated equipment, a pressure volume curve may be obtained. These tests are useful in distinguishing the hypertonic rectum of the irritable bowel syndrome from the large, insensitive rectum of megacolon. Assessment for pelvic outlet obstruction may be made with a very simple screening test: the expulsion of a 50 mL filled balloon. If the patient is unable to expel the balloon within 1 minute, this strongly suggests there is pelvic floor dysfunction (outlet obstruction). In some laboratories, additional weights are added to the balloon and patients are still unable to expel it even with 500g or more of weight on the balloon— further evidence of outlet obstruction. Paradoxical contraction of the external anal sphincter on straining (when it should normally relax to allow stool passage) supports a diagnosis of pelvic outlet destruction.

Dynamic proctography

B Figure 11.3  A Normal colonic transit. B Slow colonic transit (over 70 hours).

More sophisticated techniques involve radioisotope labelling of food material, such as bran, to allow isotope scanning to measure colonic clearance. This can provide information regarding specific emptying times for different segments of the colon.

Ano-rectal manometry, sensation and balloon expulsion Pressure within the anal canal may be recorded by perfused tubes, microballoons, or strain-gauge transducers (see Ch 16). Resting anal tone and the response to voluntary contraction and straining at defecation give useful information about the state of the pelvic floor muscles.

Video radiographic recording of defecation with contrast material in the rectum (by a defecating proctogram or magnetic resonance imaging) will demonstrate perineal descent, rectal intussusception and paradoxical sphincter contraction in some patients with obstructed defecation (Ch 16).

Motility studies Small bowel motility can be measured by placing a manometric assembly through the mouth in the upper small intestine. Chronic intestinal pseudoobstruction, a rare but important cause of slow transit constipation, can be diagnosed by this test (Ch 7). Recording of colonic motility is a research tool and is not routinely used to base diagnosis and management.

Rectal biopsy In rare cases where the history, x-ray findings and results of physiological studies suggest the possibility of Hirschsprung's disease, a rectal

11 Constipation

Chart recorder

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Inflation and rectal pressure measurement

Figure 11.4  To elicit the rectoanal reflex, a balloon is inserted into the rectum and a pressure measuring device (in this case a microballoon connected to a pressure transducer and chart recorder) is placed in the anal canal. Distension of the balloon causes an initial rise in pressure, due to the external anal sphincter contraction, followed by a more prolonged fall in anal pressure due to internal anal sphincter relaxation. This latter fall in pressure confirms the presence of intact intramural nerves, excluding Hirschsprung's disease. A false negative result is sometimes seen in patients with an idiopathic megarectum. From Kamm MA, Lennard-Jones JE, eds. Constipation. Petersfield: Wrightson Biomedical Publishing; 1994, with permission.

biopsy is usually necessary for confirmation. Traditionally, this has been of the full-thickness type, requiring general anaesthesia. More recently, suction biopsies with special stains have been shown to be useful, especially in children.

Therapeutic agents

Approach to Management

Therapeutic agents available for the treatment of constipation are listed in Table 11.1.

Once structural and metabolic disease have been excluded by appropriate investigations, it is important to reassure patients that their symptoms of constipation are not due to serious organic disease. This often has a positive effect in relieving anxiety.

General measures In general terms, many patients with constipation may be managed by a high-fibre diet containing 20–30 g of fibre. This can be achieved by adding cereal, unprocessed bran, and fruit and vegetables (especially root vegetables and legumes) in conjunction with an increased fluid intake. Bulkforming agents are useful supplements. There are two types: those derived from ispaghula, sterculia (a plant gum) or methylcellulose. Instructions should be given on regular toilet habit and exercise. A review of intercurrent

drug therapy should be undertaken and, if possible, drugs promoting constipation should be stopped.

Hydrophilic bulk-forming agents These substances are grain fibre products or pharmaceutical preparations of processed plant fibre, gums or resins. They consist of varying amounts of complex carbohydrate moieties; cellulose, the hemicelluloses, pectins; and the non-carbohydrate polymer, lignin. These agents bind water, increase stool weight and act as a substrate for colonic bacteria. Increased intake in constipated patients usually results in larger stools and reduced colonic transit time. Small bowel absorption of other substances (e.g. zinc, iron, glucose and bile salts) may be affected, but this is rarely of clinical significance. It should be remembered that severely constipated patients sometimes do not respond to these agents. In some cases, symptoms may be made worse because of the increased flatus produced. Patients with slow

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Table 11.1  Thrapeutic agents in constipation and major side effects Agents

Side effects

Hydrophilic ­ bulk-forming agents Psyllium mucilloid, sterculia, ispaghula, methylcellulose, unprocessed bran

Inadequate fluid intake may result in intestinal obstruction

Osmotic laxatives Polyethylene glycol, magnesium sulfate/ hydroxide, mannitol, lactulose, sodium salts

May cause electrolyte imbalance

Stimulant laxatives Bisacodyl, senna, cascara, danthron

Damage to the myenteric plexus with prolonged use now appears very rare after the withdrawal of phenolphthalein

Stool-softening agents Paraffin oil, dioctyl-sodium May cause mineral sulfosuccinate oil aspiration and pneumonia Per rectum evacuants Glycerine suppositories, phosphate enemas

May cause rectal or anal sphincter damage if incorrectly used

transit constipation generally do not respond to fibre (and may get worse). Osmotic laxatives These are non-absorbable compounds that produce loose or liquid stool by a direct water-binding effect. Laxatives of this type include sodium and magnesium salts and sugars, lactulose and sorbitol. Polyethylene glycol is a larger polymer and a very effective osmotic laxative that is safe. It causes less bloating and gas than other osmotic laxatives. These agents are among the safest to use on a long-term basis. Some patients find magnesium salts unpleasant and sometimes intolerable. The non-absorbed sugars often increase pain and flatus. These agents should be used on a once- or twice-daily basis to produce the necessary effect and may be continued long term if necessary. Stimulant laxatives These agents stimulate peristalsis and net fluid secretion by a direct irritant effect on the nerve, muscle or mucosa of the gut. Long-term use of these

laxatives may produce tolerance, often leading to an escalating dose regimen. However, these agents are safe and modestly effective for limited periods. Stool-softening agents Paraffin oil has been used for many years as a stool lubricant. It is sometimes combined with other laxative agents in compound preparations. There is debate about its long-term safety and effectiveness. The detergent dioctyl sodium has an effect on bile salt activity and is sometimes used as a ‘stool-wetting agent’ in combination with stimulant laxatives or alone. Per rectum evacuants Suppositories and enemas have a mild irritant effect and stimulate peristalsis. Glycerine suppositories are cheap and effective. Enemas should generally be administered by staff skilled in their use because local complications can occur. Neuromuscular and other agents Bethanechol can increase cholinergic stimulation of smooth muscle in the colon, but little data exist on its use in constipation. Pyridostigmine is an acetylcholinesterase inhibitor that can provide symptom improvement for patients with slow transit constipation. Neostigmine is sometimes used, but has significant side effects (it is effective for acute colonic pseudo-obstruction). Lubiprostone is a locally acting bicyclic fatty acid that stimulates intestinal fluid secretion through chloride channel activation. It reduces constipation but can induce nausea. In difficult cases unresponsive to usual therapy, some doctors have tried prescribing colchicine (a mucosal poison) or misoprostol (a prostaglandin analogue) in chronic constipation.

Biofeedback This technique has been used in patients with chronic constipation due to pelvic floor dysfunction on the basis of failure of rectal evacuation. Those who appear to have a paradoxically contracting anal sphincter during evacuation may be retrained to relax the sphincter during defecation straining to allow easy rectal evacuation, with a 70% success rate. This approach is superior to standard care, and should be considered if laxatives and per rectum evacuants have failed.

Surgical Treatment Colectomy Surgical therapy should be regarded as a measure of last resort in patients with very severe

11 Constipation constipation and documented slow colonic transit without other disease. The surgical procedure of choice in slow transit constipation is subtotal colectomy with ileorectal anastomosis. Extensive resection is required as lesser resection is usually associated with recurrence of constipation. The procedure should be done only in centres of excellence. While the majority of patients have increased bowel frequency after ileorectal anastomosis, some have persistent symptoms of pain and bloating, and a few develop megaileum after surgery and continued constipation. In those with documented obstructed defecation such as mucosal prolapse, perineal descent or paradoxical contraction of the anal sphincter on straining, difficulty with rectal evacuation may persist postoperatively and occasionally patients complain of diarrhoea and incontinence. Hence, pelvic floor dysfunction and small intestinal dysmotility must be excluded before colectomy is considered. Even so, currently it is still difficult to predict the outcome of surgery based upon preoperative physiological studies.

Other surgical approaches Sphincter division Internal sphincter myotomy has been reported to help selected constipated patients, although the procedure has failed to become popular. It may be most useful in those with ultrashort-segment Hirschsprung's disease. In those with pelvic floor dysfunction (paradoxical voluntary sphincter contraction during defecation), voluntary sphincter division either posteriorly or laterally has failed to improve bowel frequency or ease evacuation in the small number of patients studied. Pelvic floor repair In those patients with a disorder of defecation characterised by mucosal prolapse or excess perineal descent, repairing a rectocoele or posterior pelvic floor repair may help, but often does not. In women, it is prudent to consider repair only if better rectal evacuation can be demonstrated after placing pressure on the posterior wall of the vagina. Prolapsing anterior rectal mucosa may be injected with sclerosants, but this procedure rarely improves difficult evacuation. Stoma In some patients, the creation of a permanent stoma, either as a loop or end-ileostomy or colostomy, may be useful when all other therapeutic modalities have failed and difficult symptoms persist.

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Other treatment modalities Botulinum toxin injected into the anal sphincter may help some with paradoxical anal sphincter contraction but is not longlasting. Much research is being directed towards the complex interaction between the central and enteric nervous symptoms. New drug approaches include use of neuronal growth factors. Electrical stimulation is also being tried. In some patients with chronic constipation, there may be a psychological abnormality and alternative approaches to therapy, such as relaxation and behavioural therapy or hypnotherapy, may have a role to play, although no strong scientific evidence supports their use.

Clinical Approach to Specific Types of Constipation Simple constipation This may be defined as that caused by faulty diet, bowel habit, travel or drugs. Once organic disease has been satisfactorily excluded, treatment of this group should be along the lines outlined in the general measures above. Dietary manipulation should be used initially and laxative agents only used if the problem does not respond to simple means.

Constipation in elderly people Approximately 50% of elderly patients in primary care will complain of a disturbance of bowel function, more commonly constipation. Drug treatment given for other conditions often leads to constipation. Other factors include a low fibre intake because of poor nutrition and relative immobility producing difficulties with toilet access. Many elderly nursing home patients develop rectal impaction and this sometimes produces spurious diarrhoea. This diagnosis can be made by rectal examination. Treatment consists of cleaning out the rectum completely by digital fragmentation, lavage or polyethylene glycol (for 3 days), then prescription of an osmotic laxative, increasing the dose as needed to induce a stool every second day. Occasionally, elderly patients present with obtundation or delirium, which improves as the constipation is treated.

Hospitalised patients Constipation in hospital is usually multifactorial. If a patient has not passed stool for 2 days, and no clearcut cause is apparent, bisacodyl (10 mg at night) or magnesium hydroxide (in the morning) is reasonable first-line therapy.

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Opioid-induced constipation On initiation of an opiate for pain control, a concomitant laxative regimen is recommended to prevent constipation (e.g. docusate 100 mg orally three times daily and senna 2–8 tablets at night). If constipation occurs despite prophylactic laxatives, obstruction and impaction should be ruled out, then an osmotic laxative (e.g. polyethylene glycol 17 gm) or a bisacodyl suppository (if nauseated) tried. The peripheral opioid antagonist methylnaltrexone does not impair analgesia but does improve constipation in 50% of cases refractory to usual care; it is given by subcutaneous injections twice daily. Low dose oral naloxone is an alternative option.

Idiopathic colonic inertia (slow-transit constipation) This is a rare disorder mainly seen in young women, and the history usually dates from childhood or adolescence. Typically these patients go for weeks between bowel actions! Occasionally, the problem follows abdominal or pelvic surgery. It is now recognised that the majority of these patients have loss of the interstitial cells of Cajal, which drive intestinal smooth muscle activity as pacemakers (producing myogenic electrical slow waves). Sometimes this disorder is part of a widespread inherited or acquired defect in intestinal muscle or nerve that causes symptoms of bowel obstruction (chronic idiopathic intestinal pseudo-obstruction). There may be diffuse abnormality of smooth muscle function with abnormalities in oesophageal motility, gastric emptying, small bowel transit and bladder function. Dietary manipulation and other simple measures are ineffective, and usually these patients manage bowel evacuation only with laxatives or enemas. Other patients may have an abnormality of rectal evacuation producing a hold-up in transit. This could be due to a sensory defect in the rectum as many of these patients appear unable to satisfactorily expel liquid or solid content from the rectum due to paradoxical contraction of the pelvic floor striated muscles during defecation. Pelvic ultrasonography has not demonstrated any significant anatomical abnormality, but many of these women have descending perineum syndrome due to chronic straining at defecation. If pelvic floor dysfunction can be corrected by biofeedback, in true slow-transit constipation, the abnormal colonic function persists. Medical treatment of this group of patients remains difficult. Osmotic laxatives should be tried

in the first instance, but often are unpredictable and are associated with bloating, nausea and frequent loose stools. Occasionally, per-rectal evacuants are useful. Surgical treatment should be reserved for those with disabling symptoms that have been present for many years when all medical treatment options have been exhausted. In general terms, surgery should be performed only after appropriate physiological and psychological assessment in units with a particular surgical interest in this area. Pelvic floor dysfunction must be corrected if present before surgery is ever considered. Ileorectal anastomosis has been reported to be successful in a small number of patients.

Megacolon Megacolon is a rare disorder characterised by an increased rectal or colonic diameter on x-ray examination. Hirschsprung's disease is an important cause. Multiple genetic mutations have been identified in Hirschsprung's disease, mainly in the RET proto-oncogene. It may present for the first time in adult life and can usually be diagnosed by radiological and physiological tests. An unprepared barium enema will usually show a cone-shaped rectosigmoid transition zone (from narrowed to dilated; the narrowed segment is where there is a lack of colonic ganglion cells). The rectosphincteric reflex on anorectal manometry is absent. Rectal biopsy is needed to confirm the diagnosis. The treatment for Hirschsprung's disease in adults is surgery. Chagas’ disease is endemic in tropical South America, particularly Brazil. The disease is caused by the organism Trypanosoma cruzi and causes neuronal damage to cells in the autonomic nervous system, most particularly affecting the hollow organs and heart. Megacolon occurs during the chronic phase of the disease and is associated with a dilated, aperistaltic segment of intestine— often the sigmoid colon. Megacolon and megaoesophagus often occur together. Patients whose symptoms are uncontrolled by medical measures require surgical resection of the dilated colonic segments. Those with non-Hirschsprung's or idiopathic megacolon may be subdivided into patients whose symptoms develop in childhood and patients whose symptoms develop in later life. In the former group, faecal impaction and soiling are usually the presenting symptoms. The initial step is to disimpact the rectum as described above and then maintain the patient on regular oral laxatives. Encouragement regarding regular defecation is

11 Constipation important. Sometimes regular per-rectum evacuants are needed to maintain an empty rectum. Those whose symptoms develop in later life are usually troubled by pain and bloating and respond poorly to laxatives. Many have taken antidepressants, antipsychotics or antiparkinsonian drugs for prolonged periods. Some evidence suggests that these people may have an inherited or acquired defect in nerve or muscle of the colonic wall. Some patients have idiopathic intestinal pseudo-obstruction. If symptoms are severe and unresponsive to medical treatment and the patient is otherwise fit, colectomy usually gives good results.

Endocrine and metabolic causes Constipation is common in hypothyroidism; megacolon has been reported, and improves if the patient becomes euthyroid on treatment. Hypercalcaemia and acute porphyria can present with constipation and again respond to appropriate therapy.

ll

ll

ll

ll

ll

ll

ll

Autonomic neuropathy The most common cause is diabetes mellitus. These patients appear to lack the normal gastrocolic response following food ingestion. Prokinetic drugs may be useful in therapy.

ll

Spinal cord lesions Damage to the sacral cord leads to a distensible atonic distal colon. Constipation is thus a significant problem in paraplegia. Usually, a bowel regimen with a bulk-forming agent, stimulant laxatives and per-rectal evacuants twice or thrice weekly helps to maintain regular bowel patterns.

ll

ll

Other neurological diseases Constipation may accompany multiple sclerosis, Parkinson's disease (before other neurological signs develop) and psychosis or dementia. Constipation may be seen in depression or anorexia nervosa. Treatment should be along the usual lines in a stepwise fashion as outlined.

Key Points ll

ll

Constipation may mean decreased bowel frequency, hard stools or some difficulty or pain with bowel evacuation (excessive straining, a feeling of anal blockage, patient cannot push out all of the stool, needs to manually disimpact). The majority of patients who complain of constipation have a benign disorder of colorectal function associated with faulty diet, drugs or bowel habit.

ll

ll

ll

ll

139

Constipation may be the presenting symptom of colon cancer. Constipation may be induced by certain drugs, such as narcotics, antihypertensives or antidepressants. Constipation is common in hypothyroidism; megacolon has been reported. Hypercalcaemia and acute porphyria can present with constipation. Constipation may accompany Parkinson's disease before other neurological signs develop. Constipation dating from the neonatal period may suggest Hirschsprung's disease (congenital aganglionosis causing absent peristalsis). Severe constipation (with a defecation frequency of less than once a week off laxatives) in young women dating from adolescence may indicate colonic inertia (slow transit constipation). Some patients with a disorder of pelvic floor function (outlet obstruction) complain of a sense of difficulty with evacuation and feeling of anal blockage or obstruction; they may manually disimpact themselves. However, symptoms cannot distinguish pelvic floor dysfunction with sufficient accuracy from other causes of constipation. A rectal examination is helpful; ask the patient to try to push your finger out by straining. If the puborectalis and anal sphincter contract and increase pressure in the anal canal rather than relaxing to widen the canal, this suggests (but is not diagnostic of) pelvic outlet obstruction. Colonoscopy is the test of choice to exclude significant structural colonic disease. In younger patients (under the age of 50 years) in whom suspicion of serious underlying disease such as colon cancer is low (no alarm features such as weight loss), a trial of therapy for constipation without investigation is reasonable. Many patients with constipation may be managed by a high-fibre diet containing 20–30 g of fibre. Polyethylene glycol is a large polymer and a very effective osmotic laxative that is safe. It causes less bloating and gas than other osmotic laxatives. Biofeedback in patients with chronic constipation due to pelvic floor dysfunction (identified by anorectal manometry) has a 70% success rate. On initiation of an opiate for pain control, a concomitant laxative regimen is recommended to prevent constipation (e.g. docusate 100 mg orally three times daily and senna 2–8 tablets at night).

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Damage to the sacral cord leads to a distensible atonic distal colon; a bowel regimen with a bulk-forming agent, stimulant laxatives and per-rectal evacuants twice or thrice weekly helps to maintain regular bowel patterns.

Further reading Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol 2005; 100(suppl 1): S5–S21. Di Palma JA, Smith JR, Cleveland M. Overnight efficacy of polyethylene glycol laxative. Am J Gastroenterol 2002; 97:1776–1779. Emison ES, McCallion AS, Kashuk CS, et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 2005; 434:857– 863. Jones MP, Talley NJ, Nuyts G, et al. Lack of objective evidence of efficacy of laxatives in chronic constipation. Dig Dis Sci 2002; 47:2222–2230. Lembo A, Camilleri M. Chronic constipation. N Engl J Med 2003; 349:1360–1368.

Muller-Lissner SA, Kamm MA, Scarpignato C, et al. Myths and misconceptions about chronic constipation. Am J Gastroenterol 2005; 100:232–242. Ramkumar D, Rao SS. Efficacy and safety of traditional medical therapies for chronic constipation: systematic review. Am J Gastroenterol 2005; 100:936–971. Rao SS, Ozturk R, Laine L. Clinical utility of diagnostic tests for constipation in adults: a systematic review. Am J Gastroenterol 2005; 100:1605–1615. Talley NJ. Management of chronic constipation. Rev Gastroenterol Disord 2004; 4:18–24. Talley NJ, Jones M, Nuyts G, et al. Risk factors for chronic constipation based on a general practice sample. Am J Gastroenterol 2003; 98:1107–1111. Talley NJ, Lasch KL, Baum CL. A gap in our understanding: chronic constipation and its comorbid conditions. Clin Gastroenterol Hepatol 2009; 7:9–19. Thomas J, Karver S, Cooney EA, et al. Methylnattrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008; 358:2332–2343.

12 Perianal pain

Case Mrs JS is a 35-year-old woman who presents with severe anal pain on defecation. The pain had worsened over the previous 6 months. On further questioning she admitted to straining at stool, and the stool was sometimes hard and pelletlike. Her pain occurred spontaneously when sitting but was greatly exacerbated while passing a stool and lasted up to an hour. As a result, she was reluctant to pass stool and often held back passing a motion for 2 or 3 days. She noted bright blood on the toilet paper intermittently. She had also noted a small swelling at the anus but was not aware of any prolapse during defecation. She had a background history of two normal vaginal deliveries, without a perineal tear or episiotomy. She was otherwise fit and healthy. Abdominal examination was normal. On anal examination there was a fissure posteriorly in the midline with a sentinel tag. On gentle digital examination she was exquisitely tender posteriorly just within the anal verge, and no further internal examination or proctoscopy was carried out. There was no perianal inflammation, swelling or tenderness. Diagnosis: The history of severe acute anal pain usually suggests an anal fissure or perianal abscess (or other abscess, such as intersphincteric or ischiorectal). The finding of localised tenderness in the posterior midline within the anal canal is almost certainly due to a fissure. Haemorrhoids do not cause severe pain unless the haemorrhoids are thrombosed, in which case there are obvious prolapsed tender haemorrhoids on anorectal examination. Although haemorrhoids are more common than anal fissures overall, prolapsing haemorrhoids that are not acutely thrombosed cause slight discomfort only; the most common cause of severe pain is anal fissure. Management and progress: First-line management is with dietary changes. The patient

was commenced on a high fibre diet (of at least 30 g per day), supplemented with additional fibre such as psyllium (Metamucil™), with at least 1.5 L of water, to soften her stools. She was treated with glyceryl trinitrate (GTN) 0.2% cream (Rectogesic™) placed into the lower anal canal twice daily. She developed a troublesome headache after application of the cream. She was instructed to then reduce the amount used to the point where headaches do not occur, to continue with that dose for 2 or 3 days and then gradually increase to the recommended dose (the body adjusts to the lower dose, and the higher dose is subsequently tolerated, by the process of tachyphylaxis). Her pain improved considerably, but she returned 6 weeks later complaining of a recurrence of severe pain. She had successfully softened her stool and had complied with use of the GTN for 4 weeks to allow the fissure time to granulate. She was then progressed to the next line of treatment, which is injection of Botox®. This was carried out in hospital under sedation. A full digital examination and flexible sigmoidoscopy was also carried out to exclude other causes of pain and bleeding, and at the examination there were no signs of proctitis or other mucosal pathology, and no intersphincteric or other perianal sepsis. The fissure healed and her symptoms resolved. However she again returned after 3 months with a recurrent fissure, producing sufficient pain to cause her to miss days off work. She was advised to undergo lateral sphincterotomy, after providing clear information about the small risk of permanent faecal incontinence (usually minor). After undergoing anal manometry and endoanal ultrasound to confirm that anal sphincter function had not been affected by her vaginal deliveries (and hence place her at increased risk of

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incontinence after sphincterotomy), she underwent sphincterotomy under general anaesthetic. The fissure healed fully, with complete resolution of pain.

Introduction Perianal pain may be a mild discomfort, an acute severe pain, or a chronic debilitating symptom. The nature of the pain and any associated symptoms will provide important clues to the cause. Important points are the severity of the pain, the duration of the pain, the relationship of pain to defecation, and associated bowel symptoms such as rectal bleeding, prolapse at the anus, or discharge of pus. The causes of perianal pain are listed in Box 12.1.

History A patient presenting with severe unrelenting pain over recent hours to days, not related to defecation, is likely to have either perianal sepsis or thrombosed haemorrhoids. These patients are usually totally distracted from other activities by the pain. While thrombosed haemorrhoids cause severe, acute pain, non-thrombosed haemorrhoids are usually not associated with pain although there can be discomfort during defecation if the haemorrhoids prolapse. Typically the pain from an acute anal fissure is severe and is precipitated by defecation; it may take minutes to hours to gradually settle. The pain associated with pruritus ani is annoying but not severe, and is usually associated with the presence of faecal soiling over a raw area.

Box 12.1  Causes of perianal pain ll ll

ll

ll ll ll



Fissure-in-ano Anal sepsis – anal abscess; – anal fistula. Haemorrhoids – thrombosed internal haemorrhoids; – thrombosed external haemorrhoids. Pruritus ani Proctalgia fugax Chronic perianal pain syndromes – coccygodynia; – descending perineum syndrome; – levator ani syndrome; – idiopathic perineal pain; – referred pain.

The pain of anal fistula tends to be mild and associated symptoms are perianal discharge or bleeding. The pain of proctalgia fugax is very typical: sudden onset of a severe, dull rectal ache, often waking the patient from sleep, sometimes causing a desire to defecate, and lasting 15–20 minutes. There may be long periods without any pain. There are a number of chronic perianal pain syndromes associated with a vague dull ache. The presence of associated bowel symptoms or systemic symptoms may clearly point to the diagnosis. The patient should be asked about rectal bleeding. There may be minor perianal bleeding with anal fissure, usually apparent on the toilet paper after defecation or occasionally on the surface of the stool. With internal haemorrhoids, bleeding can be a more prominent feature than pain; the bleeding tends to be related to defecation and is most commonly noted on the toilet paper or in the toilet bowl. Pruritus ani can be associated with minor bleeding associated with wiping the perianal region after defecation. Perianal abscess is not usually associated with bleeding unless the abscess has discharged spontaneously or has been drained. There may be a minor degree of perianal bleeding with anal fistula. There should not be significant rectal bleeding with any of the chronic pain syndromes or with proctalgia fugax. Symptoms of constipation are commonly associated with a number of painful perianal conditions (Ch 11). In some cases the constipation leads to the condition, such as fissures or haemorrhoids, but in other cases of anal fissures or thrombosed haemorrhoids the constipation may be caused by the patient's reluctance to defecate because it induces or exacerbates pain. The conditions causing perianal pain should not themselves be associated with diarrhoea. Therefore, the presence of diarrhoea suggests another disease process (e.g. Crohn's disease).

Examination Inspection While the history will commonly give vital clues as to the cause of the perianal pain, local examination will usually confirm the diagnosis. The examination clearly needs to be focused in the perianal region. A general abdominal examination, however, is essential to detect inflammatory or neoplastic conditions associated with the pain. The easiest and most comfortable position for inspection is with the patient in the left lateral position with the hips and knees flexed. The buttocks

12 Perianal pain are parted with gentle pressure from the palm of the hand so that the perianal skin can be closely examined. Red excoriated skin suggests that the pain is due to pruritus ani. The presence of a sinus means an anal fistula should be sought. The presence of a spot of pus or blood in the perianal region can point to the external opening of a fistula. A perianal abscess can be associated with a perianal swelling and redness of the overlying skin, depending upon the proximity of the abscess to the external skin. There may be irregular soft tags of skin, which are asymptomatic, but most commonly associated with a fissure or haemorrhoids. The presence of a small, tense, often bluish swelling just beyond the anal verge is suggestive of a thrombosed external haemorrhoid. An anal fissure is commonly not obvious on external examination and is often very tender, requiring a particular approach in the examination (see ‘Fissure-in-ano’ below). A thrombosed internal haemorrhoid that has prolapsed may be evident at the anal verge as an oedematous 1–2 cm swelling. Internal haemorrhoids are usually not apparent on external examination. The chronic pain syndromes are not associated with perianal stigmata on inspection.

Palpation The features to be sought on palpation are: the presence of a lump; ll tenderness with or without an obvious palpable lump; ll the presence of a submucosal cord; and ll associated abnormality of sphincter tone. A perianal abscess presenting as a perianal lump with associated overlying erythema will always be focally extremely tender. Focal tenderness to palpation is also present with thrombosed internal as well as external haemorrhoids. Severe pain without focal external tenderness is due to either an anal fissure or an intersphincteric abscess (see below). The patient with an anal fissure will usually not tolerate perianal examination because of the pain. Do not part the buttocks vigorously, and insert the finger very gently (see below). The perianal regions should be gently palpated looking for a subcutaneous or submucosal cord leading from the opening of an anal fistula. This cord should be followed internally and its position in relation to the anal sphincter noted. A prolapsed thrombosed internal haemorrhoid can be distinguished from a thrombosed external haemorrhoid by a cord extending inside the anus to the upper part of the internal haemorrhoid. ll

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Deeper rectal examination may demonstrate focal tenderness associated with abscess formation inside the anus in the intersphincteric space (between internal and external sphincter) or laterally in the ischiorectal fossa. If the cause of the perineal pain is not clear at this stage, gently rocking the coccyx with posterior pressure may elicit sharp pain suggesting the diagnosis of coccygodynia. None of the conditions that cause chronic perianal pain are associated with a palpable abnormality, except the descending perineum syndrome in which the pelvic floor drops down from its usual position. If an adequate rectal examination is not possible because of perianal pain, it may be necessary to perform this examination under anaesthesia. This examination should be performed by an experienced person capable of dealing with any perianal pathology found on examination.

Proctoscopy Proctoscopy will be possible in an office setting for most patients (Ch 22). It will not be possible in patients with an anal fissure, anal abscess or thrombosed haemorrhoids. Proctoscopy will allow a diagnosis of internal haemorrhoids, which will become more prominent or evident as the proctoscope is withdrawn.

Rigid sigmoidoscopy This examination is commonly performed and provides useful information in cases where more proximal rectal disease is suspected, based on the history. Mucosal pathology in the rectum such as proctitis, polyps or cancer can be detected. Like proctoscopy, sigmoidoscopy is also not carried out when there is local anal tenderness.

Fissure-in-Ano Aetiology The majority of anal fissures are primary fissures without any predisposing cause. Although more than 50% of patients are constipated, this precedes the fissure in only 25% of cases; in other patients, the constipation results from the fissure because of a fear of defecating; 5% of fissures follow childbirth. In children, fissures are caused by constipation in the majority of cases and will heal when the constipation is treated. The condition is most common between 20 and 40 years of age, and occurs slightly more often in males. Secondary fissures are caused by Crohn's disease, ulcerative colitis, immunosuppression (e.g. chemotherapy or HIV infection) and, rarely, tuberculosis or syphilis.

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Site Eighty per cent of fissures are in the posterior midline; 10%, anterior midline; 7%, both posterior and anterior midline; and 3%, lateral.

Pathology The acute fissure is a superficial split with soft edges. A chronic fissure evolves through several phases: ll superficial—longitudinal muscle fibres of musculus submucosae ani may be seen in the base; ll deeper fissure—the edges may be indurated; transverse fibres of internal sphincter are seen; ll advanced fissure—edges are indurated and may be undermined; a skin tag (sentinel pile) develops at the lower edge; a fibroepithelial polyp (hypertrophied anal papilla) may form at the upper end of the fissure at the dentate line (see Fig 12.1); Finally, an abscess may form in the submucosal plane or in the skin tag leading to a superficial fistula, or between the internal and external sphincters (intersphincteric). Secondary fissures may be broad or long. If a fissure extends into the upper anal canal above the dentate line, it is usually a secondary fissure. These are sometimes called anal ulcers.

Pathophysiology Chronic anal fissures are almost always associated with intense spasm of the internal anal sphincter muscle. There was much debate about which came first, but it is now known that the spasm precedes

Figure 12.1  Chronic anal fissure. Note the deep chronic posterior fissure with skin tag below and fibroepithelial polyp above.

the fissure, although it is not the actual cause of the fissure. The fissure is initially produced by minor trauma to the mucosa from the passage of faeces. Why do chronic fissures often then fail to heal? Under normal circumstances a small split like a fissure would rapidly heal, but in patients where there is underlying internal sphincter spasm, the pressure generated in the mucosa by the sphincter spasm exceeds arteriolar blood pressure, resulting in ischaemia in the anal mucosa. Reversal of the sphincter spasm results in rapid healing in most cases.

Clinical features History Pain is the most common symptom. It occurs during defecation and may persist for some hours after. Some patients describe a feeling of ‘passing razor blades’, ‘passing glass’, or ‘splitting’. Bleeding occurs commonly and is bright red, usually just on the toilet paper but occasionally the blood may drip into the toilet bowl. Itching or a lump at the anus (skin tag) may be reported and frequently patients will think that the lump is a haemorrhoid. A secondary fissure resulting from inflammatory bowel disease may be associated with symptoms of proctitis or colitis. Some fissures or ulcers caused by inflammatory bowel disease produce little pain and tenderness. Syphilitic fissures are very rare, but are typically painless. When a fissure is caused by acquired immune deficiency syndrome (AIDS) or tuberculosis, there may be systemic features of those conditions. Examination In most cases the diagnosis should be made without a full digital examination since this produces severe pain. Gentle bilateral traction on the anal verge reveals tight spasm in most cases and the fissure is usually visible. If the fissure cannot be seen, gentle pressure just inside the posterior midline will produce tenderness. Only if this is not found should a deeper digital examination be done. The examining finger is inserted, pushing firmly anteriorly away from the posterior midline (since most fissures occur posteriorly), and then once the finger is inside gentle pressure in a posterior direction is applied. This may produce the classical tenderness, or the induration associated with a deep fissure may be palpated. A small proportion of primary fissures are not associated with internal sphincter spasm,

12 Perianal pain particularly postpartum fissures. However, if spasm is not present underlying pathology (secondary fissure) should be suspected. A sigmoidoscopy should then be done to look for evidence of proctitis. Serum should be collected for HIV and syphilis serology, when indicated.

Treatment Conservative In 75% of cases of acute fissure and up to 15–100% of chronic fissures healing will be spontaneous if constipation is treated. Initial conservative (nonsurgical) treatment is always indicated unless pain is so severe that immediate surgery is required. A bulking agent, such as psyllium husk or sterculia, should be used regularly. Adequate fluid intake (1.5 L in the healthy adult) should be taken in order to allow the additional fibre bulk to work effectively. If this does not soften the stool, an osmotic laxative such as Epsom salts, lactulose or polyethylene glycol (Movicol™) should be added. Warm baths have a true physiological effect since the heat has been shown to reduce internal sphincter spasm slightly. Medical Recent studies have found that the substance mediating internal sphincter function is nitric oxide. If a nitric oxide donor, such as 0.2% glyceryl trinitrate cream is applied to the anal mucosa, this produces rapid internal sphincter relaxation, with improved blood flow in the mucosa and resultant healing of a high proportion of chronic fissures. Treatment should continue for at least 4 weeks to allow the fissure to granulate. Glyceryl trinitrate is associated with headaches in about 25% of patients, but these are usually mild and will usually disappear if the dose is reduced. Calcium channel blockers such as diltazem and nifedipine cause smooth muscle relaxation by inhibiting calcium ion channels in smooth muscle, thereby causing sphincter relaxation. Topical diltazem 2% is as effective as 0.2% glyceryl trinitrate and causes fewer headaches; the main side effect is pruritus ani. Healing rates with topical treatments are about 60% in the short term and recurrences occur. If the fissure fails to heal with topical treatment, inactivated botulinum toxin (Botox™) is injected into the sphincter. This paralyses the muscle for about 3 months and allows a further proportion of fissures to heal; about 10% of patients will develop transient incontinence, which settles once the effect of the Botox wears off after 3 months. There is no evidence that

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other topical agents, including steroids or local anaesthetics, have any effect on fissure healing or pain, and these should be avoided since allergy to local anaesthetics may occur. Use of an anal dilator is an outdated treatment and should be avoided, since it is very painful to use and may damage the sphincter. Surgery Surgery is indicated only if the fissure fails to heal and remains painful despite all the above measures, because a small percentage of patients will develop faecal incontinence after sphincterotomy. The basis of surgical treatment is to disrupt the spasm in the lower part of the internal anal sphincter. Anal dilatation successfully achieves this aim but can lead to incontinence in up to one-quarter of cases, and has therefore been abandoned in favour of the more controlled method of sphincter division (sphincterotomy). Sphincterotomy was initially performed posteriorly together with excision of the fissure, but this may cause fibrosis and a keyhole deformity with resultant seepage of stool. Sphincterotomy is therefore now carried out laterally. It may be done as a closed or open technique, and the recurrence rate is less than 2%. Anal physiology tests (see Ch 16) should be performed in all patients who have had prior anal surgery, particularly multiparous women. Sphincterotomy should be avoided in those patients with low anal canal pressures. In these patients advancement flaps may be considered as an alternative treatment.

Anal Sepsis The majority of cases of anal abscess develop from a primary infection in an anal gland (Box 12.2). This infection results in the formation of an abscess in the intersphincteric space, which in turn may spread to form a perianal abscess, ischiorectal abscess or supralevator abscess. If an abscess communicates with the anal canal, and also discharges or is surgically drained through the perianal skin, a fistula has formed. Anal abscess and fistula are therefore part of the same pathological process.

Anatomy The anal canal is surrounded by two concentric muscle rings. The inner circular layer (internal anal sphincter) consists of smooth muscle, and is formed from the downward continuation of the circular muscle of the rectum. The outer layer (external anal sphincter) consists of striated muscle and is the muscle under voluntary control; it is continuous

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Box 12.2  Aetiology of anal abscess and fistula 1. Primary anal gland infection 2 . Secondary abscess: ll Inflammatory bowel disease: – Crohn's disease; – ulcerative colitis; ll Infection: – tuberculosis; – actinomycosis; – threadworm. ll Trauma ll Leucopoenia ll Immunosuppression: – HIV; – drugs. ll Diabetes mellitus ll Tumours: – benign (e.g. duplication cysts); – malignant (e.g. rectal cancer, teratoma).

at its upper border with the levator ani muscle. The space immediately above the levator ani is called the supralevator space. The space between the internal and external sphincters is called the intersphincteric space. On the outer side of the internal sphincter is a layer of longitudinal smooth muscle, which is the downward continuation of the longitudinal muscle of the rectum. This muscle sends strands laterally through the external sphincter to reach the ischiorectal fossa, and infection may spread along this plane. The lining of the anal canal consists of an upper mucosal half and a lower cutaneous half. The upper mucosal lining may be either stratified cuboidal epithelium or columnar epithelium, and this ends caudally as the dentate (pectinate) line, which consists of a series of mucosal folds. Below the dentate line is the cutaneous region, consisting of modified skin containing squamous epithelium with no hairs or sebaceous glands. The mucosa at the junction of the two regions contains four to eight glands, the ducts of which open into the anus at the level of the dentate line. The glands extend into the submucosa where they have several branches, some of which penetrate the internal anal sphincter to end blindly in the intersphincteric space. The glands appear to have no important secretory function, and their significance is that they are the focus of infection, which leads to anal abscess formation.

Pathology Primary anal gland (cryptoglandular) abscess and fistula Infection in an anal gland starts after faecal bacteria gain entry via the anal duct, resulting in an intersphincteric abscess. This may then spread: ll downwards to the perianal skin to form a perianal abscess; ll upwards to the supralevator region to form a supralevator abscess; ll laterally along the longitudinal muscle strands that penetrate the external sphincter, or down and around the lower edge of the internal sphincter, in both cases to reach the ischiorectal fossa to form an ischiorectal abscess. ll See Figures 12.2A and 12.2B. An intersphincteric, ischiorectal or supralevator abscess may spread circumferentially to form a ‘horseshoe’ abscess. Microbial culture of pus from an anal abscess yields gram-negative organisms and anaerobic organisms (mainly Bacteroides spp.) originating from the bowel. A cryptoglandular abscess should be distinguished from: ll an abscess originating in the perianal skin from infection in a hair follicle—culture of pus shows skin flora, particularly Staphylococcus aureus, and the abscess is never associated with an anal fistula; ll hidradenitis suppurativa—apocrine sweat glands are found in the axilla, groin, areola and perianal region; infection may result in abscess and chronic sinus formation; and ll pilonidal sinus—a pilonidal sinus usually occurs in the natal cleft, beginning as an ingrown hair, which results in a chronic infection in the subcutaneous tissues. Occasionally, a pilonidal sinus may occur in the perianal region and appear very similar to a true cryptoglandular abscess or fistula. A cryptoglandular abscess may progress to form a fistula of the following type: ll intersphincteric fistula (45% of fistulae): this forms from a perianal abscess which discharges spontaneously through the perianal skin or is surgically drained through the perianal skin to form a communication between the skin and the anal canal (Fig 12.3); ll trans-sphincteric fistula (35%): this forms in a similar way to an ischiorectal abscess. The fistula encloses a variable amount of external sphincter muscle, and the amount of muscle

12 Perianal pain

ll

ll

ll

A Figure 12.2A  Spread of anal infection. Infection starts in an anal gland and leads to an intersphincteric abscess. This may spread downwards, upwards, or outwards across the external sphincter. From Parks AG, Gordon PH, Hardcastle JD: A classification of fistula-in-ano. Br J Surg 1976; 63(1):1–12, with permission.

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enclosed will determine the correct surgical treatment (Fig 12.4); suprasphincteric fistula (15%): this forms when a supralevator abscess discharges downwards through the levator ani muscle into the ischiorectal fossa and then through the skin (Fig 12.5); extrasphincteric fistula (3%): in most cases there is a history of attempted surgical drainage of a fistula. Iatrogenic damage results from probing an ischiorectal abscess or transsphincteric fistula, creating a passage into the rectum instead of along the correct course into the anal canal. Very rarely an extrasphincteric fistula results from spontaneous discharge of a rectal or sigmoid abscess resulting from diverticular disease, Crohn's disease or from perforation of the bowel by a fish or chicken bone (Fig 12.6); subcutaneous fistula (2%): this is a superficial fistula that begins as an abscess in an oedematous skin tag usually associated with an anal fissure. The abscess discharges through the mucosa of the lower anal canal and through the perianal skin to form a small subcutaneous fistula.

Secondary abscess and fistula The features of these are as follows: ll inflammatory bowel disease: Crohn's disease is the most common cause of secondary abscess

Supralevator abscess

Intersphincteric abscess

Perianal abscess

Ischioanal abscess

B Figure 12.2B  Spread of anal infection. As a result of this spread, an abscess forms in a perianal, supralevator or ischiorectal position. From Gordon PH, Nivatvongs S. Principles and practice of surgery for the colon, rectum and anus. 2nd edn. Montreal: Routledge/Taylor & Francis Group; 2002, with permission.

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Figure 12.3  Intersphincteric fistula—infection does not cross the external sphincter. Perianal abscess (left) results in the fistula (right). Note that the fistula opens internally in the anal canal at the position of the infected anal gland at the dentate line. From Parks AG, Gordon PH, Hardcastle JD: A classification of fistula-in-ano. Br J Surg 1976; 63(1):1–12, with permission.

Figure 12.4  Trans-sphincteric fistula—infection crosses the external sphincter to form an ischiorectal abscess (left), which then discharges to form the fistula (right). From Parks AG, Gordon PH, Hardcastle JD: A classification of fistula-in-ano. Br J Surg 1976; 63(1):1–12, with permission.

ll

formation, which in turn may lead to fistula formation. Complicated, circuitous or multiple fistulae may form. Ulcerative colitis is a less common cause. leucopenia: leukaemia or other cause of pancytopenia may result in anal sepsis. Pain and spreading perianal infection occur. Since

ll

there is a paucity of white blood cells, an abscess does not form. Treatment is therefore with antibiotics rather than surgical drainage. immunosuppression: AIDS or drugs causing immunosuppression predispose to infection in the anal glands, with abscess and fistula formation.

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Figure 12.5  Suprasphincteric fistula—infection spreads upwards in the intersphincteric plane to form a supralevator abscess (left), which discharges downwards through the levator ani to reach the ischiorectal fossa and then through the skin to form a fistula. From Parks AG, Gordon PH, Hardcastle JD: A classification of fistula-inano. Br J Surg 1976; 63(1):1–12, with permission.

Figure 12.6  Extrasphincteric fistula (right)—develops from a trans-sphincteric fistula that is incorrectly probed so that the probe is pushed upwards through the levator ani into the rectum. Rarely the fistula forms spontaneously from pathology in the rectum (left). From Parks AG, Gordon PH, Hardcastle JD: A classification of fistula-in-ano. Br J Surg 1976; 63(1):1–12, with permission.

ll

ll

infection: tuberculosis, actinomycosis and occasionally threadworm infestation may cause abscess formation. trauma: trauma to the rectum by a penetrating injury, or by insertion of a sharp object per anum, may pierce the rectum and cause

ll

a supralevator abscess and extrasphincteric fistula. rectal carcinoma: advanced rectal cancer may undergo tissue necrosis and abscess formation, usually in the ischiorectal fossa. Another rare variety of malignant fistula occurs when a rectal

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ll

Clinical gastroenterology: a practical problem-based approach

cancer seeds malignant cells into an established primary fistula. diabetes mellitus: the incidence of diabetes mellitus is higher in patients with anal sepsis than in the rest of the population. Occasionally, anal sepsis is the presenting feature of occult diabetes.

Clinical features The cardinal feature of an anal abscess is severe pain. A perianal abscess usually causes a tender red swelling near the anal verge (see Fig 12.7). An ischiorectal abscess is placed more deeply and there is usually less tenderness and swelling, but there may be high fevers if the abscess is large. An intersphincteric abscess produces marked tenderness on digital examination of the anal canal. Usually the external opening of a fistula is easily identified. The position should be noted in order to predict where the internal opening will be found (see Fig 12.8). Supralevator extension is easily palpated on digital examination (see Fig 12.9).

Principles of surgical treatment Incorrect surgical treatment of anal sepsis can have devastating consequences, with faecal incontinence resulting from division of excessive amounts of sphincter muscle. An abscess requires immediate drainage. This is best done under general anaesthetic, both for patient comfort as well as to optimally assess the extent of the abscess. An internal opening is found in 30–50% of cases. If an internal opening is not present and culture of pus yields a growth of Staphylococcus and other skin flora, no further treatment is needed. If bowel flora are cultured, an internal opening may be present and examination under anaesthesia should be carried out 10–14 days later. If an internal opening is present at the time of abscess drainage, the fistula should be laid open (fistulotomy). An intersphincteric or trans-sphincteric fistula can be laid open if there is sufficient muscle remaining above the fistula track. If the track is too high, or if it is suprasphincteric or extrasphincteric, it should be treated either by placing a flap of mucosa and internal muscle to close the internal opening of the fistula, or alternatively with a Seton technique, where a rubber drain is placed around the fistula and gradually tightened (Fig 12.10). The use of curettage and injection of fibrin glue, or plugs made from pig small bowel mucosa, will heal 20–30% of fistulas. While the long-term healing rate of these techniques may be low, they are safe as they do not affect continence.

Figure 12.7  Perianal abscess.

Recurrent fistulae require careful assessment under anaesthesia, as well as endoanal ultrasound or magnetic resonance imaging (MRI) to help identify tracks that have not been detected during initial surgical treatment. Underlying inflammatory bowel disease should be excluded.

Haemorrhoids Haemorrhoids (also known as piles) are usually a painless condition and, although haemorrhoids may cause discomfort during prolapse, severe anal pain should not be attributed to haemorrhoids unless the haemorrhoids are found to be acutely thrombosed.

Anatomy The submucosa of the anal canal is expanded at three sites to form the submucosal cushions, located in the 3, 7 and 11 o'clock positions. The submucosa is supported by muscle fibres of the musculus submucosae ani. Within the submucosa is a plexus of vessels that joins arteries to veins without capillaries. This plexus of vessels is called the internal haemorrhoidal plexus above the dentate line, and the external haemorrhoidal plexus below the line in the lower anal canal and anal verge.

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151

Pectinate line

Transverse

Anal line Anal orifice

Anorectal ring

Figure 12.8  Goodsall's rule—a posterior fistula passes around to open internally at the posterior midline. An anterior fistula passes radially to open directly at a corresponding internal position. From Goligher JC, Duthie HL, Nixon HH. Surgery of the anus, rectum and colon. 4th edn. London: Baillière Tindall; 1980, with permission.

Figure 12.9  Supralevator induration is palpated on rectal examination. This indicates proximal extension of an abscess or fistula, and should raise suspicion of a suprasphincteric fistula. From Parks AG, Gordon PH, Hardcastle JD: A classification of fistula-in-ano. Br J Surg 1976; 63(1):1–12, with permission.

Pathophysiology The anal cushions are central to the development of haemorrhoids. During normal defecation there is a slight downward movement of the cushions together with their submucosal vasculature. If there is excessive prolapse or pressure on the cushions, such as occurs with prolonged straining at stool or with hard stools, the cushions become oedematous and the submucosal vascular plexus becomes

engorged. Damage to the musculus submucosae ani caused by chronic straining at stool results in loss of support of the anal cushions, which worsens the prolapse of the cushions. In addition, in the majority of patients with haemorrhoids there is a hypertonic internal sphincter muscle, producing very high intra-anal canal pressure. This leads to trapping of the prolapsing anal cushions outside the sphincter. All these factors result in progressive prolapse,

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Clinical gastroenterology: a practical problem-based approach amount of blood dripping into the toilet bowl during defecation. Occasionally, there may be streaks of blood on the surface of the stool, but this symptom should always raise suspicion of more serious rectal pathology. When the haemorrhoids are continuously prolapsed, spontaneous bleeding unrelated to defecation may occur with blood seeping through to the clothes. Anaemia uncommonly results from haemorrhoidal bleeding, but may occur with profuse or frequent bleeding over a prolonged period.

Figure 12.10  Anterior anal fistula. The external opening was at the top end of the wound near the surgeon's finger; the fistula has been incised down towards the anal verge; a rubber Seton has been placed through the high trans-sphincteric fistula since the fistula enclosed too much muscle to be safely divided.

oedema and engorgement of the submucosal plexus of vessels, with rupture of the vessels connecting arteries directly to veins. Bleeding then is bright red. It can therefore be seen that many traditional theories about the pathophysiology of haemorrhoids are incorrect. Haemorrhoids are not varicose veins of the anal canal, bleeding from which would be venous and hence dark red in colour. Haemorrhoids occur at 3, 7 and 11 o'clock because of the position of the anal cushions, not because the blood supply is distributed mainly at those three sites. Haemorrhoids are not accounted for by a simple rise in venous pressure, and the incidence is no higher in patients with portal hypertension. The incidence of haemorrhoids is higher in men than women, and only slightly higher in parous than nulliparous women, so that pregnancy is not the main causal factor. Similarly, lifting heavy objects or engaging in other strenuous activities does not produce haemorrhoids since there is reflex contraction of the external sphincter muscle during these actions, which supports the anal cushions and prevents them from prolapsing. Prolonged sitting or sitting on cold or hard surfaces also has no relation to the development of haemorrhoids.

Clinical features Bleeding Bleeding is the most common symptom. The blood is bright red and noted on the toilet paper. When the haemorrhoids prolapse externally beyond the hypertonic internal sphincter there may be a large

Prolapse Haemorrhoids are classified according to the degree of prolapse of the anal cushions: ll first degree: prolapse within the anal canal so that the subject is not aware of any external prolapse. Bleeding is the only symptom; ll second degree: prolapse outside the anal canal on defecation, with spontaneous reduction immediately after defecation; ll third degree: prolapse that requires manual reduction. If the patient does not reduce the haemorrhoids, they may remain external for up to some hours and then reduce spontaneously (see Fig 12.11); ll fourth degree: haemorrhoids that cannot be reduced. Discomfort External prolapse of large haemorrhoids may cause discomfort. There may be further discomfort when attempting to reduce the haemorrhoids. Severe pain is experienced only if thrombosis occurs. Thrombosed haemorrhoids Prolapse beyond the anal sphincter may result in thrombosis. There is swelling and severe pain. The prolapsed haemorrhoids are easily visible and very tender (see Fig 12.12). If thrombosed haemorrhoids are not treated surgically there is usually gradual resolution, but pain may persist for up to 2–4 weeks. Necrosis and infection may result. Most patients will be treated symptomatically with stool softeners and oral (non-constipating) medications, and once the thrombosed sections have resolved rubber banding to the internal haemorrhoids should be carried out, usually after 6–8 weeks (see below). Occasionally, thrombosed haemorrhoids may return into the anal canal and are not visible externally, but if thrombosis is established, severe pain persists and a tender lump is palpated on digital examination.

12 Perianal pain

Figure 12.11  Prolapsed third-degree (manually reducible) haemorrhoids.

Incontinence Minor seepage of faeces or mucus may occur. The perianal skin may become excoriated with resulting pruritus and pain.

Treatment Initial advice about adequate dietary fibre and fluid intake should be given. This may be supplemented with daily fibre in the form of either unprocessed wheat bran (one tablespoon) or psyllium (two teaspoons), which can be slowly increased. Improved compliance is achieved if written instructions are given. Randomised trials show only a slight advantage of fibre over placebo, however. Defecation habits should be improved by avoiding excessive straining at stool. The initial call to stool should be obeyed as soon as possible. Taking reading material into the toilet should be strongly discouraged. Adopting the squatting position to defecate does not reduce strain on the anal muscles and there is no evidence that this practice offers protection from developing haemorrhoids. The majority of patients with symptomatic haemorrhoids will require other treatment. Treatment involves: ll reducing the prolapse of the mucosal cushions containing the haemorrhoids; or ll removal of the haemorrhoids. Reducing the prolapse is achieved in several ways. Injection of a solution of 5% phenol in almond oil into the submucosa at the base of the haemorrhoid, at least 1 cm above the dentate line produces fibrosis in the submucosa, which stops the haemorrhoid prolapsing and becoming engorged. Injection has become much less popular since there is a high recurrence rate; it is suitable only for firstdegree and small second-degree haemorrhoids.

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Figure 12.12  Irreducible fourth degree haemorrhoids. Note the left lateral pedicle (centre), which is thrombosed.

Most second-degree haemorrhoids and some third-degree haemorrhoids are treated by rubberband ligation. This involves placing a small rubber band around the base of each haemorrhoid at least 1 cm above the dentate line. If the band is placed lower than this within the sensitive zone of the anal mucosa, severe pain may result. Rubber banding works by two mechanisms: it produces a fullthickness mucosal ulcer, which fixes the base of the anal cushion and prevents prolapse, and it removes the proximal part of the prolapsing anal cushion. Other methods that prevent prolapse in a similar way, but are used much less commonly, are infrared photocoagulation and cryotherapy. Circumferential prolapsing haemorrhoids may be treated with a stapled haemorrhoidopexy. This procedure removes a circular strip of mucosa and pulls the haemorrhoids back into the anal canal, thereby reversing the prolapse. It is associated with significantly less pain than conventional haemorrhoidectomy, but recurrent prolapse may be more common. If patients are carefully selected, 80% will be successfully treated by rubber banding. Less than 5% of patients require haemorrhoidectomy. The indications for haemorrhoidectomy are continued bleeding or prolapse after banding; large thirddegree haemorrhoids, particularly where there is a substantial component in the lower sensitive part of the anal canal; or fourth-degree haemorrhoids.

Thrombosed external haemorrhoids This condition is quite different from thrombosed internal haemorrhoids. It occurs as a result of thrombosis of the lower part of the external haemorrhoidal plexus of submucosal vessels. The

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term ‘perianal haematoma’ is often used but is technically incorrect, since the clot is contained within an endothelial-lined blood vessel and is therefore not a haematoma. It presents as a characteristic purple, tense, tender haemorrhoid at the anal verge, not extending any distance into the anal canal. It must be clearly distinguished from a prolapsed thrombosed internal haemorrhoid since the treatment is different. This is done by palpating from the proximal end of the lump, into the anal canal; a thrombosed internal haemorrhoid has a firm clot or cord extending internally up to the internal pedicle from which it originates. If the haemorrhoid is small and the pain level is tolerable, treatment is conservative with analgesics and warm baths. Topical 0.2% glyceryl trinitrate has been shown to be as effective as surgical incision for pain reduction, and resolution will occur in 1–2 weeks. If pain is severe, the haemorrhoid should be widely incised under local anaesthesia, and rapid relief and full resolution can be expected if the clot is fully evacuated. Patients should be discouraged from straining at stool, and constipation should be treated with dietary fibre or stool softeners.

Pruritus Ani Pruritus ani is a common condition varying from mild itching to severe intractable itching and pain. The true prevalence is unknown since many sufferers do not seek medical advice, but one study in Birmingham found that 45% of people surveyed had symptoms of pruritus within a 5-year period.

Aetiology In a minority of cases a definite cause is found. The majority of cases are idiopathic. In some cases the perianal skin is cracked and excoriated, but in many cases the perianal skin appears normal and the precise cause for the itching is unclear. The predisposing causes are as follows: ll faecal seepage: minor degrees of soiling may cause irritation of the perianal skin. Underlying anal pathology such as haemorrhoids, mucosal prolapse or anal fissure should be identified and treated. Some patients are not aware that minor seepage is occurring; ll anal disease: primary anal conditions must always be excluded. These include anal warts, skin tags, haemorrhoids, fissure, fistula, anal cancer, Bowen's disease, and generalised skin conditions such as eczema and psoriasis, which may also affect the perianal skin.

ll



ll





infection: organisms known to be associated with pruritus ani include: – f ungi—Candida albicans, tinea; – bacteria—Corynebacterium minutissimum; and – parasites—threadworm (Enterobius vermicularis), a common cause in children but a rare cause in adults. allergy: hypersensitivity of the perianal skin may result from: – topical creams or suppositories containing steroids or local anaesthetic agents; and – u nderwear, particularly nylon; – washing powders for clothing.

Management Pruritus ani is a difficult condition to treat and several steps must be followed if success is to be achieved: 1. A careful history about symptoms of local pathology and faecal seepage should be obtained. Examination for local pathology is made and any condition that predisposes to seepage is treated. Threadworms are seen at the anal verge or in the anal canal and are treated with a single dose of pyrantel. 2. If the skin is excoriated scrapings are obtained for microscopic examination and culture. A scalpel blade is used and several scrapings are placed onto a glass slide, which is then sealed in a container. If Candida is present, topical nystatin cream is used. Tolnaftate is used for tinea. 3. If there has been a recent change to nylon underwear or a change of washing powder or bath soap, these should be eliminated as a cause.

Figure 12.13  Thrombosed external haemorrhoid. Note how it is confined to a small area, compared with thrombosed internal haemorrhoids.

12 Perianal pain

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4. If no predisposing cause is found, idiopathic pruritus ani is present. Vigorous efforts at perianal hygiene are needed since collection of moisture in the area, often unrecognised by the patient, is sometimes present. Washing the area once or twice daily may not be adequate. Washing may need to occur at least three or four times daily. Thereafter, the area is dabbed dry (Box 12.3). Recent studies have shown that improvement of symptoms can be achieved with the use of intradermal injection of methylene blue in resistant cases of idiopathic pruritus ani.

in women, usually over 50 years of age. Sometimes there is a history of trauma to the coccyx. X-ray findings are normal. Rocking the coccyx on rectal examination may elicit pain.

Chronic Perianal Pain Syndromes

Proctalgia fugax

There are a number of conditions of uncertain aetiology that produce chronic perianal and pelvic pain. They may produce significant morbidity, and treatment is often unsuccessful.

This is an unmistakable clinical condition, most commonly affecting young men, although it occurs at all ages, consisting of severe pain in the area of the upper anal canal or the rectal area, lasting 5–30 minutes. It may occur during the day or night, sometimes waking the patient. There is sometimes the urge to have a bowel action, but defecation does not usually relieve the pain. The frequency of episodes varies from a few times weekly to once every few months. It is caused by an acute spasm in the levator ani muscles, similar to a nocturnal calf cramp.

Coccygodynia This presents with an ache in the lower sacrum and coccyx. The pain may radiate to the buttocks and is worse on sitting. Eighty per cent of cases are

Box 12.3  Instructions to patients with anal irritation (pruritus ani) 1. The area must be kept clean and dry. This means cleaning as instructed below at least twice during the day and once at night, and after every bowel action. It is not sufficient to clean once or twice a day only. (a) Use soft toilet paper only. (b) Wipe the area with cotton wool and warm water. ‘Baby wipes’ without alcohol can be used if preferred. (c) Gently dab the area completely dry with soft toilet paper. (d) Apply the prescribed cream only, for the length of time indicated. At the end of that period, apply a zinc oxide powder to the area in place of the cream. Do not use other powders, or any cream or ointment unless prescribed by your doctor. 2 . Use a pH-balanced soap for bathing or showering. 3. Do not scratch the skin. If irritation is severe, pinch the skin outside the clothes. 4. If there is minor seepage of mucus or bowel motion, report this at your next visit. 5. Continue treatment strictly for 3 months after the itching stops. If the symptoms recur recommence treatment.

Treatment Local points of tenderness are infiltrated with local anaesthetic; the injection of alcohol or phenol has been reported to be successful in up to 50% of cases. This treatment is best carried out in a specialised pain clinic. Coccygectomy is usually unsuccessful.

Treatment There is no effective treatment. Galvanic electrostimulation of the puborectalis muscle has been reported to be successful, but this technique is not widely available. Patients should be reassured that there is no serious pathology in the rectum.

Descending perineum syndrome Abnormal descent of the pelvic floor as a clinical sign was first recognised in 1970, and a clinical syndrome consisting of pelvic discomfort or pain, abnormal perineal (pelvic floor) descent, marked difficulty with defecation (obstructed defecation), and straining at stool was subsequently described. The pain is felt as a dull ache in the anal area and perineum, sometimes worse after defecation. There are a variety of clinical conditions in which perineal descent and straining at stool are found, including haemorrhoids, neurogenic faecal incontinence, urinary stress incontinence, solitary rectal ulcer syndrome, uterovaginal prolapse and rectocoele. This group of conditions arises as a result of a functional obstruction to rectal evacuation, which causes excessive straining during defecation.

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The importance of this concept is that treatment of any of these conditions (e.g. haemorrhoidectomy) often will not cure the anal pain, which is caused by pelvic muscle weakness rather than by the associated condition. It is therefore important to decide in each case whether the pain is due to the muscle weakness or to the associated condition, such as the haemorrhoids. Treatment should be directed at changing defecation habits and avoiding straining at stool.

Levator ani syndrome This condition presents with intermittent pain, generally lasting up to an hour, but sometimes persisting through the day. It is usually felt in the anorectal region but sometimes slightly higher in the pelvis. It is associated with a history of straining at stool, a feeling of incomplete rectal evacuation. The condition is distinct from the descending perineum syndrome since there are no signs of perineal descent or pelvic floor muscle weakness in the levator ani syndrome. Treatment Treatment is difficult but should be directed to encouraging the patient to avoid straining at stool. Initial treatment is with biofeedback therapy, in which patients are taught to evacuate the rectum by contracting the abdominal muscles effectively while relaxing the anal sphincter muscles. Muscle function is demonstrated to the patient during biofeedback using pressure sensors.

Idiopathic perianal and perineal pain Sometimes called perineal neuralgia, this is a condition of unknown aetiology affecting women in 80% of cases. The pain is characteristic and usually easily diagnosed on history; it is described as constant and unremitting, often with a feeling in the perineum like ‘sitting on a ball’. In 75% of cases, the pain has been found to radiate into various places from its position of maximal intensity in the anal area, including the sacrum, pelvis and back of the thighs. In 50% of cases the pain is exacerbated when sitting. It is not worse during defecation. Patients have often undergone a variety of unsuccessful operations in the anal area, including excision of skin tags, anal dilatation or treatment of haemorrhoids. The cause of the pain is unknown. Clinical examination of the anal area and pelvic floor muscles, the pelvic gynaecological organs, and neurological examination provide normal findings. Investigations including x-ray examination of the spine and sacrum and endoscopic examination

of the rectum and sigmoid are all unhelpful. A neuralgia affecting the sacral or pudendal nerves has been postulated. Pelvic nerve ischaemia has also been considered. Although the absence of any weakness of the pelvic floor muscles is against the neuralgia hypothesis, it is possible that the injury is not sufficiently severe to lead to muscle weakness.

Referred pain Pain referred from the lumbosacral spine should always be excluded. Compression of the sacral nerve roots may cause referred pain to the perineum. A neurosurgical opinion should be obtained when needed.

Management of chronic pain conditions It is very important to exclude other causes of chronic pain, including chronic intersphincteric or supralevator abscess, endometriosis of the pelvis or rectovaginal septum, and pelvic or spinal lesions compressing the sacral plexus. A CT scan of the pelvis, and CT scan or MRI of the lumbosacral spine should be carried out. Treatment is very unsatisfactory. Standard analgesics or tricyclic antidepressants are usually not effective. Anticonvulsant drugs have been tried, without success. Transcutaneous or spinal cord stimulation has had poor results. When needed, the patient should be referred to a specialist pain clinic.

Key Points History ll

ll

ll

The duration of the pain as well as nature of the pain is often diagnostic. Severe pain is usually due to a fissure, less commonly due to acute perianal sepsis, but not due to haemorrhoids unless they are acutely thrombosed. A history of a painful lump may indicate an abscess or thrombosed haemorrhoid.

Examination ll ll

ll ll

Evidence of previous surgery should be elicited. Inspection may reveal a thrombosed haemorrhoid or abscess. An external opening of a fistula may be present. A fissure can be seen and will be tender on digital examination. If there is marked local tenderness, do not progress to a full internal digital examination or sigmoidoscopy; this should be done once the pain and tenderness have been cured, or failing that, under general anaesthetic.

12 Perianal pain

Fissures ll ll ll ll

ll ll

Fissures are most commonly posterior. They cause pain on defecation. Stool bulking agents are first-line treatment. Topical therapy with glyceryl trinitrate cream is used to relax the internal sphincter. If topical agents fail, Botulinum toxin is injected. Sphincterotomy is definitive, but carries a small risk of incontinence.

Anal sepsis ll

ll ll

This is most commonly caused by an infected anal gland. One-third of patients will develop a fistula. Surgical treatment of a fistula depends on the amount of sphincter muscle involved in the fistula.

Haemorrhoids ll ll

Symptoms depend on the degree of prolapse. Treatment involves dietary changes and avoiding straining at stool. Most patients can be successfully treated with an injection of phenol or rubber banding of the haemorrhoids.

ll

157

Haemorrhoidectomy is reserved for patients who have large prolapsing haemorrhoids that fail to respond to rubber banding; haemorrhoidectomy is an extremely painful operation.

Further reading Allan A, Samad AJ, Mellon A, Marshall T. Prospective randomised study of urgent haemorroidectomy compared with non-operative treatment in the management of prolapsed thrombosed internal haemorrhoids. Colorectal Dis 2006; 8:41–45. Cross KLR, Massey EJD, Fowler AL, et al. The management of anal fissures: ACPGBI position statement. Colorectal Disease 2008; 10(suppl 3):1–7. Heard S. Pruritis ani. Aust Fam Physician 2004; 33:511– 513. Keighley MRB. Anorectal abscess. In: Keighley MRB, Williams NS, eds. Surgery of the anus, rectum and colon. London: WB Saunders; 1993:397–417. Lawler LP, Fleshman JW. Hemorrhoids. In: Pemberton JH, Swash M, Henry MM, eds. The pelvic floor: its function and disorders. London: WB Saunders; 2002:371–384. Lubowski DZ. Anal fissures. Aust Fam Physician 2000; 29:839–844. Williams JG, Farrands PA, Williams AB, et al. The treatment of anal fistula: ACPGBI position statement. Colorectal Disease 2007; 9(suppl 4):18–50.

13 Acute diarrhoea

Case A 70-year-old man presents with crampy, left-sided abdominal pain and bloody diarrhoea for 7 days. The patient has a background history of ischaemic heart disease and peripheral vascular disease. He also has bronchiectasis requiring regular courses of antibiotics. Examination reveals an afebrile man whose is tachycardic and hypotensive. He has evidence of left flank tenderness but no masses or distension, and bowel sounds are normal. Rectal examination reveals bright red blood on the glove. There are carotid bruits and evidence of peripheral vascular disease; otherwise the examination is unremarkable. He is anaemic with a haemoglobin of 90 (normal is 120–140) and a neutrophilia. His ESR and CRP are also both elevated. Stool examination shows red cells, but no white cells. A C. difficile toxin is positive, while blood cultures are negative. A flexible sigmoidoscopy is performed; this notes diffuse inflammation from the rectum to the splenic flexure with normal mucosa above it. Pseudomembranes are present. He is treated with metronidazole and hydration and then makes an excellent recovery. This patient has pseudomembraneous colitis from Clostridium difficile, which is an important cause of diarrhoea in the context of recent antibiotic therapy. Ischaemic colitis would be a consideration in the setting of vascular disease and acute onset of bloody diarrhoea with pain, but was not found here.

Introduction Diarrhoea remains a common problem around the world in both developing and industrialised countries. It is usually mild and self-limiting, but may develop into an overwhelming ­life-threatening

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illness. It is arbitrarily defined as acute if it is of less than 2 weeks duration.

Definition Diarrhoea is defined as a change in bowel habit with an increase in stool frequency or fluidity or both. It is the change from normal for that individual that is significant, with a normal range being from one bowel motion every 3 days to three times daily.

Normal physiology In the non-fasting state, approximately 9 L of fluid pass into the small intestine, of which only 1–2 L pass into the colon and 100 mL is present in the stool. The colon has an absorptive capacity of 3–5 L a day, and an ileal flow of greater than this will result in diarrhoea. Water is absorbed passively in both the small and large intestines because of an osmotic gradient created by active sodium transport. The co-transport of glucose with sodium in the small intestine has been well-documented. Both sodium and glucose must be bound to the carrier before transport can occur. Active transport is promoted by a sodium (Na+) gradient created by a Na/K ATPase in the basolateral membrane (K = potassium). Co-transport of other sugars and amino acids in the small intestine is also recognised. Advantage can be taken of these co-transport systems by using oral rehydration solutions containing both sodium and glucose to enhance water absorption in the patient with diarrhoea.

Pathophysiology The pathophysiological mechanisms resulting in acute or chronic diarrhoea can be divided into several major groups: osmotic, secretory, exudative and abnormal motility (see Box 13.1). Osmotic diarrhoea results when a nonabsorbable solute accumulates within the small

13 Acute diarrhoea Box 13.1  Pathophysiological mechanisms in diarrhoea Osmotic (non-absorbable solute) Carbohydrate malabsorption ll Magnesium salts ll Lactulose ll Sorbitol ll Malabsorption syndromes ll Post surgical, e.g. gastrojejunostomy Secretory (impaired electrolyte transport) ll Bacterial endotoxins ll Laxatives (non-osmotic) ll Bile salts (e.g. terminal ileal resection or disease) ll Fatty acids ll Hormone-producing tumours (e.g. gastrinoma, vasoactive intestinal polypeptide) Exudate (intestinal mucosal damage) ll Bacterial/viral/parasitic infections ll Inflammatory bowel disease ll Colonic cancer ll Gluten-sensitive enteropathy ll Drug-inducted colitis ll Irradiation ll Ischaemia ll Diverticulitis Motility (increased transit) ll Laxative abuse ll Diabetic diarrhoea ll Thyrotoxicosis ll Irritable bowel syndrome ll

intestine. The osmolality of the small intestine is adjusted to that of plasma by water influx across the small bowel and watery diarrhoea results. Examples of osmotic diarrhoea include carbohydrate malabsorption (such as lactase deficiency) and ingestion of magnesium salts. Osmotic diarrhoea ceases when the poorly absorbed solute is removed from the diet. Secretory diarrhoea results from reduced ion absorption or increased intestinal ion secretion. Bacterial toxins are a common cause and, of these, cholera toxin has been the most intensively studied. Non-osmotic laxatives, bile salts and short-chain fatty acids are other agents than can damage electrolyte transport and result in watery diarrhoea. Hormonal secretion from tumours can also cause secretory diarrhoea (e.g. gastrin and vasoactive intestinal polypeptide).

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The third main pathophysiological cause of diarrhoea is inflammatory damage to intestinal mucosal cells: exudative diarrhoea. When the large bowel is involved, blood is commonly present in the stool. Apart from invasive organisms, mucosal damage may result from inflammatory bowel disease, gluten-sensitive enteropathy and irradiation damage. The fourth major cause is increased transit in the small bowel or colon: abnormal intestinal motility. Increased transit may occur with thyrotoxicosis (due to excess thyroid hormone), diabetes mellitus or in the irritable bowel syndrome (Ch 7). It is common for a single agent to cause diarrhoea by more than one pathophysiological mechanism. For example, malabsorbed carbohydrates are fermented in the colon to short-chain fatty acids, which impair colonic absorption of water and electrolytes. Similarly, invasive enteric bacterial may also secrete toxins resulting in secretory diarrhoea. Some generalisations can be made about clinical syndromes arising from different pathophysiological causes of diarrhoea. Osmotic diarrhoea will usually stop when the poorly absorbed solute is omitted from the diet. Secretory diarrhoea will usually continue during fasting and the stools are of large volume (more than 1 L). Invasive organisms will cause inflammation, which often results in blood in the stool. However, considerable overlap exists, such as when secretory diarrhoea results from laxatives. This may cease during fasting if the laxative is also omitted. Similarly, diarrhoea due to invasive organisms may begin as watery diarrhoea when the inflammation is mild.

Clinical Approach to Acute Diarrhoea The causes of diarrhoea vary depending on the type of practice, but in all settings gastrointestinal infections are a common cause of acute diarrhoea (Box 13.2). It is clinically useful to divide acute causes of diarrhoea into clinical syndromes, watery (non-inflammatory) diarrhoea, blood (inflammatory) diarrhoea, food poisoning, diarrhoea in the traveller, diarrhoea associated with recent antibiotics or other drug use and diarrhoea in the HIV-positive (Fig 13.1) or male homosexual patient. Overlap may occur between the categories. Of course, an illness may begin as watery diarrhoea, only to progress to bloody diarrhoea later.

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History Acute < 14 days or chronic > 14 days Travel Sexual contacts New medications and antibiotics Fever and blood or mucus in stool Previous opportunistic infection CD4 status

Stool exam—ova, cysts, parasites and special staining Stool culture and C. difficile assay Stool and faecal antigen testing for Giardia, amoeba and other pathogens C. difficile assay Blood culture CD4 count CBC and EUC

Pathogen detected

Pathogen not detected

Gastroscopy, colonoscopy, duodenal aspirates and small bowel and colonic biopsies Evaluate for viral, bacterial, fungal and protozoal causes and obtain special stains including for AFB and perform electron microscopy

Treat specific pathogen Optimise HAART

No pathogen detected

Consider lactose intolerance, pancreatic insufficiency, drug induced diarrhoea and HIV enteropathy

Refractory cases: treat symptomatically with nutritional support, antimotility agents and octreotide

Figure 13.1  Practical approach to HIV-associated diarrhoea.

13 Acute diarrhoea Box 13.2  Features favouring medically important diarrhoea ll ll ll ll ll ll

Severe prolonged diarrhoea High fever/systemic toxicity Severe abdominal pain Blood in the stool Signs of volume depletion Immunocompromised host

The clinical approach to those with acute diarrhoea should focus initially on: ll separating minor from severe illness; ll selecting patients who need further investigation; and ll instituting specific therapy, where appropriate.

History A careful history is important in evaluating patients with acute diarrhoea and in separating minor from severe illness. Features that suggest the diarrhoea may not be self-limiting include severe diarrhoea, blood in the stool, severe abdominal pain or a high fever (Box 13.2). Ask about the duration of symptoms as well as severity. An abrupt onset of diarrhoea, which then gradually improves, suggests an infective process. Systemic features with infectious diarrhoea include fever, myalgia, malaise, nausea and vomiting. The onset of diarrhoea with food poisoning is often severe but short-lived. With prolonged watery diarrhoea, volume depletion is more likely to develop, especially when there is associated vomiting. Large volume, watery diarrhoea may be of small bowel origin. The presence of blood in the stool is usually due to an intestinal inflammatory process (see Box 13.3). The setting in which diarrhoea occurs also provides clues as to the diagnosis. Recent travel or consumption of food eaten from fast-food outlets suggests infective diarrhoea or food poisoning, especially if other people who ate at the same time and place are affected. A drug history is important with particular attention to antibiotics (Clostridium difficile infection), over-the-counter and herbal preparations. A dietary history including dairy products (lactose intolerance) and sorbitol ingestion may be helpful. Chronic illnesses may first present with acute diarrhoea. Recent blood diarrhoea, for example, may be the initial onset of inflammatory bowel disease.

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Box 13.3  Causes of acute watery and blood diarrhoea Acute watery diarrhoea Gastrointestinal infections: – protozoal, e.g. Giardia lamblia; – bacterial, e.g. enterotoxigenic Escherichia coli, cholera; – viral, e.g. rotavirus, norovirus. Acute blood diarrhoea ll Infectious colitis: – confluent proctocolitis (e.g. Shigella, Campylobacter and Salmonella spp., Entamoeba histolytica); – segmental colitis (e.g. Campylobacter and Salmonella spp., enteroinvasive E. coli, Aeromonas hydrophila, E. histolytica). ll Drug-induced colitis (e.g. non-steroidal ­anti-inflammatory drugs) ll Inflammatory bowel disease ll Ischaemic colitis (usually elderly patient with underlying heart disease or arrhythmias) ll Antibiotic-associated colitis ll

Physical examination The physical examination will help assess the effects of the diarrhoeal illness and may provide clues as to its cause. Effects may include volume depletion (dry mouth and orthostatic hypertension) and signs of toxicity (high fever, tachycardia and shock). The abdominal examination may reveal tenderness (inflammatory bowel disease or diverticulitis) a mass or visceromegaly (e.g. colon cancer deposits in the liver). The stool should be examined and the presence of blood noted. A rectal examination is mandatory and may document faecal impaction (overflow diarrhoea in the elderly) or a tumour.

Investigations The history and physical examination will help differentiate those with minor diarrhoea from those with a more severe illness. Those with minor resolving diarrhoea need no investigations and no specific therapy beyond maintenance of hydration. Those with features outlined in Box 13.2, where a definitive diagnosis is likely to alter management and outcome, should usually be further investigated. Those diagnostic tests should be targeted, where possible, towards a specific diagnosis according to clues from the history and physical examination.

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Blood screen A full blood count may document anaemia secondary to underlying disease or neutrophilia in bacterial infections. Atypical lymphocytes may be noted in viral illnesses. The creatinine and urea may be elevated in severe diarrhoea with volume depletion. Stool examination The presence of red or white cells helps to differentiate inflammatory from non-inflammatory causes of diarrhoea, although the specificity and sensitivity are variable. Stool cultures are often useful in patients with severe or prolonged acute diarrhoea to help target those who may respond to specific antibiotic therapy. Specific testing for various pathogens should be requested where appropriate. If the epidemiological settings suggest the possibility of C. difficile infection, a specific request for that pathogen as well as C. difficile toxin should be made. Viral cultures may need to be considered in immunocompromised patients. Sigmoidoscopy and colonoscopy Sigmoidoscopy and biopsy will help establish the presence or absence of colitis and histology may help differentiate between infectious colitis and an initial attack of inflammatory bowel disease. However, the two can sometimes be difficult to differentiate on histology alone. A colonoscopy is usually not needed in the work-up of acute diarrhoea. The presence of bleeding with a normal sigmoidoscopy or the suspicion of ischaemic colitis are situations in which colonoscopy may need to be considered.

Therapy Acute diarrhoea illnesses range from minor, selflimiting episodes of diarrhoea to devastating illnesses with overwhelming sepsis and profound dehydration. Therapy will need to be tailored depending on the severity of the illness, the nature of the underlying aetiology and the competence of the host's defence mechanism. Hospitalisation is usually necessary for those with sepsis or severe dehydration, and should be considered for those who have an impaired immune response.

Hydration Maintenance of adequate hydration is the only treatment necessary for most episodes of acute diarrhoea. In the presence of nausea, this may

require the frequent intake of small amounts of fluid orally. Soups and fruit juice will usually supply the sodium, potassium and glucose necessary for adequate fluid absorption. Oral rehydration solutions are available commercially or can be prescribed, and are used for mildto-moderate dehydration. Oral rehydration solutions play an important role in developing countries where gastrointestinal infections are common and medical facilities are limited. Intravenous fluids are indicated for severe dehydration.

Diet The tradition of limiting food during intakes of diarrhoea carries the disadvantage of restricting caloric intake during a catabolic event. Restriction of milk and milk products is usually indicated as secondary lactase deficiency may be present. Products containing sorbitol, including some fruit juices, will exacerbate diarrhoea and are best avoided. Anorexia is obviously a factor during diarrhoeal illnesses, but the maintenance of caloric intake should be encouraged.

Antidiarrhoeal agents Agents such as loperamide and diphenoxylate are widely used for the symptomatic relief of diarrhoea. They are usually effective and have few side effects. However, they should be avoided in patients with colitis in view of the potential to cause toxic megacolon. They should also be avoided in young children as they are usually infective and may prolong intestinal recovered.

Antibiotics Antibiotics should be avoided in the routine treatment of acute diarrhoea. They are usually ineffective in reducing the duration of the illnesses and in some cases may prolong excretion of the pathogen. They also have significant side effects and indiscriminate use will increase drug resistance. There are a limited number of situations where antibiotics may be helpful. Box 13.4 outlines the indication for antibiotics and these are discussed in more detail under disease headings.

Conditions Causing Food-borne Illnesses Food-borne illnesses are caused by the consumption of contaminated food and result in significant worldwide morbidity and mortality. They can be caused by the consumption of

13 Acute diarrhoea Box 13.4  Indications for antibiotics ll ll

ll

ll ll ll ll

ll

Shigella spp. Salmonella spp.: – extraintestinal infections; – associated toxicity; – predisposed individuals. Campylobacter jejuni: prolonged or severe infection Clostridium difficile infection Giardia lamblia Entamoeba histolytica Traveller's diarrhoea: moderate to severe symptoms. Yersinia enterocolitica

bacteria or bacterial toxins, viruses, parasites or chemicals. Clinical syndromes resulting from such diverse aetiological agents vary, but nausea, vomiting, diarrhoea and abdominal pain are common to most. Neurological, hepatic and renal syndromes may also occur. The rapid onset of symptoms (within 6 hours) suggests ingestion of a preformed toxin. A longer incubation period is associated with bacterial or viral agents. Some of the common causes of food-borne illnesses are discussed below under aetiological headings.

Bacterial food-borne illnesses Common causes of food-borne illnesses include Salmonella and Campylobacter species and E. coli—these are discussed later in this chapter. Other major bacterial causes of food-borne illnesses are discussed below. Clostridium perfringens C. perfringens is a common food-borne pathogen with an incubation period of 8–24 hours. The illness usually results from the ingestion of meat or poultry and results in watery diarrhoea and crampy abdominal pain. The symptoms are shortlived and usually last 24 hours. Symptomatic therapy with attention to hydration is usually all that is necessary. C. perfringens may also cause a severe and often fatal illness—enteritis necroticans or ‘pigbel’— which is seen only in underdeveloped tropical countries. Abdominal pain and bloating, vomiting and diarrhoea with shock occur, usually after a feast.

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Stool and food can be tested for toxin in special laboratories. Staphylococcus aureus Staphylococcal food poisoning results in profuse vomiting, followed by crampy abdominal pain and diarrhoea. These symptoms result from staphylococcal toxins and occur 1–6 hours after the ingestion of contaminated food. Symptomatic therapy only is necessary, with recovery occurring within 24–48 hours, although occasional deaths have been reported. Diagnosis is clinical, but food and vomitus can be tested for toxin. Bacillus cereus Food poisoning with B. cereus is associated with two distinct syndromes: a vomiting syndrome and a diarrhoeal syndrome. Ingestion of a preformed toxin will result in vomiting similar to that of S. aureus lasting about 12 hours. Fried rice has been implicated as the vehicle in the majority of cases. The diarrhoeal illness occurs 6–14 hours after the ingestion of contaminated food and results from the production of an enterotoxin. Diarrhoea, crampy abdominal pain and, less commonly, vomiting last for 20–36 hours. Vibrio parahaemolyticus V. parahaemolyticus is associated with seafood and causes food poisoning outbreaks after the ingestion of shellfish or raw fish. It causes explosive watery diarrhoea with an incubation period of 12–24 hours. The diarrhoea may be associated with nausea, vomiting and fever and occurs in about 25% of patients. Occasionally, a dysenteric syndrome may result with blood diarrhoea. A specific request must be made to the laboratory for culturing the organism. Symptoms are generally short-lived and require no specific therapy. Clostridium botulinum C. botulinum produces a heat-labile neurotoxin and outbreaks of food-borne botulism have been reported from ingestion of home-preserved foods that have been improperly prepared. Symptoms usually begin within 12–24 hours and consist of bilateral cranial neuropathy with symmetrical descending paralysis. The diagnosis is made by demonstrating the toxin in serum, stool or food ingested. Respiratory support may be necessary and an anti-toxin that can prevent further paralysis is available. Full recovery may take months.

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Non-bacterial food-borne illnesses Heavy metals including zinc, iron, tin, copper and cadmium can cause gastric irritation with abdominal pain, nausea and vomiting. Poisoning usually results from storage of food or beverages in metal containers. Neurotoxin food-poisoning syndromes can be caused by scombroid fish, ciguatera fish (see below), shellfish and mushrooms. Viral (hepatitis A) and parasitic (Trichinella spiralis and Giardia lamblia) food poisoning are further examples of non-bacterial food-borne illnesses.

Table 13.1 Aetiology of travellers’ diarrhoea Source

Rate (%)

Escherichia coli

50

Shigella spp.

10

Salmonella spp.

5

Campylobacter jejuni

3

Yersinia enterocolitica

2

Entamoeba histolytica

1

Giardia lamblia

4

Cryptosporidium parvum

3

Ciguatera fish poisoning (ciguatoxin)

Viruses

3

This results from the ingestion of fish containing a neurotoxin, which originates in algae. Symptoms begin within 5 minutes to 30 hours and consist of nausea, vomiting, diarrhoea as well as photophobia, blurred vision and paraesthesia. Bradycardia, heart block and hypotension may also occur. No specific antidote is known.

Unknown

Scombroid poisoning Diarrhoea occurs within minutes to hours of consumption of certain fish and occasionally certain cheeses and presents with flushing, urticaria and dizziness related to biogenic amines. Mushroom toxins can also produce gastrointestinal and neurological symptoms.

Travellers’ Diarrhoea International travel is now a common event and, of those travelling to developing countries, 30–50% will develop diarrhoea. Symptoms are generally short-lived but carry the potential to disrupt a well-planned holiday excursion or business trip. Pre-travel advice should include recommendations for prevention as well as treatment.

Aetiology and transmission Travellers’ diarrhoea is predominantly due to gastrointestinal infective illnesses, with an enteropathogen being documented in up to 80% of cases (Table 13.1). Causes vary considerably with country of destination, but the commonest pathogen isolated in most studies is enterotoxigenic E. coli, which accounts for up to 50% of travellers’ diarrhoea. In about 20% of cases no pathogen is isolated and this group may represent known pathogens not identified due to insensitive or inadequate culture technique, unknown pathogens or non-infectious causes of diarrhoea, such as stress, alcohol and medications.

19

Travellers’ diarrhoea is acquired through the ingestion of contaminated food or water. Enteropathogens may be found in tap water, ice, diary products, vegetables, unpeeled fruit and raw shellfish. Contaminated food is the most important cause of travellers’ diarrhoea, although waterborne transmission also occurs.

Clinical manifestations The onset of travellers’ diarrhoea is usually abrupt, with symptoms beginning within 3–4 days of arrival at the country of destination. Typically, the illness is mild, with less than six bowel actions daily, and it lasts 3–4 days in 85% of untreated sufferers. Occasionally, symptoms may be more severe with profuse watery diarrhoea leading to dehydration, or are associated with a high fever and blood in the stool. The presence of blood suggests invasive disease (see ‘Conditions causing acute blood diarrhoea’ later in this chapter).

Prevention Diet The logical approach to prevention is to avoid ingesting enteropathogenic agents. Hence, common advice to travellers is to avoid tap water, raw shellfish, dairy products, uncooked vegetables, unpeeled fruit and eating from street vendors (‘boil it, cook it, peel it or forget it’). Unfortunately, studies examining the efficacy of the recommendations have failed to demonstrate that they significantly reduce the incidence of diarrhoea. This is partly because it is difficult to follow such strict dietary advice when on holidays and partly because enteropathogens can be found

13 Acute diarrhoea in food from five-star hotels, bottled drink and food too hot to touch. Nevertheless, it remains prudent to avoid foods that obviously carry a higher risk of contamination. Antibiotics Antibiotics have been documented to be of value in reducing the incidence of diarrhoea when taken prophylactically. A wide range of antibiotics, including sulfonamides, doxycycline, cotrimoxazole, ciprofloxacin and rifaximin have been shown to reduce the attack rate for travellers’ diarrhoea by 30–85%. Despite this efficacy, routine prophylaxis cannot be recommended as travellers’ diarrhoea is usually self-limiting and effective treatment is available. Also, side effects may occur and drug resistance will undoubtedly increase if millions of travellers take antibiotics each year. Exceptions to this rule may include those especially inconvenienced by travellers’ diarrhoea or those who are at risk of severe illness, such as those immunocompromised or those with impaired gastric acidity.

Investigations Mild resolving diarrhoea does not require investigation. The presence of blood in the stool, high fever or severe watery diarrhoea should prompt stool cultures and examination, as noted under investigation of acute diarrhoea.

Treatment Hydration The only treatment necessary for most sufferers of travellers’ diarrhoea is maintenance of adequate hydration. Proprietary rehydration solutions or fruit juice and soups with added salt will help replace sodium, potassium and fluid losses. Antibiotics Antibiotics have been shown to be effective in shortening the length of the illness and should be considered in those with moderate-to-severe symptoms. Norfloxacin, ciprofloxacin, doxycycline, cotrimoxazole and rifaximin (a non-absorbable antibiotic) have all been shown to be effective. Antidiarrhoeal agents Agents such as loperamide or diphenoxylate are widely used for symptomatic relief of symptoms, although there is limited evidence to show that they shorten the course of the illness. In addition, in some settings they may prolong the excretion of pathogens and should be avoided in children

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and in those who have bloody diarrhoea, severe abdominal pain, a high fever. Medical advice Medical advice should be sought by those with bloody diarrhoea, persisting severe symptoms, severe abdominal pain or a high fever not responding to antibiotics.

Conditions Causing Acute Watery Diarrhoea Giardia lamblia G. lamblia is a flagellated protozoan. It exists as a trophozoite, the active form, and as a cyst, the inactive form. The trophozoites multiply by binary fission and encyst as they pass down the intestine. The cystic form is shed in the stool and can survive in the environment. G. lamblia has a worldwide distribution and transmission is by way of contaminated water or food when large outbreaks may occur, or by direct person-to-person spread. The latter is common in daycare centres and various institutions. Clinical manifestations Ingestion of G. lamblia cysts results in a spectrum of symptoms, ranging from asymptomatic cyst passage to an acute diarrhoeal illness or chronic diarrhoea with malabsorption. After an incubation period of 1–2 weeks, a minority of patients will develop a symptomatic infection with prolonged passage of cysts. Those who develop symptoms will report watery diarrhoea with crampy abdominal pain, nausea and excessive flatus. The stools are often malodorous and may develop typical features of malabsorption, becoming greasy, bulky, pale and floating. The symptoms usually settle after 1–3 weeks but prolonged infection with marked weight loss has been reported. Blood and pus are not found in the stool and fever is not a feature of the illness. Diagnosis A stool examination for cysts is relatively simple but not very sensitive since G. lamblia cysts are excreted intermittently—examination of three samples yields a positive diagnosis in only 50–70% of cases. Duodenal aspiration and duodenal mucosal biopsies are accurate in 95% of cases, but are relatively invasive for what is usually a selflimiting illness. Immunoassay kits using antibodies directed against trophozoites or cysts have now been developed and they have a sensitivity and specificity range of 90–100%. Serology is not

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of value in the diagnosis of acute giardiasis and suffers from the drawback that antibodies persist after infection has resolved. The polymerase chain reaction test is only experimental and in practice a therapeutic trial of metronidazole or tinidazole is more often carried out. Treatment Metronidazole or tinidazole remains the treatment of choice and can be administered as a single dose. Albendazole has also been reported to have a high efficacy in children. Treatment failures are uncommon, but persisting infection can be treated with repeated courses or prolonged therapy. Treatment of other members of the family may be necessary to prevent person-to-person spread.

Cholera Cholera is a severe diarrhoeal illness due to Vibrio cholerae, a gram-negative bacterium that elaborates an enterotoxin. It is endemic in Asia and Africa, from where pandemics spread around the world. The high mortality rate (which can exceed 50% if untreated) is due to dehydration. Stool output can exceed 1 L per hour and death may result within 2–3 hours of the onset of the illness. There are two major biotypes of cholera: ‘classical’ and El tor. They cause a similar clinical illness, although the El tor infection tends to be milder. Pathogenesis Cholera organisms elaborate an enterotoxin composed of five binding (B) subunits and an active (A1) subunit. The B subunits bind to a specific receptor on the enterocyte surface. The A subunit then becomes internalised in the cell membrane and irreversibly activates adenylate cyclase on the inner cell membrane. This results in a continuing conversion of ATP to cAMP, and raised intracellular levels of cAMP change the net absorption of fluids into the small intestine into the net excretion. Fluid loss from the small intestine results and diarrhoea occurs when the capacity of the colon to absorb excess fluid is overwhelmed. ‘Rice water’ stools may result when the purging action of the diarrhoea clears all pigment from the stool which then becomes clear fluid with flecks of mucus. Clinical features There is a spectrum of clinical manifestations from asymptomatic carrier state or mild diarrhoea through to massive faecal fluid loss with hypovolaemic shock. Symptoms usually begin with abdominal discomfort leading to cramping

abdominal pain. This is followed by diarrhoea that increases rapidly, reaching faecal outputs of 15–20 L per 24 hours in some patients. These largevolume ‘rice water’ stools become isotonic with plasma. Vomiting may also occur, compounding severe dehydration. There is a significant mortality associated with untreated cholera infection due to hypovolaemic shock. Diagnosis The diagnosis is made by stool culture using appropriate culture media. A presumptive diagnosis may be made by examining stools under dark field or phase microscopy, where Vibrio organisms display a typical ‘shooting star’ motility. Polymerase chain reaction and monoclonal-based stool tests are primarily used in epidemiological studies. Vibriocidal antibodies peak 7 days after infection and therefore are not useful in acute infection, but can be used retrospectively to confirm the diagnosis. Treatment The treatment of cholera involves adequate fluid replacement. The glucose-sodium co-transport system is not affected by the cholera toxin and oral rehydration solutions may be adequate for mild-tomoderate dehydration. Patients with more severe dehydration or persisting vomiting will require intravenous fluids. Hypokalaemia may be severe, necessitating oral or intravenous replacement. Bicarbonate is required when acidosis supervenes. Antibiotics are not used for the standard treatment of cholera, but have been shown to reduce fluid losses and marginally reduce the time of excretion of Vibrio organisms. Parenteral killed whole cell vaccine provides less than 50% protection and is not recommended. Newer oral vaccines may provide an increased level of protection and, since the B subunit of cholera is antigenically similar to the heat labile enterotoxin of ETEC (enterotoxigenic E. coli) it may provide a dual protection but the cost–benefit ratio needs to be considered.

Viral infections Occurrence and transmission Viral gastroenteritis has become recognised as a common cause of diarrhoea in adults and children. The rotavirus has been identified as a leading cause of gastroenteritis in young children and the norovirus (previously termed ‘Norwalk virus’) documented as a cause of epidemics of acute infectious diarrhoea in older children and adults. Other viruses implicated in causing diarrhoea

13 Acute diarrhoea include enteric adenoviruses and astroviruses. However, new viruses almost certainly remain to be discovered, as no viral agent can be identified in up to a third of cases of suspected viral gastroenteritis. Rotavirus Rotavirus causes gastroenteritis in children aged 6–24 months and is more likely to occur in winter months. The symptoms of vomiting and watery diarrhoea typically begin after an incubation period of 48–72 hours. The diarrhoea usually lasts 4–8 days, and the combination of diarrhoea and vomiting often leads to dehydration. A milder disease occurs in older children and adults, but most children have been found to develop antibodies to rotavirus by the age of 24 months. Human colostrum and milk contain antibodies to rotavirus and it is known that breastfeeding reduces the incidence of gastroenteritis in children. Transmission is mainly by the orofaecal route and viruses can be shed in the faeces for up to 21 days. Rotavirus infection can be diagnosed by an immunoassay using an ELISA test, by polymerase chain reaction technique or by isolated from stool samples. There are no effective antiviral agents against rotavirus and treatment involves adequate oral or, if needed, intravenous hydration. There are two live attenuated oral vaccines RV 5 and RV1 available. RV1 should not be used in individuals with latex allergy.

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overcrowding, but Shigella infections can also occur in developed countries. There are four major subgroups (S. boydii, S. dysenteriae, S. flexneri, S. sonnei) and all are capable of causing dysentery, a term that refers to diarrhoea containing blood and pus. Shigella infections occur only in humans and transmission is by the orofaecal route. The organism is highly contagious and direct personto-person spread can occur. resulting in a high secondary household transmission rate. Clinical manifestations Symptoms following ingestion of Shigella spp. organisms vary from fever, with or without mild watery diarrhoea, to typical dysentery with diarrhoea containing blood and pus. There is associated cramping abdominal pain, frequently with tenesmus. These organisms produce intestinal damage both by direct invasion of the colonic epithelium and by production of an enterotoxin. The capacity to invade colonic cells is essential for virulence and results in a localised severe inflammatory response. The development of oedema, crypt abscesses and ultimately mucosal ulceration gives rise to the typical dysenteric stool. Complications include rectal prolapse, toxic megacolon and colonic perforation. Extraintestinal symptoms include the haemolytic uraemic syndrome, febrile seizures in young children, reactive arthritis and pneumonia.

Norovirus The norovirus is a common cause of epidemics of acute gastroenteritis. Orofaecal and waterborne spread has been reported and direct person-toperson spread also occurs. The virus typically causes symptoms in older children and adults and is usually mild, with diarrhoea, nausea and vomiting occurring after an incubation period of 24–48 hours. Cramping abdominal pain, fever and myalgia may also occur and treatment is symptomatic with fluid replacement as appropriate.

Diagnosis The diagnosis of shigellosis is made by stool culture, and antibiotic sensitivity should be performed at the same time, as drug resistance is common. A patchy colitis with ulceration may be demonstrated at sigmoidoscopy and biopsies will help to exclude inflammatory bowel disease and amoebic colitis. The differential diagnosis includes other infectious cases of colitis (enteroinvasive E. coli, C. jejuni, Y. enterocolitica, C. difficile and E. histolytica) and inflammatory bowel disease.

Conditions Causing Acute Blood Diarrhoea

Treatment General supportive measures include maintaining hydration and lowering high fever, especially in children. Antidiarrhoeal drugs should be avoided. Antibiotics are indicated in most patients with Shigella infections as they reduce the severity and shorten the duration of the illness. Trimethoprimsulfamethoxazole and ciprofloxacin are generally effective, but drug resistance is emerging as a significant problem, especially for ampicillin.

The differential diagnosis is summarised in Box 13.3.

Shigella spp. Occurrence and transmission Shigella spp. organisms are more common in developing countries with poor sanitation and

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Salmonella spp. Salmonella organisms are gram-negative motile bacilli that can cause a wide clinical spectrum of illness in humans, including gastroenteritis, typhoid fever, bacteraemia and localised infection. An asymptomatic carrier state also occurs. Serotypes include S. typhi, S. paratyphi, S. enterica (previously called S. choleraesuis) and S. enteritidis. The term ‘non-typhoidal salmonellosis’ refers to enteric disease caused by infection with Salmonella organisms other than S. typhi.

Non-typhoidal salmonellosis Non-typhoidal salmonellosis is a common cause of food-borne disease around the world, and its incidence has increased in many developed countries. Food-borne epidemics are frequent and animal products, especially eggs and poultry, are recognised sources of infection. In addition, pets such as turtles and ducklings have been implicated in the spread of salmonellosis. Direct person-toperson spread seems to be uncommon. The incubation of S. enteritidis is short, within the range of 24–48 hours. There is a spectrum of symptoms ranging from mild diarrhoea to severe watery diarrhoea with cramping abdominal pain and fever. Risk factors for severe disease or complications include extremes of age, haemolytic disease, immunocompromised hosts and the presence of prosthetic devices (Box 13.5). Complications include bacteraemia, osteomyelitis, localised abscesses, meningitis and pneumonia. Diagnosis The diagnosis of non-typhoidal salmonellosis relies upon isolating Salmonella organisms from stool or blood culture. Treatment Maintenance of hydration with fluid and electrolyte replacement is indicated, as appropriate. The routine use of antibiotics should be avoided, as they do not shorten the average illness and may prolong excretion of the organisms. Antibiotics should be reserved for those with severe symptoms or at risk of complications (see Box 13.5). Antimicrobial resistance is an emerging problem. Antibiotics that are effective include quinolones, trimethoprim-sulfamethoxazole and amoxicillin.

Typhoid fever Typhoid fever is a distinctive clinical syndrome usually associated with S. typhi or S. paratyphi. The clinical features include a prolonged fever

Box 13.5  Risk factors for severe Salmonella infections and complications ll ll

ll

ll ll

Extremes of age Immunosuppression: – AIDS; – immunosuppressive drugs; – congenital and acquired immunodeficiency; – transplantation patients. Malignancies (especially lymphoproliferative disorders) Prosthetic device Haemolytic anaemia

with bacteraemia leading to the stimulation of the reticuloendothelial system and metastatic spread. Multiple organ damage follows, and may include the intestine, but despite the term ‘enteric fever’ gastrointestinal symptoms are not prominent, especially early in the syndrome. Clinical manifestations The incubation period varies from 1 week to 3 weeks, but can range up to 60 days. The illness evolves over a period of 4 weeks, beginning with a high fever, headache and chills. A bradycardia relative to the fever may occur and the typical ‘rose spots’ rash is seen during the first week in some patients. Hepatosplenomegaly is common. Intestinal manifestations are not prominent early in the disease and both constipation and mild diarrhoea may occur. The fever is persistent over a period of 4 weeks with the illness becoming more severe during the second and third week: persistent high fever, delirium and complications from waves of bacteraemia including meningitis, nephritis, osteomyelitis and hepatitis. Diarrhoea may develop at this stage of the disease with haemorrhage or perforation. Symptoms generally start to abate after the third week, but relapses may occur. Diagnosis The diagnosis is established by isolating the organism, on either blood or stool culture. Blood cultures are positive in up to 90% of cases during the first week and stool cultures do not usually become positive until the second or third week. Bone marrow culture is positive in over 90% of patients. Serological tests are less reliable and may indicate previous exposure in endemic areas.

13 Acute diarrhoea Transmission Transmission of S. typhi is usually by water or food contaminated by an individual who either has typhoid fever or is an asymptomatic carrier.

Campylobacter jejuni Occurrence and transmission C. jejuni is a common cause of acute diarrhoea illness, and in many developed countries it is the most common pathogen detected in patients with diarrhoea. It is usually a food-borne illness and sources of infection include contaminated milk, sick pets, occupational exposure to poultry and contaminated water. Clinical manifestations After an incubation period of 2–6 days, symptoms begin with the onset of diarrhoea or prodromal features of lassitude, fever, myalgia and headaches. The diarrhoea is initially watery, but may progress to contain blood and mucus. Cramping abdominal pain is common and may be severe. It can present atypically like pseudoappendicitis and colitis. Late onset complications include a reactive arthritis and Guillain-Barré syndrome. Diagnosis The diagnosis is made by stool culture. Special incubating techniques at 42°C with microaerobic conditions are necessary. Sigmoidoscopy may demonstrate colitis in up to 80% of cases, although this finding does not help in making a specific diagnosis. Treatment Maintenance of hydration is all that is usually necessary in those patients with a selflimiting illness, and in whom symptoms are usually improving at the time of diagnosis. For those with more severe symptoms or who are immunosuppressed, erythromycin is the antibiotic of choice. Quinolones are also effective, although resistance is an emerging problem.

Yersinia enterocolitica Occurrence and transmission Y. enterocolitica has a worldwide distribution and causes a gastrointestinal illness that more commonly affects children and young adults. Transmission is via the orofaecal route and numerous food and waterborne epidemics have been reported. Direct person-to-person spread has also been documented.

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Clinical manifestations Diarrhoea and abdominal pain are the two dominant symptoms resulting from Y. enterocolitica infection, but the clinical manifestations tend to vary according to age. The incidence of bloody diarrhoea in reported series is higher in children and less commonly seen in adults. The illness is self-limiting and usually last less than 2 weeks. In older children and adults, the diarrhoea may be associated with right iliac fossa pain due to an infective ileitis. These symptoms may be clinically indistinguishable from acute appendicitis or Crohn's disease. Infrequently, a more severe illness may result with enterocolitis, septicaemia and extraintestinal infective complications, such as meningitis or abscesses in bones, joints or sinuses. This is more likely to occur in immunosuppressed individuals or those with iron-overload states (e.g. haemochromatosis or haemolytic diseases) who seem particularly predisposed to infection with Y. enterocolitica. Postinfective sequelae of Y. enterocolitica include reactive arthritis, Reiter's syndrome, pericarditis, erythema nodosum, erythema multiforme, glomerulonephritis and thyroiditis. Diagnosis The diagnosis is established by culture of the organism, usually in the stool. It may also be cultured from atypical cases at surgery from lymph nodes or from free peritoneal fluid. Serological tests are also available, but their sensitivity and specificity are serotype-dependent, can crossreact with other bacteria and other inflammatory conditions and their titre can fluctuate in individuals with chronic sequelae. Treatment The illness is usually self-limiting and symptomatic treatment without antibiotics is all that is needed. Antibiotics should be administered to those with septicaemia or extraintestinal abscesses and those predisposed to Y. enterocolitica infection. Quinolones, trimethoprim-sulfamethoxazole and tetracyclines are usually effective.

Escherichia coli E. coli is a common inhabitant of the gastrointestinal tract in humans, where it may be present either as a commensal or as a pathogen. There are currently five recognisable categories of E. coli that cause diarrhoea, each with distinct clinical and epidemiological features: enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC),

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enteroinvasive E. coli (EIEC) enterohaemorrhagic E. coli (EHEC), and enteroaggregative E. coli (EAEC). Further categories may emerge in the future. Clinical manifestations ETEC is a common cause of diarrhoea in children in the developing world and it is also a leading cause of travellers’ diarrhoea. Transmission is usually by contaminated food or water, with direct person-to-person spread being uncommon. ETEC adheres to gut mucosa and produces several enterotoxins, one of which is very similar to the cholera toxin. The clinical syndrome that results consists of watery diarrhoea, cramping abdominal pain and nausea. The illness is usually mild with 5–6 loose stools per day and lasts 3–5 days. Les frequently, a cholera-like illness with profuse watery diarrhoea and dehydration may occur. Natural immunity to ETEC after infection has been documented. EPEC is a cause of diarrhoea usually in infants and young children. The clinical illness consists of watery diarrhoea, which may occasionally follow a prolonged course. Vomiting, fever and failure to thrive may also occur. It lacks invasive and toxin-producing properties with pathogenicity apparently related to its enteroadhesive properties. EIEC has the capacity to invade intestinal mucosa causing diarrhoea that often contains blood and mucus. Constitutional symptoms with fever, myalgia and general malaise are common. The illness usually last for 3–4 days, but may persist for up to 2 weeks. EHEC causes haemorrhagic colitis with bloody diarrhoea after an incubation period of 3–4 days. Outbreaks from restaurants and nursing homes have been reported. EHEC does not invade the intestinal mucosa but produces several toxins, one of which is very similar to the Shigella toxin. Complications of infection with EHEC (e.g. subtype 0157:H7) include the haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and toxic megacolon. The haemolytic uraemic syndrome occurs most often in children where the incidence ranges from 5–10%, In this syndrome, there is haemolytic anaemia, thrombocytopenia and fibrin occlusion of small renal vessels, which causes renal failure. Diffusely adhering EAEC produces mild symptoms in some volunteers given this strain of E. coli. It may play a more significant role in children and further studies are needed.

Diagnosis DNA probes are the ‘gold standard’ for detecting various pathogenic E. coli, but are not widely available, except in research laboratories. Patients with persistent bloody diarrhoea should have a sigmoidoscopy or colonoscopy and other infective and non-infective causes of colitis excluded. Treatment Mild illness resulting from pathogenic E. coli does not require any specific therapy beyond maintenance of hydration. The use of antibiotics in the treatment of enterohaemorrhagic E. coli infection remains controversial because of the potential risk that the incidence of haemolytic uraemic syndrome may be increased. The management of travellers’ diarrhoea is discussed elsewhere.

Entamoeba histolytica Occurrence and transmission E. histolytica is a protozoan parasite that exists as an invasive trophozoite and as an infective cyst. It resides in the large intestine where asymptomatic colonisation is usual, but it has the potential to become invasive, resulting in colitis or spreading to involve the liver and, rarely, other organs. There is a worldwide distribution of E. histolytica with a prevalence ranging from 1% in industrialised nations up to 50% in some developing nations. The cystic form can survive in the environment and is responsible for spread of the disease via the faecal–oral route. Direct person-to-person transmission is usual, but foodand waterborne spread can occur. Several other species of amoebae, including E. dispar, reside in the lumen of the large intestine and are nonpathogenic but need to be distinguished from E. histolytica. Clinical manifestations The motile trophozoites live in the lumen of the large intestine where they require either bacteria or tissue substrates for survival. Factors responsible for triggering invasion are incompletely understood, but include the strain of E. histolytica, intestinal factors such as the nature of bacteria within the colon, and host resistance. Host factors that increase susceptibility to invasion include extremes of age, malnutrition, pregnancy and immunosuppressive states, including AIDS.

13 Acute diarrhoea Symptoms following invasion vary from mild diarrhoea through to fulminating amoebic dysentery. A majority of patients develop a diarrhoeal illness lasting 3–4 weeks. The stools frequently contain blood and pus and most attacks resolve spontaneously or with treatment, but chronic amoebiasis or fulminating disease may result. The latter is characterised by a high fever, profuse diarrhoea with bleeding, and abdominal pain and tenderness. Complications of amoebic infection include perforation, strictures, amoeboma and involvement of extraintestinal sites, usually the liver. A liver abscess may occur during the acute attack or present weeks to months later. It may also complicate asymptomatic infections and be present in patients with no history of preceding diarrhoea. Fever, malaise and right upper quadrant pain are the common manifestations. The onset may be abrupt or insidious. Diagnosis The diagnosis of intestinal amoebiasis may be made by the identification of cysts or trophozoites in the stool or in the colonic biopsies. However, microscopic identification of the organism does not differentiate between pathogenic and nonpathogenic species of Entamoeba, which can be done by faecal and serum antigen testing. E. histolytica but not E. dispar results in the formation of detectable antibodies within 5–7 days of infection; these persist for years and hence do not distinguish acute from chronic infection. Sigmoidoscopy or colonoscopy may detect cysts or trohozoites at the edge of ulcers. The colonic lesions could be non-specific thickening or classic flask-shaped ulcers. The diagnosis of liver abscess depends on imaging and serological tests as amoebae are seldom demonstrated either in intestinal cultures or from abscess aspirate. The indirect haemagglutination assay is positive in up to 99% of patients with amoebic liver abscess, although the test may be negative early in the course of the illness. Treatment Metronidazole is the drug of choice for intestinal amoebiasis as well as amoebic liver abscess. A prolonged course may be necessary as encysted organisms can survive in the intestine and can be followed by asymptomatic passage of cysts over a long period of time. Elimination of luminal cysts requires a second agent such as diloxande furoate, paromomycin or diodohydroxyquin.

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Antibiotic-associated Diarrhoea and C. difficle Colitis Introduction Antibiotics can cause diarrhoea through a variety of mechanisms, including an osmotic diarrhoea due to an impairment of colonic fermentation of unabsorbed carbohydrates as well as toxinproducing C. difficile infection. Of those infected with C. difficile, less than half will develop a diarrhoeal illness.

Occurrence and transmission C. difficile becomes established in the large bowel, usually after the normal flora of the colon have been changed by antibiotics. Hospital acquisition of infection is common, as the two conditions for colonisation (antibiotic therapy and environmental contamination) often occur together. C. difficile forms heat-resistant spores, which act as a source of recurrent infection.

Clinical manifestations Exposure to C. difficile results in a spectrum of illness ranging from asymptomatic carriage to severe pseudomembranous colitis. More than 50% of healthy neonates are asymptomatic carriers and the majority of hospital inpatients exposed to C. difficile are asymptomatic. Those who develop symptoms usually do so during or shortly after antibiotic therapy. The illness begins as diarrhoea with cramping abdominal pain. A low-grade fever may be present together with lower abdominal tenderness. A small proportion of patients progress to colitis, which may become life-threatening, with severe bloody diarrhoea, diffuse abdominal tenderness and abdominal distension. Fulminating colitis with toxic megacolon has been reported.

Diagnosis The diagnosis is made by demonstrating the specific cytotoxin in the stool. Cytotoxin assay and culture of C. difficile must be specifically requested and a careful history of preceding antibiotic usage taken. The toxin is demonstrated by tissue culture assay and is neutralised by a specific C. difficile antitoxin. Cytotoxicity assay have been the gold standard for long time but are expensive and timeconsuming. They are highly sensitive in detecting as little as 10 g of toxin B. Enzyme immunoassay is the practical mode of testing in most hospitals and it is important to test for both toxins A and B since some strains have mutations in toxin A and others produce only

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toxin B. It is a rapid test with a good specificity but with a variable sensitivity of 60–95%. The higher false negative rate is because it requires 100 to 1000 μg of toxin. Anaerobic culture is less frequently used, but is extremely sensitive. It does not distinguish between toxin-producing and non-toxin-producing strains. The polymerase chain reaction test targets a region of the toxin B gene and is highly sensitive and specific. Sigmoidoscopy or colonoscopy may document the typical raised white plaques of pseudomembranous colitis. Although characteristic, these are uncommon, except in those with more severe symptoms. A diffuse or patchy colitis may be present and biopsy may reveal non-specific colitis ore even pseudomembranous colitis in the absence of plaques. Patchy colitis beyond the reach of the flexible sigmoidoscope has been reported. In fulminant colitis colonoscopy can be hazardous.

Treatment Antibiotic therapy should be discontinued where possible. If symptoms are severe, or mild symptoms fail to settle spontaneously, therapy with oral metronidazole or oral vancomycin is indicated. Vancomycin is expensive and to prevent the risk of development of resistant organisms such as enterococci it should be reserved for very ill patients or those who fail to respond to metronidazole. Parenteral metronidazole diffuses from the serum and interstitial fluid into the colon and hence can be used via this route in fulminant disease. Other useful drugs are rifaximin, rifampicin, teicoplannin, fusidic acid, nitazoxanide and baxitracin. Anion-binding agents like colestipol and cholestyramine are not effective as primary therapy, but can be used as an adjunct. Tolevamer is a newer toxin-binding resin. Resins can bind antibiotics and hence must be taken a few hours apart from the antibiotics. Intravenous immunoglobin and faecal bacterotherapy have also been tried. Patients with fulminant colitis may need a combination of parenteral metronidazole and oral vancomycin. In the event of fulminant disease with severe ileus, toxic megacolon or signs of peritonitis a subtotal colectomy may be required. Symptomatic recurrence can occur in 15–30% of patients. Some of these are reinfections while others are true recurrences. These are initially treated with conventional approaches, but pulsed and tapered courses of vancomycin can be used; the principle is to allow spores to germinate so that

antibiotics can be effective, as well to allow the normal colonic flora that is protective to recover.

Cryptosporidiosis Occurrence and transmission Cryptosporidium parvum is a protozoan parasite that causes diarrhoea in both normal and immunocompromised populations. Orofaecal transmission occurs from contaminated water and food and large epidemics have been reported. Direct person-to-person spread is also common. It has been estimated that C. parvum is responsible for 5–10% of infectious diarrhoea in developing countries and 1–3% of cases in the developed world.

Clinical manifestations Profuse watery diarrhoea with abdominal pain and nausea is the usual presentation. Vomiting may occur and a low-grade fever is common. The illness usually abates after 1–2 weeks, although in some individuals voluminous diarrhoea and weight loss may persist. In immunocompromised individuals, chronic diarrhoea is common and this is usually indolent, but may be devastating with profound fluid loss.

Diagnosis Cryptosporidium parvum oocysts may be identified in stool samples with appropriate concentration and staining techniques. Organisms can also be demonstrated at the luminal surface by duodenal or colon biopsies. Enzyme immunoassay kits are available and are highly sensitive and specific.

Treatment No effective treatment is available. A variety of antibiotics have been trialled with little persistent effect noted. Immune reconstitution in immunocompromised individuals is the most effective treatment available.

Diarrhoea Associated with AIDS Diarrhoea is a common gastrointestinal symptom in AIDS with a frequency ranging from 30% to 90%, depending on the stage of the illness and environmental factors. The host immunodeficiency results in persisting infection and frequent reinfection. In addition, severe illness with septicaemia and infections with organisms not usually pathogenic are common. Malnutrition may result from associated malabsorption or a chronic diarrhoea illness with anorexia. The presence of chronic diarrhoea influences quality of life as well as morbidity and mortality.

13 Acute diarrhoea

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Table 13.2 Pathogens associated with AIDS diarrhoea Bacterium

Virus

Protozoan

Myocobacterium avium-intracellulare (MAI)

Cytomegalovirus

Cryptosporidium parvum

Salmonella spp.

Herpes simplex virus

Giardia lamblia

Shigella spp.

Adenovirus

Isospora belli

Campylobacter jejuni

Entamoeba histolytica

Clostridium difficile

Microsporidium spp.

Aetiology Potential pathogens involved in AIDS diarrhoea are listed in Table 13.2 and vary with the stage of the illness and degree of immunocompetence of the host. Some patients with AIDS develop diarrhoea without any detectable pathogens and non-infectious causes of diarrhoea, including drugs, pancreatic insufficiency and tumour invasion, may be involved. The AIDS virus itself and small bowel bacterial overgrowth may also be responsible for diarrhoea in some patients.

Diagnosis Stool samples should be obtained for culture and sensitivity and be examined for cysts, ova and parasites. An assay for C. difficile toxin and special acid-fast stains for Cryptosporidium should be performed. If no cause is forthcoming with stool cultures, sigmoidoscopy or colonoscopy and biopsy may help identify cytomegalovirus and herpes simplex virus. Endoscopic duodenal biopsies for culture, histopathology and electron microscopy may help the diagnosis of G. lamblia, cytomegalovirus and C. parvum. Multiple pathogens may be present and the identification of one pathogen does not exclude the possibility of other agents causing diarrhoea.

Treatment Supportive therapy with rehydration and antimotility drugs should be introduced where appropriate. The immune response should be reconstituted where possible, although antiretroviral drugs are not available in many developing countries. Identifying the cause of diarrhoea enables specific therapy to be instituted. Long-term suppressive therapy is often

necessary, as a recurrence of infection is common. Subcutaneous octreotide may be useful in patients with refractory diarrhoea.

Key Points ll

ll

ll

ll

ll ll

Acute diarrhoea can be arbitrarily defined as diarrhoea of less than 2 weeks in duration. Most cases are self-limiting and are viral in aetiology. Detailed history and physical examination are crucial. Medically significant symptoms include the presence of fever, bloody diarrhoea, abdominal pain and dehydration. Hydration is the cornerstone of therapy. Antibiotics are not routinely required except in specific situations.

Further reading Butzler JP. Campylobacter, from obscurity to celebrity. Clin Microbio Infect 2004; 10:868–876. Cello JP, Day LW. Idiopathic AIDS enteropathy and treatment of gastrointestinal opportunistic pathogens. Gastroenterology 2009; 136:1952–1965. Clark B, McKendrick M. A review of viral gastroenteritis. Curr Opinion Infect Dis 2004; 17:461–469. Gore JI, Surawicz C. Severe acute diarrhoea. Gastroenterol Clin North Am 2003; 32:1249–1267. Greenbergand HB, Estes MK. Rotavirus: from pathogenesis to vaccination. Gastroenterology 2009; 136:1939–1951. Jabbar A, Wright RA. Gastroenteritis and antibiotic associated diarrhea. Prim Care 2003; 30:63–80, iv. Leffler DA, Lamont JT. Treatment of Clostriduim difficileassociated disease. Gastrenterology 2009; 136: 1899–1912. Resigner EC, Fritzche C, Krause R, et al. Diarrhea caused by primarily non-gastrointestinal infections. Nat Clin Pract Gastroenterol Hepatol 2005; 2:216–222.

14 Chronic diarrhoea and fatty stools

Case A 48-year-old man presents with a history of frequent watery diarrhoea for the last 3 months, up to six times daily. He travelled to Southeast Asia, including Thailand, 3 months ago. There has been no blood in the stools and they have not been excessively pale or difficult to flush away. After he drinks milk or eats gluten-containing foods, his symptoms are worse. Physical examination reveals a welllooking, afebrile man. There is no obvious lymphadenopathy, his abdominal examination is normal and the remainder of the examination is non-contributory. The patient is noted to be anaemic with a haemoglobin of 90 (normal is 120-140); the anaemia is hypochromic and microcytic. On checking his iron stores are low but his B12 and folate levels are normal. He has a low calcium and phosphate as well as a low vitamin D. Stool examination microscopy is normal, but Giardia antigen is positive. He is given a course of tinidazole, but symptoms continued on follow-up 1 month later. In view of this, he is tested for coeliac disease, and tissue transglutaminase antibodies are positive. Upper endoscopy is performed and small bowel biopsies obtained; these show partial villous atrophy consistent with coeliac disease, but no giardia. A bone mineral density scan is performed and he has evidence of osteopenia. He is treated with a glutenfree diet as well as iron, calcium and vitamin D supplements plus folic acid, and has an excellent response with resolution of his diarrhoea. He is advised to maintain a gluten-free diet for life for treatment of coeliac disease. Villous atrophy can be seen both in giardia and coeliac disease so these conditions can be confused. Testing bone mineral density is important in coeliac disease where a lifelong gluten-free diet is

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recommended to reduce complications. Patients may develop secondary lactose intolerance (and milk intolerance) with coeliac disease, but this usually recovers after a gluten-free diet is adopted.

Introduction Chronic diarrhoea can be simply defined as the frequent or urgent passage of unformed stool for at least one month. As with acute diarrhoea (Ch 13), a careful history and physical examination will often help suggest the diagnosis and direct investigations.

History The clinician needs to determine what the patient means by diarrhoea. The patient should be asked about the frequency and consistency of the stools. Diarrhoea needs to be distinguished from rectal urgency alone or faecal incontinence (Ch 16). Clues to the cause of the diarrhoea can be obtained from the history and examination (Table 14.1). Small-volume, frequent stools suggest large bowel disease and tenesmus (a constant sense of the need to defecate) suggests rectal involvement. Largevolume, watery stools are consistent with small bowel disease, whereas obvious clinical steatorrhoea with pale, bulky, oily stools that float suggests the presence of small bowel or pancreatic disease. The presence of blood may indicate local anal bleeding or other colonic disease. Bright red blood that is separate from the stool is consistent with an anal or rectal cause, but may occur with more proximal colonic disease. Altered blood, or blood with the stool is in keeping with higher colonic bleeding, such as from inflammatory bowel disease or colon cancer (Ch 10). Symptoms associated with the diarrhoea may also provide valuable information about the nature of the underlying disease process. Weight loss suggests an organic disorder and may be marked

14 Chronic diarrhoea and fatty stools Table 14.1 Clinical features in chronic diarrhoea Clinical feature

Conditions to consider

Young age

Coeliac disease, inflammatory bowel disease, lactase deficiency, irritable bowel syndrome

Oil droplets in stool

Pancreatic insufficiency

Previous surgery

Bacterial overgrowth, dumping, post vagotomy diarrhoea, ileal resection, short bowel syndrome

Peptic ulcer

Zollinger-Ellison syndrome

Medications

Laxatives, magnesium antacids, antibiotics, lactulose, colchicine

Frequent infections

Immunoglobulin deficiency

Marked weight loss

Thyrotoxicosis, malignancy, malabsorption

Arthritis

Inflammatory bowel disease, Whipple's disease, hypogammaglobulinaemia, Yersinia spp.

Hyperpigmentation

Whipple's disease, Addison's disease, coeliac disease

Fever

HIV, inflammatory bowel disease, lymphoma, Whipple's disease

Flushing

Carcinoid syndrome

Chronic lung disease

Cystic fibrosis

Neuropathy

Diabetes mellitus, vitamin B12 deficiency, amyloidosis

Family history of diarrhoea

Colon cancer, coeliac disease, inflammatory bowel disease

with malabsorption, carcinoma or inflammatory bowel disease. Large joint arthritis or sacroileitis suggests inflammatory bowel disease. Yersinia infection and Whipple's disease can also present with arthritis. Symptoms of individual nutrient deficiencies (like easy bruisability with vitamin K deficiency, night blindness with vitamin A deficiency, tetany and osteomalacia with vitamin D deficiency and stomatitis, angular cheliosis, glossitis and anaemia with iron and B group vitamin deficiency) not only help separate functional from organic diarrhoea but also may provide aetiological clues. The presence of a skin rash may suggest coeliac disease (e.g. dermatitis herpetiformis) or inflammatory bowel disease (e.g. erythema

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nodosum or erythema multiforme). Crampy abdominal pain occurs with diarrhoea of any cause, but pain shortly after eating raises the possibility of partial bowel obstruction (e.g. Crohn's disease or bowel cancer). Abdominal pain is also a feature of chronic pancreatitis, associated with malabsorption. Abdominal bloating may occur with most forms of diarrhoea but, in association with alternating diarrhoea and constipation, suggests the presence of the irritable bowel syndrome. The duration of symptoms may also be helpful, as diarrhoea occurring over many years is more in keeping with a benign process. There may be a correlation between diarrhoea and diet. Milk consumption in lactose-intolerant individuals or sorbitol intake (in chewing gum and fruit juices) can cause diarrhoea. Changing to a high-fibre diet may also cause a change in bowel habit with loose stools. A history of systemic disease may be relevant. Disorders such as diabetes mellitus and hyperthyroidism may present with diarrhoea. Previous surgical history including gastrectomy (postvagotomy diarrhoea and dumping syndrome), small bowel resection, bariatric surgeries and cholecystectomy must be obtained. A drug history may identify the cause of diarrhoea; a wide variety of medications have been implicated. Antibiotics and antacids are frequent offenders in this category. Non-steroidal antiinflammatory drugs (by causing ileal damage and bile salt malabsorption), metformin and several cardiac drugs (antiarrthymics, antihypertensives and diuretics) are other commonly used offenders and should be sought in the history. Alcohol is also a cause of chronic diarrhoea and surreptitious laxative abuse needs to be considered in difficult cases. A sexual history is important in the evaluation of a chronic diarrhoeal illness, as diarrhoea is a very common symptom in patients with HIV/ AIDS. Overseas travel before the onset of diarrhoea may implicate a gastrointestinal infection or, more frequently, a postinfectious irritable bowel syndrome. The family history should be obtained as inflammatory bowel disease, bowel cancer and coeliac disease have an increased incidence in families.

Physical Examination Evidence of malnutrition and wasting should be sought and the skin examined for rashes, pigmentation and evidence of nutritional deficiency. There may be evidence of iron

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deficiency (pallor, cheilosis, glossitis and koilonychias) or vitamin B12 deficiency (peripheral neuropathy, glossitis and knuckle pigmentation). Protein deficiency may result in peripheral oedema and white nails. Signs of thyrotoxicosis including tachycardia, systolic hypertension, sweating and tender thyroid nodule should be checked as well as all lymph node groups examined as a clue to lymphoma, malignancy and other chronic infections. Further clues to the cause of diarrhoea may be obtained from abdominal examination. An abdominal mass or liver secondaries may be identified. A rectal mass may be present on rectal examination, or faecal impaction, particularly in elderly patients, may be noted and sphincteric tone should be tested to rule out faecal incontinence. Perianal disease with fissures, fistulae and abscesses is common in Crohn's disease (Ch 12).

Assessment The history and physical examination will often direct the order and nature of investigations. Categorising the pattern of diarrhoea into osmotic (ceases on fasting), secretory (persists in fasted state), inflammatory (passage of blood) and classical steatorrhoea helps in directing investigations though overlap can occur. (See Figs 14.1 and 14.2.)

Approach to Chronic Diarrhoea In those in whom the diagnosis is not obvious, a variety of factors will influence the order and extent of investigations, especially the age of the patient and the length of the history. A long history suggests a benign illness, although disorders, such as coeliac disease and Crohn's disease, may not be diagnosed for many years because of subtle symptoms. Conversely, the development of new symptoms in a patient over the age of 40 years would raise concern about the possibility of bowel cancer. A full blood count and erythrocyte sedimentation rate (ESR) is a simple initial blood investigation and may provide information about anaemia due to iron, folate or vitamin B12 deficiency. It may also show an elevated white cell count or ESR, suggesting the presence of inflammation. The serum albumin will often be low with chronic inflammatory process or with malnutrition. The stool examination may provide information about parasites, such as Giardia lamblia, and may also document white blood cells implicating inflammation or infection, or red

blood cells in bleeding (e.g. carcinoma). The stool weight provides some evidence of the severity of diarrhoea. Sigmoidoscopy may establish the presence of inflammation or tumours. A biopsy should always be performed in patients with diarrhoea to exclude microscopic or collagenous colitis. Melanosis coli may be obvious macroscopically and will also be demonstrated on biopsy. A colonoscopy requires a full bowel preparation with sedation, but has the advantage of examining the entire bowel length and often the terminal ileum can be intubated as well. Disorders that may require colonoscopy for diagnosis include bowel cancer, polyps, segmental colitis and terminal ileitis. Radiological investigations that may aid in the investigation of diarrhoea include a plain abdominal x-ray, small bowel series, barium enema, virtual computed tomography (CT) colonography and abdominal CT scan. If small bowel disease is suspected, a small bowel biopsy (usually performed endoscopically) may provide further information. A disaccharidase assay can be carried out at the same time as a small bowel biopsy and bacterial culture. Further investigations that may be needed if no diagnosis is reached include stool examination for laxatives and blood tests for thyroid function (thyroid-stimulating hormone) and hormonesecreting tumours (e.g. gastrin and vasoactive intestinal polypeptide).

Malabsorption The basic physiological problem the body faces in assimilation of food is the passage of nutrients across the limiting cell membrane of the enterocyte. The problem is solved by breaking food particles down to basic components (digestion) and the insertion of special carrier proteins into the absorptive cells to facilitate absorption. The term ‘malabsorption’ is generally used to encompass both impaired digestion and defective absorption. A classification of malabsorption is shown in Box 14.1.

Physiology Understanding malabsorption requires knowledge of the physiology of normal digestion and absorption. The enterocyte The small intestine is lined by specialised cells called enterocytes and, like all cells, they are surrounded by a limiting membrane (a lipid bilayer) with the function of preventing the loss of cytosol and the entry of unwanted molecules. The purpose of digestion is to break

History Onset Congenital Abrupt Gradual

Stool characteristics Watery Bloody Fatty

Pattern Continuous Intermittent

Fecal Incontinence

Abdominal pain Inflammatory bowel disease Irritable bowel syndrome Ischaemia Weight loss Malabsorption Neoplasm

Duration Epidemiology Travel Food Water

Iatrogenic diarrhoea Drugs Radiation Surgery

Aggravating factors Diet Stress Mitigating factors Diet OTC drugs Rx drugs

Factitious diarrhoea Laxatives

Systemic diseases Hyperthyroidism Diabetes mellitus Collagen-vascular disease Tumour syndromes AIDS lg deficiencies

Previous evaluation

Physical examination General Fluid balance Nutrition

Skin Flushing Rashes Dermatographism

Thyroid Mass

Chest Wheezing

Heart Murmur

Abdomen Hepatomegaly Mass Ascites Tenderness

Anorectal Sphincter competence Faecal occult blood test

Routine laboratory tests

Weight

Electrolytes Osmotic gap

pH Carbohydrate malabsorption

Faecal occult blood test Bleeding

Stool WBCs Inflammation

Fat output Sudan stain Quantitative

Laxative screen

Complete blood count Anaemia Leukocytosis Chemistry screen Fluid/electrolyte status Nutritional status Serum protein/globulin

Categorise Secretory Inflammatory diarrhoea

Fatty diarrhoea

Watery diarrhoea Osmotic

Figure 14.1  Flow chart 1. From Fine, KD, Schiller, LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116:1464.

14 Chronic diarrhoea and fatty stools

Stool analysis

Extremities Oedema

177

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Clinical gastroenterology: a practical problem-based approach

Osmotic diarrhoea

Secretory diarrhoea

Stool analysis Low pH Carbohydrate malabsorption

Exclude infection Bacterial pathogens ‘Standard’ Aeromonas Plesiomonas

Other pathogens ‘Standard’ ova + parasites Coccidla Microsporidia Giardia antigen

Dietary review Breath H2 test (lactose) Lactase assay

Exclude structural disease Small-bowel radiographs

Sigmoidoscopy or colonoscopy with biopsy

High Mg output Inadvertent ingestion Laxative abuse

CT scan of abdomen

Small-bowel biopsy and aspirate for quantitative culture

Selective testing Plasma peptides Gastrin Calcitonin VIP Somatostatin

Cholestyramine trial for bile acid diarrhoea

Urine 5-HIAA Metanephrines Histamine

Other tests TSH ACTH stimulation Serum protein electrophoresis Immunoglobulins Exclude structural disease

Fatty diarrhoea

Small-bowel radiographs Inflammatory diarrhoea

CT scan of abdomen MRI EUS

Small-bowel biopsy and aspirate for quantitative culture

Exclude structural disease Small-bowel radiographs

Sigmoidoscopy or colonoscopy with biopsy

CT scan of abdomen

Small-bowel biopsy

Exclude pancreatic exocrine insufficiency

Exclude infection Bacterial pathogens ‘Standard’ Aeromonas Plesiomonas Tuberculosis

Other pathogens Parasites Viruses

Secretin test

Stool elastase

Empiric trial pancreatic enzymes

Figure 14.2  Flow chart 2. Adapted from Fine, KD, Schiller, LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116:1464.

14 Chronic diarrhoea and fatty stools Box 14.1  Classification of malabsorption and example of causes Lipolytic phase defects Chronic pancreatitis, pancreatic carcinoma ll Cystic fibrosis Micellar phase defects ll Bacterial overgrowth ll Terminal ileal disease or resection under 100 cm—bile salt diarrhoea over 100 cm— steatorrhoea Mucosal phase defects ll Coeliac disease ll Tropical sprue ll Lymphoma, Whipple's disease, small bowel ischaemia or resection, hypogammaglobulinaemia, amyloidosis, AIDS Delivery phase defects ll Intestinal lymphangiectasia ll Tumour infiltration of lymphatics ll

down nutrients into molecules small enough to be absorbed. The lipid bilayer allows diffusion of fats into the cell and is equipped with carriers to enable the absorption of sugar and amino acids. Anatomical modifications in the small intestine (valvulae conniventes, villi and microvilli) increase the luminal surface area by approximately 600-fold. Carbohydrate digestion and absorption Carbohydrates in Western society account for 50% of dietary energy and comprise about 60% starch, 30% sucrose and 10% lactose. Starch is a high-molecular-weight compound consisting of two polysaccharides: amylose and amylopectin. Amylose is a straight-chain polymer of glucose linked by 1,4 glycosidic bonds. Amylopectin is similar, but in addition to the 1,4 linkages there are 1,6 linkages for every 20–30 glucose molecules. Starch is digested by salivary and pancreatic alpha amylase. An endoenzyme breaks 1,4 linkages. Terminal 1,4 linkages, 1,6 linkages and 1,4 linkages near 1,6 bonds are resistant. Thus the products of amylose digestion are maltose, maltotriose and alpha limit dextrins (small carbohydrates of four to six molecules containing 1,6 linkages). The brush border enzymes maltase and sucrase isomaltase hydrolyse maltose and maltotriose to glucose. Sucrase and lactase break down sucrose (to glucose) and lactose (to glucose and galactose). Glucose and galactose are actively

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transported across the enterocyte membrane by a sodium-dependent carrier. Fructose is transported by facilitated diffusion. Protein assimilation Protein digestion begins in the stomach with the action of pepsin, which breaks down protein into large polypeptides. These enter the duodenum and are further hydrolysed by pancreatic enzymes. Pancreatic secretion is stimulated by pancreozymin/cholecystokinin from the duodenal mucosal cells. Each pancreatic enzyme is secreted as an inactive precursor, with the initial activation being carried out by enterokinase. This is secreted by the mucosal brush border and converts trypsinogen to trypsin. Intraluminal digestion of protein occurs by the sequential action of the proteolytic endopeptidases (trypsin, chymotrypsin and elastase) and exopeptidases (carboxypeptidase A and B). The products of luminal proteolysis are amino acids and small peptides of two to six amino acid residues. Peptidase in the brush border breaks down the small peptides to amino acids, which are actively transported into the enterocyte. Small peptides are also actively transported across the brush border and are broken down to amino acids within the enterocyte by peptides in the cytosol. Fat assimilation The various processes involved in fat absorption include the secretion of bile and pancreatic juice, emulsification of fats, enzymatic hydrolysis of triglycerides, solubilisation with micelles, uptake by the enterocytes, intracellular reassembly of triglycerides and release of fat as chylomicrons. The process begins with bile salts, which form micelles and function as detergents, thus solubilising fats. The pancreas secretes bicarbonate, as well as lipase and co-lipase. Bicarbonate raises the pH to 7 or 8 where the lipase is maximally active. Lipase acts on triglycerides, cleaving the ester linkages at positions 1 and 3, yielding free fatty acids and monoglycerides. Co-lipase displaces bile salts from triglycerides to enable the lipase to be maximally active. Enterocytes absorb free fatty acids and monoglycerides and carry fats to the interior surface membrane. Bile salts are finally absorbed in the terminal ileum. Within the enterocyte, monoglycerides are re-esterified to triglycerides and coated with small amounts of protein to form a chylomicron. These pass into the mesenteric lymphatics and enter the blood stream via the thoracic duct.

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Clinical Approach to the Patient with Malabsorption Diagnosis in malabsorption requires firstly suspecting its presence, secondly confirming its existence and thirdly demonstrating the cause (Table 14.2).

Suspecting malabsorption Suspecting the presence of malabsorption may be easy when it is gross, but early symptoms are often subtle and non-specific. The diagnosis is usually considered in patients with marked weight loss and the presence of typical steatorrhoea: pale, bulky offensive stools that are difficult to flush and may contain oil. Anaemia is common and may be due to malabsorption of vitamin B12, folate or iron. Deficiency of fat-soluble vitamins may cause bruising (vitamin K), tetany and bone pain (vitamin D), or hyperkeratosis of the skin. Night blindness may occur with vitamin A deficiency. Protein deficiency may result in muscle wasting and oedema from hypoalbuminaemia. Peripheral neuropathy may occur following vitamin B12 deficiency.

Early malabsorptive symptoms are often nonspecific and may include minor weight loss, general malaise, loss of energy and a slight change in bowel habit. Presentation with a single-nutrient deficiency (e.g. iron deficiency anaemia) is quite common. Aphthous ulcers, glossitis and cheilosis may also occur. Presentation in children is usually with diarrhoea, irritability and growth failure.

Confirming malabsorption Faecal fat excretion The 3-day faecal fat estimation remains the ‘gold standard’ for malabsorption. A 100 g fat per day diet must be maintained for 3 days prior to and during the stool collection for accurate results. Fat excretion of more than 7 g per day is considered abnormal. Qualitative estimation of faecal fat by staining faecal smears with Sudan III is simpler but less sensitive. Breath tests The triolein breath test for fat malabsorption involves the ingestion of 14C-labelled triolein and measures of 14CO2 in the expired air. Its lack of sensitivity has limited its clinical use.

Table 14.2 Typical test results in malabsorption Investigation

Coeliac disease

Bacterial overgrowth

Terminal ileal Whipple's disease disease

Chronic pancreatitis

Stool fat

High-normal

High

High

High

Very high

D-xylose*

Low

Low

Low

Normal

Normal

Schilling's test with/without intrinsic factor†

Normal (rarely abnormal due to ileal movement)

Abnormal

Normal

Abnormal

Abnormal (40%)

Folate (serum)

Low (> 50%)

High-normal

Low

Normal

Normal

Small bowel biopsy (proximal)

Flat biopsy (subtotal/total villous atrophy)

Normal

Clubbing and flattening of ville PAS-positive inclusions§

Normal

Normal

Small bowel x-ray‡

Normal (unless lymphoma)

Normal (may Normal find diverticular)

Abnormal

Normal

*This is a test of proximal small bowel function. Falsely low values occur in chronic renal failure, dehydration, ascites, hyperthyroidism and in elderly patients. † While pernicious anaemia corrects with intrinsic factor, ileal disease does not correct. Bacterial overgrowth corrects with antibiotics and pancreatic insufficiency with pancreatic supplements. False negative results occur with incomplete urinary collections, decreased extracellular volume and renal disease. ‡ A small bowel series may be abnormal in severe mucosal disease (e.g. dilatation, flocculation of barium and loss of fine mucosal pattern), but this not specific. It should be ordered to exclude anatomical abnormalities (e.g. diverticula and Crohn's disease). A wireless capsule endoscopy study may provide additional information in difficult cases, and appears more accurate than a small bowel x-ray. § May also occur with Mycobacterium avium intracellulare in AIDS patients. PAS = periodic acid–Schiff technique From Talley NJ. Internal medicine. 2nd edn. Sydney: McLennan & Petty; 2001, with permission.

14 Chronic diarrhoea and fatty stools Hydrogen breath tests have been used to measure carbohydrate malabsorption. In the mammalian body, hydrogen is produced only by bacterial action, usually on unabsorbed carbohydrate in the colon. Thus if a carbohydrate that is normally absorbed in the small intestine is malabsorbed, a breath hydrogen peak will occur about 90 minutes after its ingestion when it first arrives in the colon and is broken down by bacterial action. Similarly small bowel bacterial overgrowth will be detected by an early hydrogen peak. Malabsorption of lactose or a standard rice meal can be detected in this way. Unfortunately, the limited sensitivity and specificity of breath hydrogen tests restrict their usefulness. D-xylose test This test measures small bowel mucosal absorption and involves the ingestion of D-xylose and measuring its excretion in the urine. As well as mucosal absorption, bacterial action, renal function, the completeness of urine collection and the action of drugs can influence the results. Nutritional status Nutritional status can be determined by the body mass index, mid-arm circumference and skintold thickness. Blood tests that have been used to asses nutritional status include serum albumin, transferrin, serum prealbumin and lymphocyte count. Specific nutrient deficiencies should be sought by serum iron studies, vitamin B12 and folate levels, calcium, international normalised ratio (vitamin K) and vitamin assays (A, D and E). A full blood count may document anaemia, macrocytosis, microcytosis or a mixed picture or even the presence of hypersplenism (seen in coeliac disease).

Finding the cause of malabsorption History The list of causes of malabsorption (Box 14.2) is daunting, and a thorough history is essential to target investigations. Common causes of malabsorption include coeliac disease, chronic pancreatitis, small bowel bacterial overgrowth and gastric surgery. A cause may be obvious from the history if gastric surgery or a small bowel resection has been performed or there is known chronic pancreatitis. Childhood diarrhoea, failure to thrive or anaemia may suggest the possibility of coeliac disease. An associated skin rash of dermatitis herpetiformis (Fig 14.3) or a positive family history may also be clues to the diagnosis of coeliac disease.

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Abdominal pain, alcohol excess or a history of passing ‘oil’ suggests chronic pancreatitis. Abdominal pain may also be a feature of Crohn's disease and there is sometimes a positive family history of inflammatory bowel disease. Intestinal lymphoma and mesenteric ischaemia may also present with abdominal pain. A careful history may elicit drugs that may result in malabsorption including cholestyramine, neomycin, colchicine and cathartics. The history should also be directed towards identifying systemic disorders that may be associated with malabsorption, including AIDS, scleroderma, thyrotoxicosis or diabetes mellitus. Investigations The nature and order of investigations carried out is dependent on the history. In many instances a cause will be suggested and investigations can be targeted. For example, upper abdominal pain may suggest pancreatitis, directing investigations towards demonstrating pancreatic disease. Crampy lower abdominal pain and diarrhoea Box 14.2  Causes of malabsorption More common Coeliac disease ll Chronic pancreatitis ll Postgastrectomy ll Crohn's disease ll Small bowel resection ll Small intestinal bacterial overgrowth ll Lactase deficiency Less common ll AIDS (Mycobacterium avium intracellulare, AIDS enteropathy) ll Whipple's disease ll Intestinal lymphoma ll Immunoproliferative small intestinal disease (alpha heavy chain disease) ll Radiation enteritis ll Collagenous sprue ll Tropical sprue ll Non-granulomatous ulcerative jejuno-ileitis ll Eosinophilic gastroenteritis ll Amyloidosis ll Zollinger-Ellison syndrome ll Intestinal lymphangiectasia ll Systemic mastocytosis ll Chronic mesenteric ischaemia ll Abetalipoproteinaemia (autosomalrecessive) ll

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A

B

Figure 14.3  Dermatitis herpetiformis. Typically, the lesions are grouped and distributed over the scapulae, sacrum and buttocks (A), elbows and knees. Severe pruritus accompanies the disease and results in much excoriation and ‘dug-out’ skin (B). From Misiewicz JJ, Bantrum CI, Cotton PB, et al. Slide atlas of gastroenterology. London: Gower Medical Publishing; 1985, with permission.

would lead investigations towards exclusion of Crohn's disease. Specific investigations are set out below. A plain abdominal x-ray may show pancreatic calcification, which establishes the diagnosis of chronic pancreatitis. An abdominal CT scan is more sensitive in documenting calcification and may show a dilated pancreatic duct or pancreatic mass. Endoscopic retrograde cholangiopancreato­ graphy will document changes of chronic pancreatitis with dilated and/or irregular ducts. A magnetic resonance pancreatogram is less invasive and may also document typical pancreatic duct changes. An endoscopic ultrasound can detect chronic pancreatic disease with changes categorised as parenchymal and ductal. Parenchymal changes include increased lobulation and the presence of calcification whereas the ductal changes include dilated ducts, hyperechoic ductal margins and prominent branch ducts. It is important to note that structural changes seen on imaging do not necessarily translate to pancreatic insufficiency since individuals with a lot of changes on imaging may have no insufficiency, and the reverse also is true. Direct tube tests such as the secretin stimulation test remain the ‘gold standard’ for the assessment of exocrine function, but are seldom used today. They involve placement of a tube into the second part of the duodenum, the administration of

secretin or cholecystokinin and the measurement of bicarbonate or enzymes in the aspirated duodenal juice. These tests are expensive to perform and uncomfortable for the patient, and may yield false positive results if duodenal collection of juice is inadequate. Alternative noninvasive tests for pancreatic function have been developed and include the bentiromide test, the pancreolauryl test, the faecal chymotrypsin assay and the faecal elastase assay. None of these tests has achieved sufficient sensitivity or specificity to attract widespread use, but this is a developing area. In children with malabsorption, a sweat test is required to exclude cystic fibrosis. If small bowel disease is suspected, a small bowel biopsy at upper endoscopy is usually performed in a patient with unexplained malabsorption. This may be preceded by serological tests for coeliac disease (see later). In addition to the diagnosis of coeliac disease (a common cause of malabsorption), rare causes of malabsorption such as lymphangiectasia and Whipple's disease can also be detected. Giardia lamblia trophozoites may sometimes be visible on routine histology and a disaccharidase assay can be performed. Barium studies of the small bowel may define defects that give rise to malabsorption, such as strictures, diverticula or fistulae. Small bowel endoscopy or wireless capsule endoscopy can be useful in difficult cases.

14 Chronic diarrhoea and fatty stools Small bowel bacterial overgrowth can be reliably detected only by the measurement of viable counts of bacteria in fasting proximal small intestinal aspirates obtained at upper endoscopy. This requires small intestinal intubation as well as a specialist unit experienced in anaerobic bacterial culture. The presence of an elevated serum folate and a reduced B12 is a laboratory clue to bacterial overgrowth since bacteria produce folate and utilise B12. A variety of indirect tests have evolved for the diagnosis of small bowel bacteria overgrowth. These include the 14C glycocholate test, which relies upon bacterial deconjugation of bile acid and an increase in 14CO2. This test has a high falsepositive and false-negative rate. The 14C-D-xylose breath test relies upon bacterial metabolism of 14C-D-xylose by bacteria in the proximal small intestine. 14CO2 is formed, and is then absorbed and excreted in the breath. Although some reports suggest that this test has a high sensitivity and specificity, others have been unable to substantiate this claim. This test's role in the investigation of small intestinal bacterial overgrowth remains unclear. Other indirect tests, including the lactulose breath test, glucose breath hydrogen test and rice breath hydrogen test, all have unacceptable sensitivity and specificity levels. Ileal absorptive function can be determined by Schilling's test performed with intrinsic factor in three stages (without intrinsic factor, with intrinsic factor and after a course of treatment), or with a SeHCAT (Se-labelled homocholic acid taurine) test. Vitamin B12 and bile acids are absorbed in the terminal ileum. The Schilling test is frequently abnormal with and without intrinsic factor in terminal ileal disease. Vitamin B12 absorption in pernicious anaemia corrects with intrinsic factor. SeHCAT is the taurine conjugate of a synthetic bile acid and the test includes measurement of body Se retention after the administration of SeHCAT. Retention of less than 50% after 3 days suggests bile acid malabsorption.

Disorders that may Cause Chronic Diarrhoea or Malabsorption Coeliac disease Coeliac disease (gluten-sensitive enteropathy) is a disorder of the small intestine caused by sensitivity to gluten, a protein component of cereals found in wheat, rye, barley, triticale and possibly oats. Exposure to gluten causes small bowel damage characterised by inflammation and villous trophy.

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Aetiology The current understanding of the aetiology of coeliac disease is that gluten triggers mucosal damage due to an immune response in genetically predisposed individuals. Virtually all those affected are HLA-DQ2 or DQ8 positive. With increased screening it is now considered that the prevalence of the disease is one in 100 but only 10–15% are diagnosed—the so-called tip of the iceberg. There is 70% concordance rate in twins and a 10–15% prevalence rate in firstdegree relatives. Non-HLA genes as well as other environmental factors may be involved in the development of the disease since not all HLA DQ2 and DQ8 carriers develop the disease. Clinical features Individuals with coeliac disease may present with classical malabsorptive symptoms of steatorrhoea: pale bulky stools, crampy abdominal pain, abdominal distension and weight loss. Growth failure or failure to thrive in children is also common. In adults, symptoms may be much more subtle: abdominal bloating, occasional diarrhoea or nutrient deficiencies. Other presentations include infertility, miscarriage, mouth ulcers, osteoporosis or unexplained anaemia. With the availability of serological screening programmes, many individuals have been diagnosed who are asymptomatic. Iron deficiency anaemia is common and combined iron and folate deficiency is typical of coeliac disease. Bruising due to vitamin K deficiency or tetany due to vitamin D deficiency and hypocalcaemia may be the presenting features. Dermatitis herpetiformis (see Fig 14.3) presents with a pruritic papulovesicular rash on extensor surfaces of the limbs and also on the buttocks. Small bowel changes of coeliac disease are usual, but may be patchy. The condition responds to a gluten-free diet. Diagnosis The diagnosis of coeliac disease is made by documenting the typical mucosal changes (Fig 14.4) on small bowel biopsies, which are usually obtained at endoscopy. Multiple biopsies should be obtained from the second part of the duodenum. It is important to ensure that the patient is on a gluten diet before performing a biopsy, otherwise an adequate challenge of gluten (the equivalent of four slices of bread per day for 4–6 weeks) should be administered and the development of positive serology checked before performing a biopsy.

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Flat mucosal surface

Increase in crypt depth

Figure 14.4  Subtotal villous atrophy showing total absence of villi and a corresponding increase in depth of the crypts, producing an apparently increased mucosal thickness. Illustration based on photomicrograph from Misiewicz JJ, Bantrum CI, Cotton PB, et al. Slide atlas of gastroenterology. London: Gower Medical Publishing; 1985, with permission.

Small bowel biopsies do, however, have their limitations (see Box 14.3). Serological tests, useful for screening in coeliac disease are now available (Table 14.3). Tissue transglutaminase appears to be the target antigen detected by the endomysial antibody assay. Note that up to 5% of individuals with coeliac disease are IgA deficient and will have a falsenegative screening test to IgA antigliadin antibody, endomysial antibody and transglutaminase antibodies. A diagnosis of coeliac disease should not be made on serological tests alone and a small bowel biopsy is always required for confirmation. Screening tests are useful for those with a low probability of coeliac disease and to monitor the response to a gluten-free diet. In individuals with suspected coeliac disease but negative serology, it is worth repeating the test with another laboratory and ensuring that the patient is not IgA deficient. The possibility of a false-positive biopsy should also be borne in mind. Those with

Box 14.3  Limitations of small bowel biopsy False positive Peptic duodenitis Small bowel bacterial overgrowth Enteric infections Tropical sprue False negative Patchy disease Inadequate biopsies Patient on gluten-free diet Subtle disease Distal disease

true negative serology and definite biopsy-proven coeliac disease will require monitoring of their response with clinical and laboratory parameters; it is worth repeating the biopsy at a later stage. It is worth following first-degree relatives who share the HLA genotype but whose serology is

14 Chronic diarrhoea and fatty stools Table 14.3 Serological tests in coeliac disease Test

Sensitivity (%)

Specificity (%)

IgA AGA

75–90

82–95

IgG AGA

69–85

73–90

EMA

85–90

97–100

TGA

93–96

99–100

AGA = antigliadin antibody; EMA = endomysial antibody; TGA = tissue transglutaminase antibody.

negative and repeating the serology in 2 years. If the serology becomes positive a small bowel biopsy is indicated. Treatment The treatment of coeliac disease requires a lifelong gluten-free diet and the exclusion of wheat, rye, barley and triticale from the diet. It is not clear whether oats cause disease, but they should be avoided as oats are often contaminated with small amounts of gluten from wheat barley. Patients should be educated in the importance of maintaining a gluten-free diet and referred to a dietician who is experienced in advice to patients with coeliac disease. Clinical improvement occurs in 2–6 weeks in most patients. Serological improvement takes 4–6 weeks and histological recovery in up to 2 (sometimes more) years. The commonest cause of failure to respond is due to non-compliance. The other causes of persistence of symptoms include lactose intolerance, pancreatic insufficiency, small intestinal bacterial overgrowth, microscopic colitis, irritable bowel syndrome and wrong diagnosis. True refractory disease and development of lymphoma are the rarer but important possibilities. The treatment options for refractory disease include steroids (including budesonide), immunosuppresives, infliximab, hypoallergenic elemental enteral feeds, parenteral nutrition, cladribine, alemtumuzab, stem cell transplantation and anti-IL-15. Malignancy risk is elevated although not as high as previously thought with an increased incidence of gastrointestinal malignancy: oropharyngeal cancer, oesophageal squamous cell cancer, small bowel adenocarcinoma and enteropathy-associated T-cell lymphoma. Associations with coeliac disease Patients with coeliac disease have a greater incidence of a variety of other disorders, including malignant disease and diseases

185

associated with altered immunity. The incidence of malignancies, particularly lymphoma and gastrointestinal malignancies, is significantly increased. This increased risk is reduced or eliminated after maintaining a gluten-free diet for a number of years. Ulcerative jejuno-ileitis and coeliac disease refractory to treatment may both represent early T-cell lymphoma, complicating coeliac disease. Autoimmune disorders associated with coeliac disease include autoimmune thyroid disease, type 1 diabetes mellitus, hyposplenism, dermatitis herpetiforms, autoimmune liver disease and infertility. There are also associations with neurological disease (ataxia and epilepsy) as well as Down and Turner's syndromes (see Box 14.4).

Tropical sprue Tropical sprue is a diarrhoeal disorder characterised by malabsorption occurring in residents of tropical areas. It may also occur in visitors to the tropics who stay for more than 4 weeks. Current evidence suggests it is caused by small bowel bacterial overgrowth. The diagnosis is established by demonstrating villous atrophy on small bowel biopsy in an appropriate clinical setting. Other causes of villous atrophy, including coeliac disease, need to be excluded. Tropical sprue responds to folic acid, which often reverses its signs and symptoms. Antibiotic therapy is also effective, although it often needs to be prolonged and relapses occur.

Whipple's disease Whipple's disease is a rare disorder characterised by chronic diarrhoea, abdominal pain, skin pigmentation, arthralgia and low-grade fever, usually in middle-aged men. The small intestine is always involved, but multiple other sites can also be involved including the brain, heart, synovium and kidney. Central nervous system involvement becomes more common with time and may lead to dementia or cranial nerve signs. Whipple's disease is caused by a bacillus, Tropheryma whipplei and can be diagnosed by small bowel biopsy. PAS-positive macrophages can be identified in the small bowel biopsy and the diagnosis can be confirmed by electron microscopy if necessary. Treatment with antibiotics has changed the course of the disease, resulting in recovery in most patients. Trimethoprim with sulfamethoxazole has replaced tetracycline as the antibiotic of choice

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Clinical gastroenterology: a practical problem-based approach

Box 14.4  Coeliac disease: associations and manifestations Neurological Ataxia Cerebral calcifications Cognitive deficits Seizures Peripheral neuropathy Migraine

Psychiatric Attention deficit disorder Irritability Schizophrenia Depression

Cutaneous Dermatitis herpetiformis

Immunological Selective IgA deficiency

Gynaecological Delayed menarche Early menopause Infertility

Obstetric Low birth weight Intra uterine growth retardation Increased miscarriages

Liver Fatty liver Autoimmune cholangitis Primary biliary cirrhosis Primary sclerosing cholangitis

Gastrointestinal Microscopic colitis Irritable bowel syndrome

Endocrine Metabolic bone disease Type 1 diabetes mellitus Autoimmune thyroid disease Altered sperm motility and morphology with androgen resistance

Haematological Anaemia (classically iron deficiency but also folate and B12 can occur) Coagulopathy due to vitamin K deficiency Hyposplenism

Cardiac Autoimmune myocarditis

Miscellaneous Down syndrome, Turner's syndrome Chronic fatigue syndrome

due to the high relapse rate with tetracycline. Treatment needs to be prolonged.

Intestinal lymphoma Both primary (arising from the gastrointestinal tract) and secondary lymphomas can involve the intestine and cause chronic diarrhoea and malabsorption. Primary gastrointestinal lymphomas can be classified into T- or B-cell lymphomas. Enteropathy-associated T-cell lymphoma (EATL) occurs as a complication of coeliac disease. Symptoms include failure to respond to a gluten-free diet, abdominal pain, diarrhoea with malabsorption and weight loss. EATL can sometimes be the initial presentation of coeliac

disease. An abdominal CT scan may reveal a small intestinal mass or lymphadenopathy, and a small bowel biopsy may provide the diagnosis. Laparoscopy is sometimes necessary for confirmation. Immunoproliferative small intestinal disease is a B-cell lymphoma occurring in Middle Eastern countries and seems to be associated with poor sanitation and small bowel bacterial overgrowth. Chronic diarrhoea, malabsorption and weight loss occur with advanced disease.

Eosinophilic gastroenteritis Eosinophilic gastroenteritis is characterised by eosinophilic infiltration of the gut wall, often associated with peripheral blood eosinophilia.

14 Chronic diarrhoea and fatty stools Clinical features Symptoms and signs of eosinophilic gastroenteritis depend on the layer of the gastrointestinal tract involved, and it is usually classified as predominantly mucosal disease, muscle-layer disease or subserosal disease. Mucosal disease may present with abdominal pain, bloating, nausea and diarrhoea. Symptoms are often non-specific and similar to irritable bowel symptoms. The eosinophilic infiltration involves the muscle layer of the gut and often produces obstructive symptoms of the area involved, which may be oesophageal, antral, small bowel or colonic (muscle layer disease). Subserosal disease results in eosinophilic ascites characterised by a very high eosinophil count. The diagnosis of eosinophilic gastroenteritis should be considered in patients with peripheral eosinophilia. It is confirmed by demonstrating eosinophilic infiltration on biopsy. The treatment depends on the severity of symptoms, with steroids usually considered for more severe symptoms. Dog hookworm has been implicated as causing cases of ileocolonic disease in Australia and will respond to a course of mebendazole (100 mg twice a day for 3 days).

Short bowel syndrome The small bowel intestine has a functional reserve of around 40–50% and when disease or resection exceeds this, diarrhoea and malabsorption results. As well as the extent of resection, the site of resection (jejunum or ileum), the loss of ileocaecal valve and the loss of the colon will determine the severity of symptoms. Aetiology The short bowel syndrome in adults may follow vascular injury, for example due to mesenteric vascular occlusion or bowel obstruction with strangulation. Multiple bowel resections for Crohn's disease may also cause a short bowel syndrome and small intestinal function may be further compromised by disease in the remaining small bowel. A deliberately induced short bowel syndrome will follow jejuno-ileal bypass for the management of obesity. If part of the terminal ileum is resected, bile salt malabsorption may result in watery diarrhoea. With more extensive terminal ileal resection (over 100 cm), bile salt loss results in steatorrhoea.

187

Clinical features Diarrhoea is the prominent symptom and fluid losses may be massive, especially shortly after resection before adaptation occurs. Malabsorption results from loss of surface area, malabsorption of bile salts, small bowel bacterial overgrowth and gastric hypersecretion of acid with inactivation of pancreatic enzymes. Weight loss, dehydration and nutritional deficiency may follow. Management Maintenance of hydration and nutrition is the primary aim in the early phase. Early enteral feeding will encourage intestinal adaptation, but should be introduced slowly. Small frequent feeds will help reduce the osmotic load in the gut. Vitamin and trace element levels should be monitored and replaced as necessary. Cholestyramine will help control diarrhoea in patients with limited (less than 100 cm) terminal ileal resection. Acid suppression with a proton pump inhibitor will help control gastric hypersecretion. Long-term parenteral nutrition or small bowel transplantation will need to be considered in those patients whose nutritional needs cannot be met by enteral feeding.

Lactose deficiency This is discussed in Chapter 18.

Small intestinal bacterial overgrowth The small intestine is usually relatively sterile with bacterial colony counts being less than 10 per millilitre of jejunal fluid. This relative sterility is maintained by normal small intestinal motility, gastric acidity, surface mucus and mucosal immunity, including secretory IgA. Small bowel bacterial overgrowth may lead to mucosal damage and malabsorption of certain nutrients. Patients may be asymptomatic or have abdominal bloating, watery diarrhoea and weight loss. Multiple mechanisms are responsible for malabsorption, including intestinal mucosal damage with loss of disaccharidases, and bacterial deconjugation of bile salts. Vitamin B12 malabsorption is common, due to bacterial utilisation of this vitamin. The production of toxins may be important in certain liver diseases such as cirrhosis and non-alcoholic steatohepatitis. Causes of small intestinal bacterial overgrowth Small intestinal bacterial overgrowth usually occurs with conditions causing small intestinal stasis. Those with impaired immunity and the elderly are also susceptible (Box 14.5).

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Box 14.5  Causes of small intestine bacterial overgrowth ll ll ll

ll

ll



Gastric surgery: Billroth II (see Ch 6) Small bowel diverticula Small bowel stricture: – Crohn's disease; – radiation enteritis. Impaired small intestinal motility: – scleroderma; – diabetes mellitus; – chronic intestinal pseudo-obstruction (see Ch 6). Miscellaneous/multifactorial: – elderly; – immune deficiency syndrome; – chronic pancreatitis; – cirrhosis.

Diagnosis Small intestinal aspiration and culture remains the ‘gold standard’, but is technically difficult and requires a unit experienced in the test with appropriate microbiological support. Breath tests include the 14C-glycocholate test and the 14C-Dxylose test, but they are neither very sensitive nor specific. Treatment Correction of the underlying cause is ideal (e.g. surgery for strictures), but is usually not possible. Antibiotics remain the mainstay of therapy and often need to be used long term.

Radiation enteritis Radiation to the small intestine may result in either acute or chronic damage. Acute injury during radiotherapy is common and results in diarrhoea, abdominal pain and nausea. Mucosal damage is frequently present with inflammatory changes and partial villous atrophy. Chemotherapy may potentiate radiation damage. Symptoms often begin shortly after commencement of radiotherapy and resolve within 2 weeks of cessation of therapy. Chronic radiation damage to the small intestine may present months or years after treatment. It is mediated primarily by ischaemic changes induced by arteritis. Symptoms depend on the site of injury and include diarrhoea, malabsorption, weight loss, nausea and bloating

as well as abdominal pain. Complications include intestinal obstruction due to strictures and perforation. Incomplete obstruction with strictures may result in bacterial overgrowth with malabsorption. Treatment Treatment depends on the nature and site of the underlying damage. Symptomatic treatment for diarrhoea may be necessary. A low-fibre diet helps in the presence of a stricture. Antibiotic therapy is useful when intestinal stasis occurs and surgery may be required for tight strictures. A parenteral diet may be necessary as well as nutritional replacement with malabsorption. Hyperbaric oxygen has been used in this setting.

Protein-losing enteropathy The passage of plasma protein across the mucosa and loss into the gut may occur with inflamed or ulcerated mucosa (e.g. coeliac disease) or increased lymphatic pressure (e.g. carcinoma, lymphoma and intestinal lymphangiectasia). Patients present with oedema and features of the underlying disease. Protein loss may be identified in the stool by measuring stool alpha-1 antitrypsin levels or by the use of intravenously administered radio-labelled macromolecules such as indium-111. Treatment Management involves treatment of the underlying condition where possible. A low-fat, highprotein diet supplemented with a medium-chain triglyceride may be beneficial together with replacement of fat-soluble vitamins, minerals and trace metals as necessary.

Endocrine diseases Steatorrhoea may occur in: diabetes mellitus due to intestinal stasis causing small bowel bacterial overgrowth or exocrine pancreatic insufficiency, or because of co-existing coeliac disease; ll hyperthyroidism (from rapid intestinal transport); ll Zollinger-Ellison syndrome (see Ch 6); ll carcinoid syndrome (usually diarrhoea rather than steatorrhoea plus cutaneous flushing); ll adrenal insufficiency (rare); or ll hypoparathyroidism (rare). ll

Inflammatory Bowel Disease Ulcerative colitis and Crohn's disease are discussed in Chapter 15.

14 Chronic diarrhoea and fatty stools

Collagenous and Microscopic Colitis Collagenous colitis is a diarrhoeal disorder characterised by thickening of the subepithelial collagen plate in the colon. Intraepithelial lymphocytes are also often increased. In microscopic colitis, there is no increased collagen. A typical syndrome of watery diarrhoea results usually in middle-aged to elderly women. At colonoscopy the macroscopic appearance is often normal and biopsies are necessary to establish the diagnosis. Symptoms may improve with sulfasalazine or corticosteroids, but, often, symptomatic therapy with loperamide or diphenoxylate is all that is necessary.

Key Points ll

ll

ll

ll

ll

ll

ll

Chronic diarrhoea is arbitrarily defined as diarrhoea lasting more than a month. Detailed history and a thorough clinical examination often provide clues. Weight loss, nocturnal awakening and blood in the stool are red flags that distinguish organic from functional diarrhoea. Mucus in the stool alarms patients, but it alone is of no diagnostic significance. Distinguishing steatorrhoea from watery or bloody diarrhoea helps narrow down the possibilities. Medications (prescription and nonprescription) and laxative abuse should never be overlooked. A judicious step-wise evaluation with history, stool tests, metabolic parameters, small bowel and colonic biopsies and imaging helps diagnose most cases.

ll

189

Treatment is based on the aetiology, but a few unresolved cases may require antimotility agents and occasionally somatostatin analogues in refractory cases.

Further reading D'Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional mangement in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008; 371:660. Dubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterolgy Hepatol 2004;2:731– 743. Duggan JM. Coeliac disease: the great imitator. Med J Aust 2004; 180:524–526. Headstrom PD, Surawicz CM. Chronic diarrhoea. Clinical Gastroenterology Hepatology 2005; 3:734– 737. Kagnoff MF. AGA Institute medical position statement on the diagnosis and management of coeliac disease. Gastroenterology 2006; 131(6):1977–1980. Kucik CJ, Martin GL, Sortor BV. Common intestinal parasites. Am Fam Physician 2004; 69:1161–1168. Mahnel R, Marth T. Progress, problems, and perspectives in diagnosis and treatment of Whipple's disease. Clin Exp Med 2004; 3:39–43. Pardi DS. Microscopic colitis: an update. Inflammatory Bowel Dis 2004; 10:860–870. Schiller LR. Chronic diarrhea. Gastroenterology 2004; 127:287–293. Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a populationbased study. Gastroenterology 2010; 139:112–119.

15 Inflammatory bowel disease

Case A 28-year-old female presents with a 3-month history of diarrhoea, weight loss, fatigue, and right lower quadrant abdominal pain. She complains of six to eight non-bloody bowel movements daily with at least one at night that awakens her from sleep. She has lost 10 kg since her symptom onset. She has fevers to 38.5°C without chills. She also complains of perianal pain with purulent drainage. She has generalised joint aches with intermittent swelling of the knees and mouth sores. Her past medical history is otherwise unremarkable and she does not take any medications. She denies taking any non-steroidal anti-inflammatory drugs. She is an active smoker of one pack a day for the last 5 years. She has no family history of inflammatory bowel disease. On examination, she is a normally developed, thin-appearing female in no distress. Her heart rate is 110 beats per minute, blood pressure is 90/40 mmHg and temperature 38°C. There are aphthoustype ulcerations in the buccal mucosa of the mouth. There is mild right knee effusion without erythema. Abdominal examination reveals soft diffuse tenderness with localisation to the right lower quadrant and a possible mass. There are no guarding and no rebound. Rectal exam finds a draining perianal fistula without fluctuance, and a mild anal stricture. Pertinent admission studies of blood haematology and chemistry show the following: haemoglobin 9 g/dL, haematocrit 27, white blood cell count 24,000, blood urea nitrogen 30, creatinine 1.0, anion gap 12 and albumin 2.8 g/dL. Abdominal and chest plain films are negative. CT enterography shows terminal ileal thickening with narrowing. There is mesenteric stranding with borderline enlarged lymph nodes.

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Stool studies show Clostridium difficile toxin, ova and parasites; culture, Escherichia coli O157:H7 pending. The patient was admitted. Intravenous hydration and antibiotics were administered. Intravenous methylprednisolone 50 mg daily was started for a presumptive diagnosis of Crohn's disease. A tuberculosis skin test (PPD) was placed. On day 2 the patient was afebrile and underwent a colonoscopy, which showed ulceration of the terminal ileum and right colon and also in the lower rectum (biopsies subsequently showed findings consistent with Crohn's disease). Patient shows some signs of clinical improvement on day 3 with better volume status and some decrease in diarrhoea. Stool studies and PPD were negative. Methylprednisolone was switched to oral prednisone. She was infused with infliximab and continued to show clinical improvement and was discharged on hospital day 5. Prednisone was tapered off over 4 weeks. She was seen after her second infliximab infusion 9 days later. Her diarrhoea had cleared, her energy improved and her mouth sores and joint symptoms resolved. Her perianal drainage, while still present, had decreased. Infliximab was continued for remission maintenance. At last follow-up 6 months later she was completely asymptomatic and her perianal fistula had closed.

Introduction Inflammatory bowel disease (IBD) is traditionally divided into ulcerative colitis (UC) and Crohn's disease (CD). Unlike infectious colitis that is typically self-limited, IBD is a chronic illness that is punctuated by disease exacerbations and remissions. While some similarities exist, UC and CD are very different diseases with regard to their clinical presentation, pattern of bowel

15 Inflammatory bowel disease

Table 15.1  Pathological features in inflammatory bowel disease Ulcerative colitis

Crohn's disease

Distribution ll ll

Colon only Always continuous

ll

Colon and/or small intestine May be discontinuous

Macroscopic appearance ll ll ll

Granular mucosa Superficial ulcers Pseudopolyps Exudate of blood and pus

ll ll ll

Aphthoid ulcers Deep serpiginous ulcers Strictures

Microscopic appearance ll ll

Mucosal inflammation Crypt damage*

*Preservation

Box 15.1  Common symptoms in inflammatory bowel disease Ulcerative colitis Diarrhoea ll Rectal bleeding and mucus ll Abdominal pain ll Constitutional symptoms: fever, weight loss, anorexia Crohn's disease ll Abdominal pain ll Diarrhoea ll Rectal bleeding and mucus ll Constitutional symptoms: anorexia, weight loss, fever, lassitude ll Growth retardation (children) ll

ll

ll

191

ll ll

Transmural inflammation Granulomas (less than 15%)†

of crypt architecture suggests acute self-limited

colitis. † Granulomas may occur in tuberculosis, schistosomiasis and syphilis.

involvement, response to therapy and prognosis (Table 15.1 and Box 15.1). With current methods, proper diagnosis of CD or UC can be made, although 10–15% of patients are labelled indeterminate colitis. Incidence and prevalence rates for UC and CD vary throughout the world but are highest in developed countries of northern Europe and North America.

Ulcerative Colitis Aetiology The aetiology of ulcerative colitis is unknown. Current research focuses on genetic associations and interactions of bowel flora with the colonic mucosa but no definitive cause has been found. While genetic predisposition is the strongest risk factor for the development of UC its contribution is minor with only about 10% having a positive family history. Cigarette smoking appears to be protective, either by reducing the risk of UC development or delaying its onset. Diet appears not to influence disease onset or course while emotional stress may lead to disease flares.

Clinical presentation UC typically presents in the third or fourth decade of life. Clinical presentation is based on disease location and severity. Severity is classified as mild, severe or fulminant with

moderate disease between mild and severe (Table 15.2). Diarrhoea, usually bloody with cramping typically awakening the patient from sleep, signifies mucosal inflammation. Mild disease may be accompanied by frequent diarrhoea but is not associated with significant life impairment. Moderate disease, between mild and severe, typically leads to significant symptoms including profound diarrhoea (usually bloody), dehydration, fatigue and weight loss. This may progress to severe disease, which may require hospitalisation. Fulminant disease is most severe often requiring intensive care or surgery. UC may be associated with extraintestinal manifestations in some patients (Table 15.3) which may be associated with disease activity (Fig 15.1). Those not associated with disease activity may run a clinical course independent of the disease and persist after colectomy.

Disease extent and location UC can be divided into three groups based on the disease location: proctitis or proctosigmoiditis (continuous involvement, from the anus, of the rectum or rectosigmoid); left-sided colitis (continuous involvement up to the splenic flexure); and pancolitis (continuous involvement extending proximal to the splenic flexure). Patients with more extensive disease have a worse prognosis. Proximal progression is common. Approximately half the patients with proctitis and two-thirds of patients with left-sided colitis will progress to a more proximal involvement aover time. Frequent low-volume bowel movements, urgency, rectal bleeding and tenesmus alone suggest proctitis. However, patients with or without these

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Table 15.2 Determination of severity in ulcerative colitis Variable

Mild disease

Severe disease

Fulminant disease

Stools/day

Less than 4

Over 6

Over 10

Blood in stool

Intermittent

Frequent

Continuous

Temperature (°C)

Normal

Over 37.5

Over 37.5

Pulse

Normal

Over 90

Over 90

Erythrocyte sedimentation rate (mm/h)

Over 30

Over 30

Over 30

Radiographic features

Normal gas pattern

Edematous colon wall, thumb printing

Dilated colon

Haemoglobin

Normal

More than 75% of normal value

Transfusion needed

Clinical examination

Normal

Tender abdomen, no rebound tenderness

Distended abdomen, decreased bowel sound, rebound tenderness

From Truelove SC, Witts LS. Cortisone in ulcerative colitis. Brit Med J 1955; 2:1041–1043.

Table 15.3 Common extraintestinal manifestation of inflammatory bowel disease Location

Manifestation

Disease

Associated with active disease

Ocular

Episcleritis

UC, CD

Yes

Uveitis

UC, CD

Sometimes

Peripheral arthritis

CD > UC

Yes

Sacroileitis, ankylosing spondylitis

UC, CD

No

Aphthous ulcers

UC, CD

Yes

Erythema nodosum

CD > UC

Yes

Pyoderma gangrenosum

UC, CD

Sometimes

Primary sclerosing cholangitis

UC >> CD

No

Joints Mucocutaneous

Liver

UC = ulcerative colitis; CD = Crohn's disease. From Veloso FT, Carvalho J, Magro F. Immune-related systemic manifestations of inflammatory bowel disease. A prospective study of 792 patients. J Clin Gastroenterol 1996; 23:29–34.

symptoms may also present with prostration, fever, tachycardia, dehydration and complications of blood loss, suggesting more severe disease or more extensive bowel involvement. Advanced cases may present with massive abdominal distention because of megacolon. In fulminant colitis, severe diarrhoea and high C-reactive protein despite intensive treatment predict eventual colectomy. Fortunately, the presentation of fulminant colitis is relatively uncommon.

Differential diagnosis The presenting clinical features of ulcerative colitis are non-specific, especially among patients without a prior history. Acute colitis secondary

to infection and ischaemia are important considerations depending on the patient and are of particular importance in elderly patients. A history of previous episodes is important but distinguishing a flare of UC from an infectious colitis is not possible on clinical grounds alone. Crohn's disease that is confined to the colon may be difficult to distinguish from UC, but may present with rectal sparing and skip lesions.

Diagnosis Among patients without a prior history of ulcerative colitis, presenting features are non-specific so that additional diagnostic testing is required. Diagnosis is confirmed by clinical features, endoscopic and

15 Inflammatory bowel disease

193

Figure 15.1  Pyodermagangrenosum on the lower leg.

histological findings as well as stool examination to exclude acute colitis. Infection, ischaemia, nonsteroidal anti-inflammatory medication-induced colitis, diverticular colitis and Crohn's disease are important considerations.

Stool studies Infectious colitis may present independently or result in a flare of existing UC. Exclusion of enteric infection is paramount since these infections can mimic clinical and endoscopic features of active UC. Specific stool studies to exclude common enteric pathogens such as Shigella spp., Campylobacter spp., Yersinia spp., Entamoeba spp. and enterohaemorrhagic Escherichia coli are essential. Stool studies may be negative even in the presence of infection and it is very important that the clinician understand what is routinely tested for in his or her facility when stool culture, ova and parasite analysis are ordered. Exclusion of C. difficile infection among patients with UC is very important. While commonly associated with prior antibiotic use, hospitalisation or residence at a long-term care facility, patients with IBD are at a higher risk for this infection even in the absence of these usual risk factors. Stool C. difficile toxin should be requested on all patients with IBD presenting with symptoms of a flare.

Stool biomarkers Reliable stool biomarkers to predict disease activity, recurrence or likelihood of relapse in IBD would avoid invasive endoscopy and/or radiation exposure. Calprotectin, a biomarker that can easily be detected in stool, has been shown to be a sensitive and specific marker of relapse in UC but not CD. Faecal lactoferrin is elevated in active IBD and may increase prior to IBD relapse. Unfortunately, while results are encouraging, data on biomarkers are

Figure 15.2  Left-sided colitis on barium enema.

limited. More information is needed before they can be reliably used in clinical practice.

Haematology and biochemistry Haematological measurements may vary based on the severity and duration of the colitis. Patients with mild colitis may have minimal abnormalities whereas patients with more severe disease may have a leukocytosis related to inflammation and anaemia due to blood loss. Anaemia may be more pronounced and associated with frank iron deficiency with longer duration of illness. Thrombocytosis may also be present due to inflammation or iron deficiency. Albumin may be low due to severe disease or malnutrition. C-reactive protein or sedimentation rate may be elevated. Electrolyte imbalance and prerenal azotemia may occur secondary to dehydration. Alkaline phosphatase may be elevated if primary sclerosing cholangitis is present or as a result of drug toxicity.

Radiology Plain abdominal x-rays should be performed to exclude toxic megacolon and perforation among severely ill patients. Computed tomography (CT) scanning may be considered if there is concern of other aetiologies such as Crohn's disease. CT of the abdomen may reveal colonic thickening and provide additional information as to the extent of the disease. Barium enema is rarely performed because of the widespread use of sigmoidoscopy and colonoscopy (Fig 15.2).

Sigmoidoscopy, colonoscopy and biopsy Endoscopic visualisation with biopsy is essential for all patients with suspected UC and is often necessary to document disease activity for a

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suspected flare. Disease activity, if present, should be visible in the rectum and may extend more proximally. Rectal sparing or segmental colitis raises the possibility of infection, ischaemia, Crohn's disease or other aetiology. Biopsies confirm the presence of chronic colitis and exclude acute colitis as seen with infection. Among patients with colitis refractory to therapy, especially if they are receiving corticosteroid or immunosuppressive therapy, cytomegalovirus should be excluded by biopsy with special studies. Severely ill patients may undergo an unprepped flexible sigmoidoscopy whereas patients with mild to moderate disease are often prepped for colonoscopy. There is usually little value in performing a complete colonoscopy on patients with active UC and it may be dangerous. However, prepping for colonoscopy, if possible, will allow for better visualisation above the sigmoid colon, especially if findings are not typical for UC or it is important to determine extent of disease for therapy. Flexible sigmoidoscopy with biopsy is often sufficient for those with established disease to confirm disease activity. Among patients with long-standing quiescent disease proximal to the rectum, colonoscopy with biopsies is routinely performed for dysplasia surveillance.

Pathology Ulcerative colitis results from chronic inflammation confined to the mucosal layer of the colon. Inflammation is continuous and may involve only the rectum or may spread more proximally. Confusion with CD occurs when patients with UC have a discrete area of inflammation in the caecum (a ‘caecal patch’), or those with a flare of pancolitis have an inflamed terminal ileum (‘backwash ileitis’). Both of these presentations are consistent with ulcerative colitis.

Treatment Treatment goals for UC are induction and maintenance of remission and are based on disease extent, clinical severity and previous medication history.

Mild to moderate disease Oral mesalamine The best option for patients with mild to moderate UC is mesalamine (5-aminosalicylate), orally or rectally. Response rates vary because of differences in dose, disease activity and definitions of outcomes but about two-thirds will respond. Sulfasalazine, the first of this class, is

both an inexpensive and effective medication. It remains essentially unchanged until it reaches the colon where it is cleaved into the active moiety 5-aminosalicylate and sulfapyridine by bacteria. Sulfapyridine (a sulfa antibiotic) is responsible for most of the observed toxicity that includes allergic reaction or renal toxicity (Box 15.2). The remaining mesalamine formulations differ on their mechanism and site of drug delivery. Newer preparations release in the colon, require fewer tablets and can be dosed once or twice daily to improve compliance. These medications are well tolerated. Headache is the most common adverse effect and, rarely, renal toxicity occurs. A baseline serum creatinine should be determined prior to starting therapy. Pancreatitis has also been described with sulfasalazine due to its sulfa moiety but also with mesalamine, although the likelihood with mesalamine is extremely low. Mesalamine is not useful in moderate to severe UC and in mild to moderate disease is often administered at too low a dose. In appropriate doses all are probably equally effective. Sulfasalazine

Box 15.2  Side effects of sulfasalazine* Dose-related: slow acetylators ll Nausea, vomiting, anorexia (most common) ll Headache (common) ll Diarrhoea ll Macrocytosis (folate deficiency) ll Haemolysis (Heinz body) ll Proteinuria, haematuria Non-dose-related ll Skin rash (and Stevens-Johnson syndrome) ll Agranulocytosis, aplastic anaemia ll Reversible male infertility (oligospermia, dysspermia) ll Hepatitis ll Pancreatitis ll Fibrosing alveolitis ll Vasculitis, lupus *Start at one 500 mg table, twice daily on the first day

after meals, then increase by two tablets every second day until the patient is taking the full amount (typically, 1 g four times a day in acute disease; and 1 g twice a day for prophylaxis). Usually efficacious within 2–4 weeks (in 40–80% of patients) A blood count and urinalysis should be performed before starting therapy and then regularly during the first 3 months of treatment, and thereafter every 6 months. Supplement with folate, 1 mg/day orally. The drug may also be of specific benefit for the arthropathy in ankylosis spondylitis associated with inflammatory bowel disease.

15 Inflammatory bowel disease is relatively inexpensive and once or twice daily preparations will enhance compliance. Olsalazine should be avoided if possible, because it can cause secretory diarrhoea. Common preparations with the usual doses to induce and maintain remission are outlined in Table 15.4. Topical preparations The most underutilised group of mesalamine medications are the topical rectal preparations. These are effective for symptoms of urgency, pain and tenesmus. In distal colitis they are more effective than oral preparations and a combination of oral and topical mesalamine enema improves overall efficacy. Patients with proctitis (disease limited to the last 15 cm of the colon) benefit from mesalamine suppositories, 1000 mg once or twice daily, while mesalamine enema therapy (4 g at bedtime) is useful for treatment of disease up to the splenic flexure. For patients who cannot hold a whole enema, start with half of the preparation, which will also be beneficial, and work up to a full enema daily. Oral corticosteroids are rarely required for disease confined to the rectosigmoid region. Hydrocortisone enema may be added in the morning if the patient has not responded to rectal mesalamine after a period of 2–3 weeks. Rectal corticosteroids are helpful in resistant cases but mesalamine enemas are more effective as first-line therapy. After response, wean the topical steroids and maintain rectal and topical mesalamine. If after several weeks response is maintained, try to taper topical mesalamine but it may be required indefinitely. Oral mesalamine should be continued as maintenance therapy to prevent relapse.

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Moderate to severe colitis In cases of moderate to severe UC systemic corticosteroids or infliximab are the best options. Systemic corticosteroids The most common errors made with corticosteroids are an inadequate or excessive starting dose, tapering too quickly and use for remission maintenance. Although various preparations have been tested, parenteral methylprednisolone and oral prednisone are most commonly used. Once-daily dosing of 50 mg methylprednisolone parenterally in hospitalised patients and 40–60 mg of prednisone daily in outpatients are adequate doses for efficacy. Parenteral hydrocortisone (300 mg) is equally effective and may be substituted for methylprednisolone (60 mg). Larger doses are associated with more side effects and do not improve efficacy. These medications should be tapered over a period of 3–4 months, with a taper to 20 mg of prednisone by about 2 months and gradual taper thereafter based on symptoms. These medications should be used only to induce remission, and not as chronic maintenance therapy, because they are ineffective. They have many short- and long-term side effects. The most concerning are hypertension, diabetes, osteoporosis, avascular necrosis of the hip, cataracts and glaucoma. Infliximab Infliximab, an antibody to tumour necrosis factor alpha (TNF-α), is an important option for the both the induction and maintenance of remission among patients with moderately to

Table 15.4  Oral mesalamine preparations for induction and maintenance of remission in mild to moderate ulcerative colitis Optimal daily dose for remission (g) Drug

Induction

Maintenance

4–6

2–4

Oral mesalamine Sulfasalazine Eudragit S coated

3.6–4.8

2.4–3.6

Ethylcellulose coated

3–4

2–3

Balsalazide

6.75

3–4.5

Mesalamine suppository

0.5–1 twice daily

1 daily

Mesalamine enema

4 nightly

4 nightly or every other night

Topical mesalamine

From Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. Am J Gastroenterol 2010; 105:501–523.

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severely active ulcerative colitis. It is typically reserved for patients whose disease is refractory to corticosteroids, and resistant to corticosteroid tapering for those who have had significant steroid related side effects. Skin testing for tuberculosis and chest x-ray should be obtained prior to starting therapy because this agent has been associated with the reactivation of tuberculosis. It is also rarely associated with reactivation of histoplasmosis or hepatitis B and specific testing of at-risk groups should be performed. Cyclosporine In cases of severe colitis refractory to corticosteroids or infliximab, although medical therapy may be attempted, surgical therapy must be strongly considered. The early inputs of a gastroenterologist and colorectal surgeon are essential. Parenteral cyclosporine has been of benefit in the short term for most patients with severe refractory colitis, but in the long term the majority of patients will still need colectomy if continued on oral cyclosporine alone. Better success has been achieved when cyclosporine has been used to induce remission and another medication such as azathioprine is used to maintain remission. After parenteral cyclosporine, oral cyclosporine is started, because of the delay in effect of azathioprine, and eventually tapered. Oral cyclosporine should be instituted after parenteral cyclosporine because of concern regarding absorption and efficacy in severe UC. Significant complications with cyclosporine include seizures, acute renal insufficiency and opportunistic infections. Infliximab should not be administered with cyclosporine because of profound immunosuppression and risk of toxicity. Cyclosporine should be used only by experienced clinicians after discussion with the patient and his or her family. Surgery remains the best option for patients with severe UC who fail cyclosporine.

Maintenance of remission Mesalamine Mesalamine is the best treatment to maintain remission in cases of mild to moderate colitis where remission was induced by one of these medications. It may also maintain remission on selected patients whose remission was induced by corticosteroids and who were not taking mesalamine or were taking too low a dose of these medications. Maintenance dosing for various preparations in outlined in Table 15.4.

Box 15.3  Azathioprine and 6-mercaptopurine (6-MP) side effects ll ll ll

ll ll

ll

ll ll

Allergy (high fever, rash, arthritis) (2%) Nausea, vomiting, anorexia (1%) Bone marrow suppression (leucopoenia, infections)* (1%) Pancreatitis (1%) Abnormal liver function tests (transaminases increase)* Cholestatic jaundice (rare: may progress despite stopping drug) Malignancy (rare) Male infertility (reversible depression of spermatogenesis)

*Dose-related side effects—reduce the dose.

Azathioprine or 6-mercaptopurine Azathioprine or 6-mercaptopurine should be considered for patients with moderate to severe colitis who require corticosteroids to induce remission but who cannot be successfully weaned from these medications despite concurrent treatment with mesalamine. Azathioprine (2–2.5mg/kg) and 6–mercaptopurine (1–1.5mg/kg) are equally effective in 60–70% of patients in maintaining remission and allowing corticosteroid tapering but are slow to act, requiring 3–4 months or more to take effect. Clinical and haematological monitoring by experienced clinicians is necessary. Pancreatitis, hepatitis and severe leukopenia are important adverse events. Pancreatitis and hepatitis are idiosyncratic whereas leukopenia is dose dependent (Box 15.3). Once ingested, azathioprine is rapidly converted to 6-mercaptopurine. The main competing pathways for the metabolism of 6-mercaptopurine are conversion to 6-thioguanine (6-TG), the active therapeutic moiety, and 6-methylmercaptopurine(6-MMP), an inactive excretion product associated with liver toxicity (Fig 15.3). Elevated 6-TG results in immunosuppression and leukopenia and levels may correlate with efficacy, but this is controversial. The enzyme responsible for conversion to 6-MMP is thiopurine methyltransferase (TPMT). Its activity is genetically determined and can be normal, intermediate or absent. Patients with normal TPMT (88%) can start either medication at the target dose, 2–2.5 mg/kg azathioprine or 1–1.5 mg/ kg 6-mercaptopurine. Those with an intermediate TPMT level (11%) are usually started on half this dose while those unable to metabolise the drug

15 Inflammatory bowel disease

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6-TUA XO AZA

6-MP

HPRT

6-TGN (levels associated with efficacy)

TPMT 6-MMP (levels associated with liver toxicity)

Figure 15.3  The metabolism of azathioprine (AZA) and 6-mercaptpurine (6MP). Enzymes: TPMT = thiopurine methyltransferase; XO = xanthene oxidase. Metabolities: 6TUA = 6-thiouric acid; 6TGN = 6-thioguanine; 6MMP = 6-methylmercaptopurine; HPRT = hypoxanthine-guanine phosporibosyl transferase. From Swaminath A, ­Kornbluth A. Optimizing drug therapy in inflammatory bowel disease. Curr Gastro Rep 2007; 9:513–520.

(0.3%) should not receive it. Diminished capacity of TPMT results in elevated 6-TG and subsequent toxicity manifested by profound leukopenia. Assays for TPMT, 6-TG and 6-MMP assist in the proper use of these medications. Infliximab For patients whose remission is achieved with infliximab, this agent should be continued indefinitely. Despite high initial response rates, up to one-third or more of patients will lose response over time. For these patients medical options are limited and colectomy should be considered. Nicotine Nicotine as an adjunctive therapy may be useful in patients who developed UC after smoking, but it is generally ineffective. Methotrexate has no proven benefit, but might be helpful if a patient refuses colectomy. Antibiotics can be helpful in severe colitis to guard against bacteraemia and as a prophylactic measure for possible surgery, but have no role in the treatment of the underlying UC. Complications Fortunately, complications related to severe colitis are rare. The most important are toxic megacolon leading to colonic perforation and massive gastrointestinal bleeding. Toxic megacolon results from the dilation of a severely inflamed colon leading to abdominal distention. Patients may present with severe pain, peritoneal signs (if perforation is present) and fever. Diarrhoea may decrease significantly as the colon loses its ability to function. Dilation of the colon is confirmed by abdominal x-ray and the condition is treated by intravenous antibiotics and prohibiting oral intake.

For patients with evidence of perforation, surgery is necessary. Massive gastrointestinal bleeding is treated with supportive care and treatment directed at the colitis. Uncontrolled bleeding may require colectomy. Complications of ulcerative colitis can also be related to extraintestinal manifestations as outlined previously, and to therapies such as corticosteroids and immunomodulators.

Colorectal neoplasia Ulcerative colitis patients are keeping their colons longer as a result of better medical therapies. Patients with UC are at risk for colorectal cancer based on the anatomic extent and the duration of their disease. The risk is highest in patients with pancolitis beginning after 8–10 years of disease, then increases nearly 1% every year thereafter. Risk is also present with left-sided colitis, lagging behind pancolitis by about 5–10 years. The risk with proctitis is probably no greater than the general population but progression to the proximal colon may occur. Earlier age at onset of colitis (under 15 years old) and primary sclerosing cholangitis are independently associated with higher colorectal cancer risk. Disease activity does not correlate with colorectal cancer risk. This is extremely important because many patients will have long durable remissions so that the risk of loss to follow-up becomes higher. Patients in remission may be lured into a false sense of security about their disease with disastrous consequences. The methods to avoid development of colorectal cancer include prophylactic colectomy and surveillance colonoscopy. Surveillance colonoscopy is preferred but colectomy should be considered for patients with longstanding disease

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especially if their disease is refractory or requires immunosuppressive therapy. Decisions must be individualised based on patient preference with understanding of the risks and benefits of each strategy. Patients with pancolitis and disease longer than 8–10 years should have surveillance colonoscopy yearly or every other year. Patients with left-sided disease follow a similar schedule but some begin surveillance later. In patients with UC who have primary sclerosing cholangitis, surveillance should begin at diagnosis, given the risk of earlier cancer. Colorectal cancers in UC can be flat and missed by colonoscopy. The goal of surveillance is to detect microscopic dysplasia, which can be associated with either a missed cancer in the existing colon or the development of later cancer. Patients with high grade dysplasia, a dysplasia associated mass or cancer should have a colectomy. Low grade dysplasia, confirmed by an experienced pathologist, initially thought to be more benign, may be associated with synchronous cancer not evident on colonoscopy. The management of low grade dysplasia is patient specific but colectomy should be considered. A controversial area in UC cancer surveillance is the meaning of an adenomatous polyp. As patients keep their colons longer, the likelihood of finding sporadic (non-UC associated) polyp increases. Since these polyps by nature are dysplastic, should a patient with long-standing disease undergo colectomy if one is found? This depends of the age of the patient, the duration of the UC, the characteristics of the polyp and whether the area around the polyp is dysplastic. Patients who are older and have no dysplasia around the polyp can be probably treated by simple polypectomy whereas younger patients should be considered for colectomy.

Surgical treatment UC can be cured by colectomy and in many cases the patient's overall quality of life improved. Colectomy is indicated for treatment failures, development of acute complications from active disease, chronic complications such as dysplasia, carcinoma and recurrent haemorrhage, or growth retardation in children (Box 15.4). The surgical procedure of choice is the ileal pouch anal canal anastomosis (IPAA). First the colon is completely removed and a ‘J’shaped ileal pouch constructed with anastomosis to the anal canal. A diverting loop ileostomy is created to allow the anastomosis to heal. The ileostomy is closed 2 months later. Although this surgery is becoming more common, results are still dependent on the surgeon's experience. Pouch failure rates vary but are generally under 10%. Most patients can

Box 15.4  Indications for surgery in inflammatory bowel disease Ulcerative colitis Failed medical therapy (fulminant colitis) ll Toxic megacolon ll Perforation ll Massive haemorrhage ll Chronic disabling symptoms ll Carcinoma or high risk of carcinoma Crohn's disease ll Acute colitis: same as ulcerative colitis ll Chronic disabling symptoms ll Bowel obstruction ll Fistulae ll Abscesses ll Perforation ll Perianal complications ll Growth retardation (children) ll

expect to have about five bowel movements a day and one nocturnal bowel movement after IPAA. This can be much higher when the patient has refractory pre-existing diarrhoea-predominant irritable bowel syndrome (IBS). These patients might be better off with a standard ileostomy.

Pouchitis Pouchitis is an important complication of IPAA manifesting with urgency, tenesmus, faecal incontinence, cramping, malaise and fever. Its cause is unknown and diagnosis is confirmed by pouchoscopy. About half of patients will develop acute pouchitis over time, with about 10–15% developing severe chronic pouchitis refractory to therapy and requiring pouch excision. Crohn's disease or ischaemia of the pouch is possible, but most cases are idiopathic. Most patients respond to antibiotics such as metronidazole, ciprofloxacin or amoxicillin/ clavulanic acid, given in a short course (10–14 days) or in chronic cases as prolonged suppressive therapy. Topical mesalamine or corticosteroids and short-chain fatty acid enemas have had some success. Oral probiotics may prevent recurrence.

Crohn's Disease Aetiology Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease affecting primarily young adults. While, like UC, family history is the most important risk factor, only about 10% of

15 Inflammatory bowel disease

Table 15.5  The Montreal classification of Crohn's disease Age at diagnosis

A1 below 16 years A2 between 17 and 40 years A3 above 40 years

Location

L1 ileal L2 colonic L3 ileocolonic L4 isolated upper disease*

Behaviour

B1 non-stricturing, non-penetrating B2 stricturing B3 penetrating

Perianal disease Present or absent *Isolated upper disease is a modifier that can be added to other locations when concomitant upper disease is present. From Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus and implications. Gut 2006; 55:749–753.

patients overall have an affected family member. It tends to occur within families and is more common in individuals of Jewish ethnicity. Unlike UC, where cigarette smoking is protective, in CD it results in an earlier age at diagnosis and a worse disease course.

Clinical presentation Crohn's disease is a heterogeneous disorder with clinical presentation, prognosis and response to therapy is based on age at diagnosis, site of involvement and behaviour (Table 15.4). Younger age at diagnosis is associated with a worse prognosis. CD may be associated with extraintestinal manifestations in some patients (Table 15.5), which may be associated with disease activity. Those not associated with disease activity may run a clinical course independent of the disease and persist after treatment.

Disease location and behaviour Most patients (40%) present with disease involving their terminal ileum and caecum, 30% have isolated small bowel, 25% have isolated colonic and 5% have oesophageal, gastric or duodenal involvement. While the location of disease tends to remain constant, behaviour may change. Inflammation may be confined to bowel wall (non-stricturing, nonpenetrating) initially, only to progress to fistula, abscess or perforation (penetrating) or result in fibrosis causing bowel obstruction (stricturing). Nonstricturing, non-penetrating disease leads to fever,

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diarrhoea, rectal bleeding or temporary obstructive narrowing. Penetrating disease can present as high fever, abdominal pain or peritonitis. Fistula to the bladder results in persistent urinary tract infection or pneumaturia, to the vagina causes vaginal discharge, and to the skin results in external drainage. Perianal fistulae are also a common manifestation of Crohn's disease (see Ch 22 on perianal disease). Stricturing disease leads to repeated episodes dominated by obstructive signs or symptoms.

Differential diagnosis CD is a chronic and relapsing disease that, compared to UC, is more likely to present with weight loss, anorexia, chronic fevers and, in children, growth retardation along with bowel symptoms. Coeliac disease, bacterial overgrowth or microscopic colitis should be excluded in cases where diarrhoea and weight loss are the predominant features. Bacterial overgrowth is common among CD patients with fibrotic stricture or previous abdominal surgery. Small bowel lymphoma, while rare, can mimic CD (especially among older patients where small bowel CD is less common) or complicate existing CD. Tuberculosis should be considered in endemic areas. Functional bowel disease or IBS may occur in patients with Crohn's disease. IBS can mimic some of the features of active CD and can confuse the clinical picture, making a thorough diagnostic evaluation crucial.

Diagnosis Stool culture and examination The first step in the diagnosis of CD and its subsequent management is to exclude other causes. Bacterial infections such as Clostridium dificile should be excluded in patients with diarrhoea or rectal bleeding. C. dificile is more common among patients with CD even in the absence of previous antibiotic usage or hospitalisation. It is particularly important to consider Yersinia enterocolitica, which can mimic ileal CD. Stool biomarkers As discussed in the UC section, data on biomarkers, while encouraging, are limited. They can not be recommended for routine use in practice but may be of benefit in the future. Haematology and biochemistry Complete blood count is often abnormal among patients with CD. Leukocytosis may be secondary to active disease, infection or chronic corticosteroid usage. Anaemia is common and its cause may be multifactorial. Iron deficiency leading to anaemia

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may result from blood loss. Macrocytosis may result from folate or vitamin B12 deficiency. Vitamin B12 deficiency is typically found among patients with disease involving the terminal ileum. Thrombocytosis may occur from acute inflammation or iron deficiency. Blood chemistries may be abnormal secondary to diarrhoea and dehydration. Antibody testing Antineutrophil cytoplasmic antibodies are positive in about 70% of patients with UC whereas antisacchromyces cervesiae antibodies are positive in about 60% of patients with CD. Neither of these tests has the sensitivity or specificity to make the diagnosis of UC or CD. They may be useful in some cases of indeterminate colitis, especially when surgery is being considered. Sigmoidoscopy, colonoscopy and biopsy Colonoscopy with biopsy is the best method to establish the diagnosis because most patients with CD have involvement of the colon, terminal ileum or both. Inflammation and ulceration may be patchy with normal intervening areas (‘skip areas’). Superficial (‘aphthous ulcers’) or deep ulceration may be present. Unlike UC, the rectum may be uninvolved. Terminal ileum inflammation is common in CD but may be present in severe extensive UC (‘backwash ileitis’). Sigmoidoscopy may be performed among severely ill patients when colonoscopy is not necessary or safe or to assess known distal colonic disease. Wireless capsule endoscopy images may suggest CD, but biopsies can not be performed with this technique. Significant small or large bowel narrowing must be excluded prior to ingestion of the capsule to reduce the risk of the capsule causing bowel obstruction. If the capsule does not pass, endoscopic or surgical removal may be required. In cases where imaging shows disease outside of the reach of conventional endoscopes, double balloon endoscopy may be required for assessment and biopsy.

considered, especially among patients receiving chronic corticosteroids or immunomodulators. Special studies on biopsy specimens are required to exclude these aetiologies.

Radiology For patients with severe abdominal pain or findings suspicious for perforation, plain abdominal x-rays should be performed. Contrast enemas are rarely used because of the wide availability of colonoscopy. Contrast enemas usually employ a water-soluble agent and may be performed to assess colonic strictures that cannot be traversed by the endoscope. Contrast CT scanning of the abdomen is useful to evaluate for the presence of fluid collections such as an abscess and for a general assessment of the bowel wall thickening. Barium small bowel series can identify areas of inflammation, stricturing and the presence of bowel dilation (Fig 15.4). CT enterography is fast replacing small bowel series as the preferred method for assessing the small bowel. It is more accurate in assessment of disease activity and complications of stricture and abscess. It is common for patients with CD to have perianal fistula or penetrating complication in the pelvis. CT scanning is inaccurate in the assessment of these complications and magnetic resonance imaging (MRI), endoscopic ultrasound or examination under anaesthesia are the procedures of choice. CT scanning has become pervasive among nonIBD patients for many disorders. Recent studies have led to significant concerns regarding radiation

Pathology Biopsy is essential to document chronic intestinal inflammation. While the finding of granulomas in the setting of chronic inflammation is highly suggestive of CD, granulomas are not specific and found in only 20% of patients. Unfortunately, while endoscopic and histologic appearance are suggestive of CD, they are not diagnostic and must be interpreted along with other clinical information. Tuberculosis can rarely involve the terminal ileum and should be considered in highrisk patients. Cytomegalovirus should also be

Figure 15.4  Terminal ileal disease due to Crohn's disease (string sign).

15 Inflammatory bowel disease exposure because of the associated higher rates of malignancy and death compared to the general population. This risk is particularly important among patients with CD where CT is commonly and frequently performed. MRI enterography is attractive in the assessment of the small bowel disease since it avoids radiation exposure and may replace CT enterography in the future.

Complications CD may be complicated by bowel obstruction or abscess. Obstruction may be due to disease activity and treated effectively with medical therapy or may be due to scarring that would be more amenable to surgery. An abscess should be suspected among patients with known penetrating disease or who present with high fever and signs and symptoms of localised or systemic infection. Corticosteroids may mask abdominal pain or infection. Exclusion of an abscess is important since corticosteroids, immunomodulators and biological therapies are contraindicated in this setting. If an abscess is detected it should be drained prior to starting therapy.

Treatment Treatment is based on severity, but indices from clinical studies are difficult to apply in practice. Generally, patients with mild disease may have mild diarrhoea, rectal bleeding or abdominal pain but are ambulatory with no systemic symptoms (fever, weight loss and hypotension). Patients with moderate disease have worse symptoms (low grade fever and weight loss) although most can be managed as outpatients. Those with severe disease usually require hospitalisation because of severe diarrhoea, rectal bleeding, bowel obstruction, complications of fistula or failure of outpatient therapy. In addition to severity, the appropriate therapeutic options for a patient with CD depend on the disease location and behaviour. Penetrating and non-penetrating, non-stricturing disease must be distinguished because of differences in response to therapy. True stricturing disease responds poorly to medical therapy and surgical therapy is usually required. The therapeutic options in CD are focused on the induction and maintenance of remission and are quite complex; the involvement of an experienced gastroenterologist is essential. Approaches may vary slightly between clinicians. Medications can be broadly divided into mesalamine formulations, corticosteroids, immunosuppressive and biological medications. The section below outlines treatment for nonstricturing, non-perforating CD.

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Mild to moderate disease Mesalamine formulations Mesalamine (5-aminosalacylate) use in mild to moderate CD is controversial. While widely used, it has not consistently shown to be effective. It is not effective in penetrating disease and efficacy in other disease locations has been disappointing. Oral and rectal formulations may have some benefit in Crohn's colitis. Antibiotics Metronidazole has been used both in inflammatory and fistulising (see below) CD. Oral metronidazole can prevent recurrence after the first year after surgery but high doses (1000–1500 mg/day) are required and are difficult for most patients to tolerate. In addition to the typical side effects of nausea, metallic taste and interaction with ethanol, the clinician and patient must be wary of the development of peripheral neuropathy, which requires discontinuation of the drug. Enteric-release corticosteroids Enteric-release budesonide is very effective for inducing remission among certain patients with CD and is discussed below.

Moderate to severe disease Corticosteroids The mainstay for treatment of moderate to severe inflammatory CD is corticosteroids, usually in the form of parenteral methyl prednisolone, oral prednisone or rectal hydrocortisone. Methyl prednisolone (50 mg IV daily) for severe cases followed by oral prednisone (40 mg daily) after response or oral prednisone alone achieve remission in two-thirds of patients within about 2 months. Higher doses do not result in greater improvement and lead to more side effects. Rectal hydrocortisone is a useful adjunct in cases of proctitis or leftsided Crohn's colitis refractory to oral and topical mesalamine. Although, corticosteroid preparations are useful in inducing remission, they should not be used for maintenance therapy because they do not prevent recurrence and can result in significant steroid-related side effects (e.g. osteoporosis, avascular necrosis of the hip, hypertension, diabetes, cataracts and glaucoma). Enteric-release budesonide Enteric-release budesonide is an important corticosteroid agent that is very effective among patients with active CD involving the terminal ileum or ascending colon. Its benefit rests in its

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high first pass metabolism in the liver, resulting in decreased systemic side effects. A dose of 9 mg/day is dramatically better than mesalamine and nearly equivalent to prednisone. At a dose of 9 mg/day some adrenal suppression and steroidrelated side effects do occur, but are less than those of prednisolone. It has now become a firstline therapy to induce remission among patients with CD involving the terminal ileum or ascending colon, but it does not maintain remission. TNF-α antibodies Infliximab is a parenterally administered chimeric antibody (part-mouse and part-human) to TNF-α. TNF-α is important cytokine in the inflammatory response resulting in Crohn's disease. After administration of infliximab, the majority of patients will improve and half will go into remission with onset of effect at about 2 weeks after the infusion.In order to maintain response and minimize infusion reactions patients continue on this medication indefinitely. Adalumimab and certiluzimab are two additional agents that work through the same mechanism, have similar efficacy and are also continued indefinitely to maintain response. The use of additional immunosuppressive medications with these agents is controversial. Improved prognosis has led some to advocate earlier use in patients to alter the natural history of their disease. However, a significant number of patients may become intolerant or lose response to these medications over time. Contraindications are listed in Box 15.5. Natalizumab Natalizumab is a recombinant, humanised, IgG4 monoclonal antibody to alpha-4 integrin that results in inhibition of white blood cell migration to areas Box 15.5  Contraindications to TNF-α antagonists Anaphylaxis Infections ll Untreated tuberculosis, bronchiectasis, septic arthritis, infected prosthesis and indwelling catheters, untreated hepatitis B ll Congestive cardiac failure (class III or IV) NYHA class III or IV ll Chronic skin ulcers except for pyoderma gangrenosum ll Demyelinating disorders ll Malignancy less than 10 years posttreatment except for basal cell carcinoma (less than 5 years) ll ll

of inflammation. It has been shown to be effective in CD, but is reserved for those who are refractory to other agents prior to surgery. This is because of the possibility of a rare but often fatal development of progressive multifocal leukoencephalopathy. Azathioprine and 6-mercaptopurine Azathioprine (2–2.5 mg/kg) and 6-mercaptopurine (1–1.5 mg/kg) are equally effective in two-thirds of cases in maintaining remission and allowing corticosteroid tapering. As with UC, they are slow to act, requiring 3–4 months or more to take effect; this limits their use in active disease. Clinical and haematological monitoring by experienced clinicians is necessary. Pancreatitis, hepatitis and severe leukopenia are important adverse events. The metabolism of these agents was previously discussed in the UC section and the mechanism of action in treating inflammation in CD appears to be the same. TPMT should be checked prior to starting therapy (Fig 15.1). Methotrexate Methotrexate is an important alternative to azathioprine or 6-mercaptopurine, especially among patients who have failed or are intolerant to these agents. To be effective in CD it must be given parenterally. At doses of 25 mg intramuscularly (IM) about one-third of patients will go into remission by 4 months. However, this response is not sustained; most will relapse after 1 year but two-thirds of responding patients can be kept in remission with 15 mg IM weekly. This drug does have potential toxicities including leukopenia, mucositis, pneumonitis and hepatic fibrosis. Frequent haematological monitoring is essential. There is a slightly increased risk of opportunistic infections and malignancy. Use with corticosteroids and mesalamine appears safe. However, use with azathioprine, 6-MP or trimethoprim sulfamethoxazole can cause severe leukopenia. Patients should take folate while on this drug to decrease stomatitis and other gastrointestinal side effects. Like other immunosuppressives, use of this medication should be reserved for experienced clinicians.

Perforating (fistulising) Crohn's disease The treatment of perforating (fistulising) Crohn's disease is problematic. Mesalamine, corticosteroids and methotrexate do not heal or close fistulae. Metronidazole in doses of 1–2 g/day decreases fistula drainage and in some cases results in healing but must be maintained indefinitely to maintain its effect. Ciprofloxacin in doses of 1–1.5 g/day

15 Inflammatory bowel disease has also shown a similar benefit in small studies. Azathioprine is effective in fistulizing Crohn's disease with about one-third of fistulas closing. Slow time to onset in addition to low closure rates remain significant problems. This response may be improved at the higher doses currently used today. Infliximab is a very important advance in the management of fistulising Crohn's disease. About two-thirds of patients will show a decrease in fistula drainage and half will close their fistulas completely. Responses are highest for perianal fistula with other fistulae such as entero-entero, enterocutaneous, enterovaginal or bladder fistula more resistant to therapy. Response to therapy is rapid, usually within 2 weeks, but usually lasts only about 3 months. Continued use is necessary to maintain fistula closure but may not be effective. There are limited data on adalumimab and certiluzimab for fistula closure.

Nutritional therapy Malnutrition is quite common in patients with CD, especially children. The cause is multifactorial with increased caloric requirement and problems with malabsorption due to small bowel disease or short bowel. Elemental diets and total parenteral nutrition have been tried as primary or adjunctive therapy for active CD with some success although the results are controversial. Total parenteral nutrition has fallen out of favour as primary therapy for CD, but may still be used in cases of malnutrition. It may also be given for severe refractory fistulising disease as an adjunctive treatment or to ready a patient for surgery.

Surgery It is very likely that an individual with CD will require surgery at some point in the course of the disease. Surgery may be required acutely in cases of bowel obstruction or perforation but more commonly because of failure of medical therapy. While surgery may induce remission, medical therapy is required to reduce risk of recurrence. The selection of the appropriate therapy may be difficult. As in UC, surgery may also be required for dysplasia or findings suspicious for malignancy.

Risk of malignancy The risk of gastrointestinal malignancy is increased in CD, although the risk of small bowel tumours incidence remains low and there is no effective screening for this complication. The risk of anorectal malignancies is also increased in patients with longstanding perianal disease. Like those with UC, patients with Crohn's colitis have an increased

203

risk of colon cancer that is related to the duration and extent of disease. Surveillance guidelines for UC should also apply to these patients.

Inflammatory bowel disease and pregnancy Fertility rates for UC and CD overall are similar to the general population. Fertility rates are significantly diminished after colectomy and IPAA for UC. IBD must be kept in remission during pregnancy to decrease the risk of preterm labour and adverse fetal outcomes. The potential effect of medications on the fetus varies. Mesalamine preparations are considered US Food and Drug Administration Category B and are generally safe. Teratogenicity of antibiotics is agent specific. Azathioprine and 6-mercaptopurine are Category C, meaning that teratogenicity is possible but these agents may be continued in selected patients where the benefit outweighs the risk. Methotrexate, however, is Category X and should not be used in pregnancy because of clear teratogenicity. TNF-α inhibitors including adalumimab, certiluzimab and infliximab are Category B and probably safe although data are limited. If a medication is to be discontinued before pregnancy an appropriate wash-out period may be required to prevent teratogenicity. Secretion of medications in breast milk varies and is agent specific. The decision to become pregnant is patient specific and should involve an experienced gastroenterologist and obstetrician.

Health maintenance in IBD patients IBD and its treatment can affect the general health of patients. The disease and its therapy influence rates of vaccination, the development of osteoporosis and malignancy. Primary care physicians and gastroenterologists need to work together and educate patients to prevent these complications. While for adult IBD patients vaccination schedules are similar to the general population, there are important exceptions. Live vaccines are contraindicated among patients on immunosuppressive (including more than 20 mg prednisone or equivalent) or biological therapy. Although patients on immunosuppressive therapy or biological therapy had lower responses to influenza and pneumococcal vaccines, they should still be vaccinated. Clinicians must be sure that patient vaccination schedules are up to date and vaccinations given prior to the institution of immunosuppressive therapy if possible. Patients with IBD are at increased risk of osteoporosis. This risk is compounded by

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Box 15.6  Key management issues in Crohn's disease Diagnosis Confirm diagnosis of ulcerative colitis or Crohn's and define extent and activity including any extraintestinal manifestations Pretreatment work-up Infective screen ll History of prior infection exposure including tuberculosis, fungal infection and viruses ll QuantiFERON gold test as a screen for latent tuberculosis ll Chest x-ray to screen for tuberculosis and histoplasmosis ll Hepatitis B serology (HepBsAg, HepBcAb and HBV DNA), hepatitis C serology ll Baseline Epstein-Barr virus and cytomegalovirus serology ll Chemoprophylaxis with isoniazid for latent tuberculosis ll Yearly influenza vaccine and 5-yearly pneumococcal vaccine ll HPV, influenza and Pneumococcus spp. vaccine and immunise against hepatitis B if not yet immune ll Avoid live vaccines (varicella and typhoid) while on immunosuppressives ll Appropriate travel advice and chemoprophylaxis depending on area of travel Metabolic screen ll Baseline full blood count, erythrocyte sedimentation rate, C-reactive protein, liver function tests, electrolytes, urea, creatinine, blood sugar and other nutritional parameters (B12, folate and iron levels) ll Bone mineral density

corticosteroid use. Current recommendations are for dual-energy absorptiometry scanning (DEXA) in postmenopausal women, men over the age of 50 years, and those with greater than 3 months of steroid usage, a history of low trauma fracture or hypogonadism. Prevention rests on the limited use of corticosteroids in favour of steroid-sparing agents, supplemental calcium and vitamin D. Patients with IBD are also at risk for extraintestinal malignancies. Women on immunosuppressive therapy (especially those who smoke) are at higher risk for abnormal Pap smears compared to control patients. Screening guidelines from the American College of Gynecology should be followed. Human papilloma virus vaccination should be administered to all female IBD patients taking immunosuppressive medications unless contraindicated. Anal cancer,

Cancer screen Regular dermatological check-up when on immunosuppressives, and use SPF 30 sunscreen ll Regular Pap smear ll Colonic surveillance for dysplasia Treatment approach ll Address psychological issues. ll Treat nutritional deficiency and folic acid supplementation. ll Address issues of male and female fertility as well as issues of teratogenicity due to drugs and effects of surgery. Methotrexate is contraindicated in pregnancy. ll Tailor treatment in ulcerative colitis to the severity as well as direct the treatment to the specific area with the appropriate delivery systems (e.g. enemas, topical foams and suppositories for left-side disease). ll Discuss the issues of gradual step-up therapy or more aggressive treatment with immunosuppressives and biologics in Crohn's disease. ll Monitor for drug side effects. ll Distinguish flares from infection. ll Do periodic colonic surveillance for cancer and regular skin and Pap smear screening. ll Arrange surgical consultation for complications: toxic megacolon, fistulas, strictures and bowel obstruction. ll

even in the absence of perianal disease, is also more common among IBD patients and is also linked to human papilloma virus infection. Anal Pap smears are employed by some but have not been generally adopted. Skin cancer rates are also increased among IBD patients on immunosuppression so that extra vigilance is required. A summary of the key management issues is presented in Box 15.6.

Key Points ll

ll

There is no one single test to diagnose inflammatory bowel disease. Diagnosis is based on clinical, radiographic, endoscopic and pathology findings. Enteric infections (particularly C. difficile) and non-steroidal anti-inflammatory medications

15 Inflammatory bowel disease

ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

can mimic many of the findings of IBD or make existing IBD worse. Other conditions such as lymphoma, carcinoid or intestinal tuberculosis may need to be considered because they can also mimic Crohn's disease). Ulcerative colitis (UC) is classified based on disease extent into proctitis (involving only the rectum), left-sided colitis (continuous involvement from the anal verge above the rectum but no further than the splenic flexure) and pancolitis (continuous disease from the anal verge proximal to the splenic flexure). UC extent predicts response to therapy with proctitis having the best prognosis. Surgery for UC is most often done for dysplasia and consists of colectomy with, in most cases, an ileal pouch anal anastomosis. Mesalamine in the mainstay of therapy for both the induction and maintenance of remission of mild to moderately active UC. Topical mesalamine therapy is very effective for disease involving the rectum and left colon. Corticosteroids are the treatment of choice to induce remission for more severe UC or if mesalamine therapy has failed. Corticosteroids are not effective to maintain remission and may cause significant adverse effects. Infliximab therapy is reserved for severe UC, where corticosteroids are ineffective (or cannot be used), to induce and maintain remission. Azathioprine and 6-mercaptopurine require 3 months to be effective. They allow steroid tapering and maintenance of remission in UC. UC does increase the risk of colon cancer when more than just the rectum is involved. Patients with pancolitis or left-sided colitis should undergo surveillance colonoscopy yearly or every other year after 8 and 10 years of disease respectively. Recommendations also apply to Crohn's colitis. Crohn's disease (CD) is classified based on anatomic location and disease behavior. Disease confined to the lining of the bowel (inflammatory) is generally more responsive to medical treatment than penetrating (fistulising) disease. Fibrostenotic disease (scarring) does not respond to medical treatment and may require surgery. CD may be complicated by fistula, abscess, bowel obstruction or perforation. Mesalamine is generally ineffective in CD but may be effective in Crohn's colitis. Corticosteroids are effective in induction of remission for inflammatory CD, but should

ll

ll

ll

ll

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not be used for remission maintenance or for fistulising disease. For disease of the terminal ileum or right colon, oral enteric release budesonide is very effective with far fewer side-effects compared to conventional steroids. Tumour necrosis factor inhibitors (adalumimab, certiluzimab and infliximab) are highly effective agents in the induction and maintenance of remission of both inflammatory and fistulising CD. Like UC, azathioprine and 6-mercaptopurine are effective in remission maintenance and to facilitate steroid tapering, but are less effective in fistula closure compared to tumour necrosis factor inhibitors. Parenteral methotrexate is effective in CD to facilitate steroid weaning and for maintenance therapy as an alternative to azathioprine or 6-mercaptopurine. Most patients with CD will undergo surgery during their lifetimes. Most common indications are failure of medical therapy or development of complication (abscess, fistula or obstruction).

Further reading Farmer, RG, Easley KA, Rankin GB. Clinical patterns, natural history and progression of ulcerative colitis—a long term follow-up of 1116 patients. Dig Dis Sci 1993; 38:1137–1146. Kornbluth A, Sachar DB Ulcerative colitis practice guidelines in adults: Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn's disease in adults. Am J Gastroenterol 2009; 104:465–483. Mac Kalski BA, Bernstein CN. New diagnostic imaging tools for inflammatory bowel disease. Gut 2006; 55:733–741. Mahadevan U. Fertility and pregnancy in the patient with inflammatory bowel disease. Gut 2006; 55:1198–1206. Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflamm Bowel Dis 2009; 15:1399–1409. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus and implications. Gut 2006; 55:749–753. Swaminath A, Kornbluth A. Optimizing drug therapy in inflammatory bowel disease. Current Gastrenterol Rep 2007; 9:513–520.

Acknowledgement Dr V Duncanbe and J Almeida contributed to the preparation of this chapter.

16 Faecal incontinence (leakage of stool)

Case Mrs C.B. is a 58-year-old woman who presents complaining of worsening faecal incontinence over 2 years. She had noticed soiling of her underclothes two or three times per week and needed to wear a pad. This occurred particularly if the stool was loose but also occasionally with formed stool. She also had incontinence to flatus. The incontinence took the form of urgency, with inability to defer defecation and soiling if she did not make the toilet in time. At other times there was involuntary seepage without awareness. In terms of risk factors for incontinence, she had three vaginal deliveries, the first being complicated by a third degree tear. She was not aware of haemorrhoidal or rectal prolapse, and there had been no prior surgery for an anal condition. On digital anorectal examination the sphincter felt weak and the sphincter ring felt intact. There was no external rectal prolapse, or internal prolapse seen at rigid sigmoidoscopy when asking the patient to strain down. Anorectal manometry showed a low resting and squeeze pressure, and normal rectal compliance. Pudendal nerve conduction studies showed delayed conduction along the nerves, and endoanal ultrasound showed a thin sphincter anteriorly, but the sphincter was otherwise complete. The findings indicated neurogenic weakness of the internal and external sphincter as the cause of incontinence. Management and progress: Mrs B was prescribed psyllium (Metamucil™) and loperamide (Imodium™) to attempt to bulk up the stools and make them more solid. She was given biofeedback treatment to try to strengthen the sphincter muscles. There was no significant improvement in her incontinence. She was then treated with sacral nerve stimulation and had a good result

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with the test electrode; she then went on to have a permanent stimulator inserted, with good effect.

Introduction Faecal incontinence (leakage of gas or stool) is a common condition, occurring in 10% of the adult population. Men and women are affected in equal proportions, although in men the incontinence is generally much less severe. Incontinence can cause restriction of lifestyle or even social isolation. In many cases, it is the factor resulting in an elderly person requiring entry into a nursing home. It has been estimated that only one-fifth of people with incontinence consult their doctor about the problem—the remainder fail to do so, citing as their reason embarrassment or the belief that no treatment is available. A recent analysis has shown that treatment of faecal incontinence in Australia costs several hundred million dollars annually and places a significant financial burden on the community. It is therefore vital to understand the condition, and improve treatment as well as methods of prevention.

Definitions Continence is defined as the ability to control the onset of rectal evacuation. Minor incontinence refers to mucus discharge or incontinence of liquid or solid stool less than once per week. Major incontinence is loss of liquid or solid stool more than once a week, or sufficiently frequently to be causing social embarrassment for the patient. A more objective numerical continence scoring system, taking into account the exact frequency and nature of incontinence, is now commonly used in specialist centres and a simplified version is helpful for routine clinical assessment (Table 16.1).

16 Faecal incontinence (leakage of stool) Box 16.1  Causes of faecal incontinence

Table 16.1 Simplified Wexner scoring system for faecal incontinence (0–20): 0 = normal continence, 20 = severe incontinence Never

< 1/ month

< 1/ week

< 1/ day

> 1/ day

Leakage of solid stool

0

1

2

3

4

Leakage of liquid stool

0

1

2

3

4

Flatus

0

1

2

3

4

Pad used

0

1

2

3

4

Lifestyle changed

0

1

2

3

4

Normal sphincter Diarrhoea ll Anorectal conditions: – anal fissure; – haemorrhoids; – mucosal prolapse; – rectal carcinoma; – proctitis; – abnormal rectal sensation. Abnormal sphincter ll Congenital abnormalities ll Anal sepsis ll Neurological conditions ll Rectal prolapse ll Sphincter trauma ll Neurogenic incontinence ll

It is important to focus on the exact nature of the incontinence as described above in order to decide whether the condition warrants full investigation and treatment.

History The causes of faecal incontinence are summarised in Box 16.1. A good history about the nature of the incontinence will often provide clues about the cause. Physical examination and tests of anorectal function will determine whether the sphincter is normal, and will identify the likely pathology in most cases. The three most common causes of faecal incontinence requiring surgical treatment are rectal prolapse, sphincter trauma and neurogenic incontinence. These conditions account for the majority of patients who suffer severe longstanding symptoms. The features in the history that need to be established in these patients are: ll Is the incontinence for solids, liquids or gas? Determine whether complaints of incontinence reflect only perianal soiling by mucus, or whether there is leakage of stool. Mucus seepage occurs with local anal conditions such as anal mucosal prolapse and haemorrhoids. ll Is it passive incontinence, where there is involuntary seepage of stool without awareness? Passive incontinence occurs with internal sphincter weakness. ll What is the frequency and duration of the incontinence, and has it been progressive? ll Is urgency present? Is the patient able to defer defecation for a reasonable time? Urgency and incontinence may occur when the sphincter is normal, such as in proctitis and rectal cancer, or with diarrhoea. With diarrhoea, incontinence results from rapid transit of

207

ll

ll

stool through the lower colon. It may be preceded by lower abdominal pain prior to the incontinent event. Importantly, urgency and incontinence are also caused by external sphincter weakness. Does the incontinence date from a particular medical event, such as perianal surgery or a difficult vaginal delivery? Perianal trauma may not present with incontinence immediately after the event, but rather many years later. Thus, the anal sphincter mechanism can compensate for a badly damaged sphincter due to anal surgery (e.g. for fistula), an unsatisfactorily repaired episiotomy or third-degree tear, or prolonged stretching of the pudendal and sacral nerves during second-stage vaginal delivery. Are there any other symptoms of anal or rectal disease?

Examination The patient is examined in the left lateral position with the hips flexed to allow the examiner good access to the perineum and anal region. The area is inspected for soiling, and for excoriation of the perianal skin as evidence of chronic irritation secondary to incontinence. Any external prolapse at the anus (Box 16.2) and an asymmetrical sphincter caused by trauma and perianal scarring are looked for. Digital anorectal examination is carried out next and the resting tone (produced by the internal sphincter) is noted. The functional length of the anal canal in centimetres should be estimated. The

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Box 16.2  Causes of external prolapse at the anus Anal canal Haemorrhoids ll Anal mucosal prolapse ll Fibroepithelial polyp Rectum ll Rectal mucosal prolapse ll Full-thickness rectal prolapse ll Rectal polyp Colon ll Intussusception of pedunculated adenoma ll

strength of the pelvic floor muscles is assessed by pressing posteriorly and laterally. External sphincter strength is assessed by asking the patient to contract the sphincter and, thereafter, to cough. A shortened, weak sphincter is found in neurogenic incontinence. A weak sphincter of normal length is caused by a sphincter defect due to trauma. The sphincter is examined circumferentially between the thumb and index finger and a defect may be palpable. The rectal mucosa is then examined circumferentially for proctitis or a tumour; this should not be done at the beginning of the examination since discomfort from deep pelvic examination may impair the subsequent ability of the patient to cooperate with contraction and relaxation of the sphincter. The patient is next asked to bear down while the examiner looks for rectal prolapse. The ischial tuberosities are palpated and the plane of the perineum assessed in relation to the position of an imaginary line drawn between the tuberosities. If the perineum descends below this line when the patient is asked to bear down, this is evidence for abnormal descent associated with neurogenic weakness of the pelvic floor muscles. If rectal prolapse is suspected but not demonstrated in this position, the examination should be repeated with the patient squatting over a paper towel or sitting on a commode. If there is a history suggestive of a neurological condition, a full neurological examination should be carried out.

Proctoscopy and sigmoidoscopy At proctoscopy, anal mucosal prolapse and haemorrhoids can be diagnosed. Sigmoidoscopy is essential to exclude rectal pathology including proctitis and rectal tumours (Ch 22). The patient

is asked to strain down on the sigmoidoscope and prolapse of the rectal wall can often be detected in this way.

Physiological Anorectal Assessment Before considering physiological investigation of anal incontinence it is important to consider the physiology of continence. Continence is maintained by a complex process that has both sensory and motor components.

Physiology of continence Normal continence depends on an interaction of the following factors. The anal canal is surrounded by a muscular tube that produces a high-pressure zone exceeding the pressure in the rectum. The sphincter contains two layers (Fig 16.1): an inner layer of involuntary smooth muscle (internal sphincter) and an outer layer of skeletal muscle (external sphincter). The internal sphincter is a distal continuation of the circular muscle of the rectum and is in a state of constant contraction, maintained by a process of intrinsic muscle stimulation. Relaxation of the muscle occurs during defecation, mediated by a local neural reflex within the wall of the anorectum in response to distension of the rectum by the faecal bolus, as well as by extrinsic autonomic control via the presacral sympathetic nerves. The external sphincter is under voluntary control but also contracts involuntarily in response to an increase in intraabdominal pressure via a spinal reflex through the anterior horns of the S2–S4 spinal segments and the Onuf nucleus in the spinal cord. The puborectalis muscle lies immediately above the external sphincter and forms a muscular sling behind the anus (Fig 16.2). It supports the anus and produces the anorectal angle, which is felt posteriorly at the upper end of the anal canal when doing a rectal examination. There are three anal cushions in the 3, 7 and 11 o'clock positions formed from expansions of the submucosa of the anal canal. The cushions are compressed when the sphincter pressure is high, but expand at other times and lie in apposition to each other. They play a small role in assisting to maintain continence. The anal mucosa contains an abundance of sensory nerve endings. Spontaneous relaxation of the upper part of the internal sphincter occurs intermittently to allow the anal mucosa to ‘sample’ the contents of the rectum (the sampling reflex). This allows us to normally distinguish flatus from stool in the rectum.

16 Faecal incontinence (leakage of stool)

Pararectal space

Levator ani muscle

Ischiorectal fossa External sphincter

209

Puborectalis Internal sphincter

Intersphincteric plane

Figure 16.1  Anal sphincter. The internal sphincter is continuous above with the muscle of the rectum. The external sphincter lies below the puborectalis and levator ani muscles. From Parks AG, Gordon PH, Hardcastle JD: A classification of fistula-in-ano. Br J Surg 1976; 63(1):1–12, with permission. Symphysis pubis

Anal canal

Rectum

Coccyx

Figure 16.2  The puborectalis muscle forms a sling behind the junction of the anus and rectum. From Anderson JE, ed. Grant's Atlas. 7th edn. Baltimore: Williams & Wilkins; 1978, with permission from the publisher.

The consistency of the stool in the rectum has an important influence on continence, a fact often overlooked. The rectum is a storage organ and its wall must be compliant in order to fulfil this reservoir function. Diseases affecting the rectal wall may make it less compliant and impair continence.

Diagnostic tests Anorectal manometry Pressure in the anus and rectum is measured using a narrow diameter multichannel catheter. Each channel is perfused with water and connected

to a pressure transducer and digital recording apparatus; sequential channels open at 0.75 cm intervals from the tip of the catheter (Fig 16.3). The pressure at rest reflects the strength of the internal sphincter, and pressure during voluntary contraction of the muscles is a measure of the external sphincter strength (Fig 16.4). Relaxation of the internal sphincter is tested by inflating a balloon positioned in the rectum at the tip of the manometry catheter, while recording anal pressure. Manometry is a very useful test because it defines which muscle is affected in a patient with sphincter weakness. It also demonstrates

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Clinical gastroenterology: a practical problem-based approach that sphincter function is normal in a patient whose incontinence is due to diarrhoea or excessive colonic propulsion, or due to a local anal condition such as haemorrhoids and, hence, confirms that sphincter weakness is not the cause of the incontinence.

Figure 16.3  Manometry catheter. Water perfusion catheter showing balloon at the tip inflated by waterfilled syringe. Several pressure recording points are found at short intervals from the balloon to measure pressure along the anal canal.

Electrophysiology In patients with suspected neurogenic incontinence the function of the pudendal nerves is tested. Motor conduction is measured by transrectal stimulation of the nerves, using a fine disposable electrode mounted on the gloved index finger (Fig 16.5). The left and right pudendal nerves are stimulated at the point that each passes around the ischial spine and the conduction time to the external anal sphincter is recorded (Fig 16.6). Stretch-induced damage to the nerves caused by difficult vaginal delivery or chronic excessive straining at stool is reflected in the slowing of conduction in the nerves due to axonal degeneration. Sensory conduction is

Figure 16.4  Anorectal manometry. Manometry recording—pressures recorded simultaneously at three levels in the anal canal and one site in the rectum. Pressure at rest reflects the internal sphincter; an increase above the resting pressure is produced by a squeeze or cough, due to the external sphincter contraction. The rectoanal reflex (RAR) shows relaxation of the internal sphincter (seen as a fall in pressure in the anal recording) due to distension of the rectum with a balloon (seen as a rise in pressure in the rectum).

16 Faecal incontinence (leakage of stool) measured by delivering a small current to the anal mucosa. The current is increased in fractions of a milliamp until a slight, painless, tapping feeling is reported by the patient, and the threshold of stimulation is measured. With pudendal nerve damage there is loss of sensation, reflected as an increased threshold of stimulation. Electromyography is carried out using a fine needle electrode inserted into the external sphincter muscle. Muscle contraction is amplified and displayed as spikes of electrical activity. Normal muscle activity can be clearly distinguished from non-functional scar tissue, allowing the site and extent of a sphincter defect to be clearly defined (Fig 16.7). Electromyography is

211

used less commonly, with the advent of endoanal ultrasound. Ultrasound Endoanal ultrasound has become a valuable tool to study anal function. It is very accurate in identifying a defect in the internal or external sphincter, and is less invasive than electromyography. The ultrasound probe records through 360° to give a complete image of the sphincter (Figs 16.8 and 16.9). Proctography Barium studies of the anorectum are used to test the ability of the anal sphincter to maintain continence. Semisolid barium paste of similar consistency to soft stool is instilled into the rectum. Lateral x-ray examination is made of the rectum and anus while the patient coughs, moves and during a Valsalva manoeuvre, and the amount of leakage is assessed (Fig 16.10). This examination is used to confirm the diagnosis of neurogenic incontinence.

Conditions Causing Incontinence with a Normal Sphincter Diarrhoea

Figure 16.5  Pudendal electrode strapped to index finger. Stimulating electrodes are at the tip and recording electrodes at the base of the finger.

Aetiology Diarrhoea, either acute or chronic, may overcome the ability of the normal sphincter to resist the forceful passage of liquid stool. High pressures generated in the colon may exceed the maximum pressure of the anal sphincter, and incontinence is then inevitable. Incontinence may even occur when stool consistency and frequency are normal, due to sudden excessive colonic propulsion.

500 µV

2 ms

Figure 16.6  Recording of pudendal motor latency. The arrow indicates the onset of the stimulus delivered to the pudendal nerve; there is then a delay (2 ms) due to the conduction time along the nerve (pudendal latency), followed by contraction of the external sphincter shown by a rise and fall in the trace. Damage to the pudendal nerve results in an increase in pudendal latency.

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Clinical gastroenterology: a practical problem-based approach

Clinical features In patients with diarrhoea, incontinence is sometimes preceded by lower abdominal pain or a sudden urgent call to stool. Other clinical features are discussed in Chapters 13 and 14. Treatment When there is a colonic cause for incontinence, simple antidiarrhoeal medication may produce a very dramatic improvement in some patients. Chronic diarrhoea should be investigated with fresh stool specimens sent for microscopy and culture, and with sigmoidoscopy or colonoscopy. Special tests for malabsorption or more rare causes of diarrhoea (see Ch 14) will be indicated in some cases. Once secondary causes have been excluded, diarrhoea should be treated with a small regular prophylactic dose of loperamide, usually one 2 mg tablet taken daily in the morning. The aim of treatment is to suppress colonic activity sufficiently to produce slight firmness of the stool. There is no benefit gained from taking this medication after a loose stool is passed. Loperamide also has the added benefit of producing direct contraction of the internal sphincter muscle and, hence, raising resting anal pressure in some patients.

Anorectal conditions Anal mucosal prolapse and prolapsing haemorrhoids can result in incontinence. Prolapse is caused by straining at stool. Most commonly the anterior mucosa is affected, but circumferential prolapse may also occur. Anal fissure may produce a keyhole deformity near the anal verge as a result of chronic fibrosis through which seepage of mucus and stool may occur. In older patients with a short history of incontinence, conditions to consider include rectal cancer (Ch 22), inflammatory bowel disease (Ch 15) and ischaemic proctitis (Ch 4). In a small number of patients there is loss of rectal sensation so that there is reduced awareness of faeces in the rectum with resulting overflow incontinence. The cause for this sensory loss is unknown. Treatment With a normal sphincter, treatment, if successful, will result in the return of normal continence. Rectal cancer presenting with incontinence is treated by surgery according to conventional principles (Ch 22). Prolapsing haemorrhoids and anal mucosal prolapse causing incontinence usually require rubber-band ligation (Ch 12). Occasionally when the prolapse is large, surgical

Figure 16.7  Electromyography of the external sphincter showing normal muscle activity at 3, 7, 8, 9 and 12 o'clock, and loss of activity at 6 and 11 o'clock due to sphincter damage.

16 Faecal incontinence (leakage of stool)

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excision is required. Anal fissure causing incontinence is always a deep chronic fissure, which should be treated surgically by lateral sphincterotomy. Abnormalities in rectal sensation may respond to loperamide because of the constipating effect of the drug.

Conditions Causing Incontinence with an Abnormal Sphincter Congenital abnormalities There are two basic forms of anorectal abnormalities. Low defects affect only the lower anal canal and are usually easily corrected in infancy, with normal continence resulting. High defects affect the anal sphincter, pelvic floor muscles and, in some cases, also the urogenital tract, and surgery may be accompanied by varying degrees of incontinence in later life. Many of these patients require a permanent colostomy, although recent developments in sphincter reconstruction allow this to be avoided in some cases.

Anal sepsis

Figure 16.8  Ultrasound machine, showing endoanal probe stored on the left side of the machine.

Perianal sepsis may be severe enough to result in sphincter destruction and incontinence (Ch 12). Complex anal fistulae with longstanding sepsis and hidradenitis suppurativa (infection in perianal apocrine glands) are the most common causes.

Figure 16.9  Endoanal ultrasound in a patient with incontinence. The internal sphincter is seen as a black ring, which is incomplete in this patient due to an anterior sphincter defect (shown between the arrows). The external sphincter is seen as the white band outside the internal sphincter.

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Figure 16.10  Proctography. Lateral X-ray film of the rectum (r) and anal canal (a) showing leakage of barium during coughing in a patient with neurogenic incontinence.

Neurological conditions Faecal incontinence due to a neurological cause is not commonly encountered. Nevertheless, this diagnosis is an important one to consider because localised conditions such as spinal cord or pelvic tumours may be amenable to surgery or radiotherapy. Neurological conditions causing incontinence may be supranuclear or infranuclear, depending on their relation to the Onuf's nucleus. Supranuclear lesions The cerebral control of sphincter function is located in the orbitofrontal cortex and conditions affecting this area, such as dementias, are particularly liable to present with incontinence. Upper motor neurone lesions also result from multiple sclerosis, multifocal atherosclerotic vascular disease or spinal trauma above the S2 level. Some disorders, especially motor neurone disease, are accompanied by widespread muscle wasting but relative preservation of the sphincter muscles because of sparing of the motor neurones in the Onuf nucleus. Infranuclear lesions Lower motor neurone lesions cause denervation of the sphincter muscles and hence incontinence. This results from damage to the sacral nerve roots in the pelvis or within the cauda equina. Cauda equina disease results from sacral spondylosis, disc prolapse, trauma, or intraspinal neoplasms. Pelvic lesions include tumours—either primary presacral tumours or recurrent carcinoma after excision of the rectum.

Treatment There is no effective curative treatment for most supranuclear lesions, including multiple sclerosis, and for most dementias. Localised spinal conditions such as disc prolapse or tumours may be amenable to surgical treatment.

Rectal prolapse Rectal prolapse is a circumferential intussusception of the rectum, which passes through the anal sphincter and beyond the anal verge to the exterior (Fig 16.11). It occurs in females in 90% of cases. In over two-thirds of patients there is associated neurogenic weakness of the anal sphincter (see neurogenic incontinence), but unlike patients with neurogenic incontinence, where almost all are multiparous women, almost half the women with rectal prolapse are nulliparous. Aetiology Rectal prolapse is a primary intussusception of the bowel. Constipation and impaired rectal evacuation leading to straining at stool are sometimes present and may contribute to the development of prolapse. Trauma during childbirth is probably not a significant contributing factor as many women with prolapse are nulliparous. Almost all cases of prolapse in children are due to constipation and straining. Clinical features The condition is most common over the age of 50 years, and a smaller number of patients are in the 20–50-year age group. It occasionally occurs in children.

16 Faecal incontinence (leakage of stool)

Figure 16.11  Rectal prolapse.

Most elderly patients complain of a prolapse during defecation, which either reduces spontaneously or must be manually reduced. Sometimes the prolapse occurs spontaneously when the subject walks about. The prolapse is accompanied by mucus discharge. There are two distinct forms of rectal prolapse: 1. In two-thirds of cases there is associated marked neurogenic weakness of the anal sphincter and faecal incontinence is present. 2. In one-third of cases the anal sphincter is normal—there is mucus discharge, but incontinence usually does not develop. Treatment Rectal prolapse in children is usually due to constipation and straining and should be treated conservatively with dietary measures (Ch 11). In adults, if the prolapse is small, it reduces spontaneously and is not accompanied by incontinence, it can be treated conservatively. With mild symptoms or a patient with poor functional status, conservative treatment including encouragement to avoid straining at stool and treatment of constipation with bulk-forming agents (e.g. psyllium or sterculia) might be all that are indicated. If the prolapse is more severe surgery is needed. There are many operative procedures used in the treatment of rectal prolapse, indicating that no procedure produces an entirely satisfactory result. There are two approaches that can be used: an abdominal procedure or a perineal procedure. With an abdominal operation there is a low longterm incidence of recurrent prolapse and also a 75% chance of curing the incontinence, but this is achieved with the risks and morbidity that

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accompany a major abdominal operation. This is particularly relevant in very elderly patients with prolapse. Perineal procedures are associated with very little pain or other morbidity, but carry a higher incidence of recurrent prolapse. Incontinence is cured less frequently by these procedures than by an abdominal procedure. The choice of a particular procedure in a patient therefore needs to take into account such factors as the age and general medical status of the patient, the expected remaining lifespan, and the severity and nature of the symptoms. For example, a young patient with prolapse and severe incontinence would be well suited to abdominal rectopexy; an elderly, frail patient with a large prolapse and less severe incontinence would be treated with a perineal procedure. Abdominal rectopexy involves mobilising the rectum out of the pelvis, and then securing it to the sacrum with sutures to prevent prolapse. This procedure can now be done using laparoscopic techniques. Anal encirclement procedures involve placing a stainless steel wire or nylon suture subcutaneously around the anal canal after reducing the prolapse. Although still used today in some centres for highrisk patients, it is rarely used since the wire (being too loose) inevitably fails to control the prolapse, or ulcerates through the skin, or is too tight, resulting in constipation. The Delormes procedure involves excision of the mucosa over the prolapsing section of rectum and then plication of the underlying rectal wall. Reported recurrence rates range from 5% to 30%. Perineal rectosigmoidectomy involves excision of the entire prolapsing section of rectum and sigmoid, with anastomosis of the colon to the anus. In principle this is a very sound procedure, but the reported recurrence rates are as high as with the Delorme procedure. The high rates found in some series are probably because of incomplete removal of the prolapsing bowel, and in those centres where a more complete excision is practised, recurrence rates as low as 5% are found. Since there is minimal blood loss with the procedure and virtually no morbidity, this is a very good option for elderly patients.

Sphincter trauma Aetiology Direct trauma to the sphincter is most commonly due to an obstetric tear, or damage resulting from surgery for anal fistula. Other less common causes

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are impalement on a sharp object, pelvic fracture, stab wound or gunshot wound. Obstetric injuries are the most common cause of sphincter trauma. In North America and some parts of Europe where midline episiotomy is practised routinely, division of the anal sphincter and imperfect repair may cause a sphincter defect; while in Australia, the UK and most of Europe, lateral episiotomy is made and third-degree perineal tears are the cause. Recent studies of the anal sphincter using the technique of intraanal ultrasound have identified injuries to the anterior sphincter in a much higher proportion of cases than is recognised clinically, and in some of these cases of occult sphincter injury incontinence will develop in later life. Surgery for anal fistula is the most common iatrogenic cause of incontinence. Laying open of a fistula that has not been recognised as suprasphincteric or extrasphincteric will result in incontinence. However, these fistulae are rare, and more commonly incontinence results from treatment of a trans-sphincteric fistula that crosses more than 50% of the external sphincter muscle. Impalement injuries generally result from falling astride a sharp object, such as a fence, and can result in severe damage. Secondary infection may occur if adequate surgical debridement is not performed, resulting in further tissue loss. There may be an associated injury to the rectum above the sphincter. Pelvic fractures may produce widespread disruption of the anal sphincter and can present a particularly difficult problem for surgical repair. There are several iatrogenic injuries apart from those resulting from fistula surgery. These injuries are due to poor surgical technique and should be completely avoidable. Minor incontinence after haemorrhoidectomy is well recognised and occurs in up to 10% of cases in some series, usually due to damage to the internal sphincter or lower part of the external sphincter during the haemorrhoidectomy, but in some cases anal dilatation carried out at the time of haemorrhoidectomy may be the cause of the incontinence. Lateral sphincterotomy for anal fissure should include only the lower part of the internal sphincter—if the external sphincter is divided, incontinence will result. Anal dilatation has been advocated for haemorrhoids and anal fissure. Although this procedure is an effective treatment for these conditions by disrupting the internal sphincter spasm, it is a frequent cause of incontinence, particularly in multiparous women, and should be completely avoided.

Clinical features A damaged sphincter may be recognised by a visible keyhole defect externally or a palpable defect on physical examination. The defect is best assessed prior to surgical intervention with endoanal ultrasound. Treatment Repair of the damaged sphincter ranges from a relatively simple procedure when the sphincter has been cleanly divided, to a very complex procedure when the sphincter has been widely disrupted with accompanying sepsis and tissue necrosis. Preoperative establishment of the precise extent of the scar tissue greatly facilitates planning of the procedure and accurate repair. In most cases, a covering stoma is not required, and the use of a stoma is restricted to three situations: underlying Crohn's disease; repeat sphincter repair; or with a very extensive injury. The principles of surgery are to expose the injured area, excise the scar tissue, and create an overlapping repair using healthy muscle on either side of the scar. The results of sphincter repair are very satisfactory. Almost 70% of patients will achieve continence and up to half of the remaining patients will be partially improved, although the results deteriorate over time. In those cases where there is no improvement and severe incontinence persists, the two available alternatives are a permanent colostomy or reconstruction of a new sphincter mechanism. Complete sphincter reconstruction involves the procedure called stimulated graciloplasty, in which the gracilis muscle in the thigh is detached from its insertion on the tibia and tunnelled around the anus to construct a neosphincter. Since the gracilis is a conventional fast-twitch skeletal muscle that fatigues quickly, it must be stimulated using an implanted subcutaneous pacemaker, which converts it to a fatigue-resistant slow-twitch muscle by continuous low-frequency stimulation, eventually allowing it to remain continuously contracted. Patients in whom there is an isolated internal anal sphincter injury may benefit from injection of a bulking agent into the sphincter. This bulking agent may be silicone-based (PTQ™) or carbonbased (Duosphere™). Continence has been shown to be improved in some patients. Recent studies have suggested that sacral nerve stimulation (see below) probably improves continence even in the presence of a sphincter defect.

16 Faecal incontinence (leakage of stool)

Neurogenic incontinence Aetiology A global weakness of the anal sphincter and pelvic floor muscles is a common cause of severe incontinence requiring surgery. This condition was previously known as ‘idiopathic incontinence’, but new methods of investigation have shown that the sphincter weakness is due to an injury to the distal part of the nerve supply to the anal sphincter and pelvic floor muscles. The nerve supply to the external anal sphincter is via the pudendal nerve (arising from S2–S4 sacral segments). The puborectalis and levator ani (pubococcygeus) muscles are supplied by direct branches from the sacral nerve plexus (S3, S4) (Fig 16.12). During vaginal delivery there is marked descent of the pelvic floor with stretching of the pudendal and sacral nerves, and a temporary reversible nerve injury occurs in some cases. Somatic nerves can normally withstand a stretch injury of up to 12% of their length and it has been calculated that stretching of 20% may occur during vaginal delivery. In the majority of cases, the neuropraxia resolves over a 6-week period, but a permanent injury remains in others. This may not result in muscle weakness immediately, but as the pelvic floor muscles age, particularly after menopause, a cumulative weakness develops, leading to incontinence.

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Factors shown to be associated with nerve damage are prolonged second stage of labour, forceps delivery and high infant birth weight. In addition to vaginal delivery, chronic straining at stool due to constipation has a similar effect by causing a repeated stretch injury to the pelvic nerves. Women who have a combination of multiple vaginal deliveries and chronic constipation are, therefore, particularly likely to develop neurogenic incontinence. It can be seen that since direct sphincter trauma and neurogenic muscle weakness are both associated with difficult vaginal delivery, these two conditions may co-exist in some women. Recognition of this dual pathology has important implications for surgical treatment in many cases. Clinical features On examination, the sphincter is found to be shortened and gaping, and voluntary squeeze is found to be reduced to absent. The puborectalis sling is lax and there is loss of posterior support of the anus. Anorectal manometry and electrophysiology will confirm the abnormalities. Treatment Initial treatment is with stool bulking agents such as psyllium, in combination with loperamide (Imodium™), which firms the stool and also directly stimulates the internal anal sphincter.

Figure 16.12  Pudendal nerve supply to the external anal sphincter; sacral nerves to the puborectalis muscle. From Henry MM, Swash M. Coloproctology and thepelvicfloor. London: Butterworths; 1985, with permission from the publisher.

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Incontinence

Endoanal ultrasound Manometry

Normal sphincter

Neurogenic weakness

Sphincter trauma

PTQ Sphincter repair

Diet change Loperamide

Graciloplasty

Success

Postanal repair Sacral nerve stim

Success

Failure

Failure Stoma

Caecostomy irrigation

Figure 16.13  Incontinence algorithm.

Biofeedback may be used, where the patient is taught to contract the external sphincter muscle more effectively by showing the patient sphincter pressure measurements during physiotherapy exercises. If this is not successful, sacral nerve stimulation may be effective. In this procedure an electrode is placed trancutaneously under x-ray control into the S3 or S4 sacral foramin. The electrode is connected to a stimulator that is implanted subcutaneously in the gluteal region. This has a success rate of over 70% in carefully selected patients. Alternative surgical treatment is a procedure in which the left and right limbs of the puborectalis muscle are plicated posterior to the external sphincter (postanal repair). This has the effect of increasing the functional length of the anal sphincter and improving the efficacy of the puborectalis. This operation does not reverse the denervation process and merely realigns the weakened muscles to create a high-pressure sphincter zone. Over 50% of patients achieve satisfactory restoration of continence. In selected patients in whom these procedures fail, or when there is a severe anatomical deficiency of the sphincter ring following sphincter trauma, and severe incontinence persists, the gracilis

neosphincter can then be considered. In this procedure the gracilis muscle is mobilised from the thigh and wrapped around the weak anal sphincter to create a functioning neosphincter. A further surgical option for the treatment of incontinence is antegrade colonic irrigation. This involves placing a caecostomy tube via the appendix (if present) or caecum. The patient is taught to irrigate the colon regularly (e.g. daily) while on the toilet until the colon is evacuated, thereby preventing soiling during the course of the day. If all measures fail and incontinence is severe, formation of a stoma may be offered. The treatment of faecal incontinence has multiple options, and treatment must be based on a sound clinical history and examination, assisted by tests of anorectal physiology. An algorithm for treatment is shown in Figure 16.13.

Key Points History ll

ll

Nature of incontinence (involuntary soiling or urgency with difficulty deferring defecation), duration and frequency. Risk factors for incontinence: obstetric (perineal or sphincter tear, long second stage of labour),

16 Faecal incontinence (leakage of stool) anal surgery such as fistulotomy, or perineal trauma; rectal prolapse; elderly; diarrhoea; neurological conditions.

Examination ll

ll

A weak patulous anus indicates internal sphincter weakness; reduced muscle squeeze indicates external sphincter weakness. Look for an underlying cause, such as anal fissure, prolapsing haemorrhoids or rectal prolapse.

Investigations ll

ll

Endoanal ultrasound and manometry are the critical tests to determine whether or not the anal sphincters are functioning normally or are weak, and whether they are anatomically intact. If the incontinence has come on suddenly and recently, then mucosal pathology such as malignancy or inflammatory bowel disease should be excluded.

Management ll

ll

Ensure the stools are not very loose and use antidiarrhoeal medications. These are best taken prophylactically in the morning on a regular basis (it is not helpful to take an antidiarrhoeal tablet after the event). Treat any underlying cause, such as haemorrhoids or rectal prolapse.

ll

ll

ll

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Sphincter defects may be treated with a sphincter repair, or injectable bulking silicone agents of sacral nerve stimulator. Neurogenic incontinence may be treated with biofeedback, postanal repair or sacral nerve stimulation. If incontinence is severe and treatments fail, then a colostomy is a good option of last resort.

Further reading Bartlett L, Ho YH. PTQ™ anal implants for the treatment of faecal incontinence. Br J Surg 2009; 96:1468–1475. Jarrett ME, Varma JS, Duthie et al. Sacral nerve stimulation for faecal incontinence in the UK. Br J Surg 2004; 91:955–961. Keighley MRB, Williams NS. Faecal incontinence. In: Keighley MRB, Williams NS, eds. Surgery of the anus, rectum and colon. 3nd edn. London: WB Saunders; 2008:591–692. Leung FW, Rao SSC. Fecal incontinence in the elderly. Gastroenterol Clin N Am 2009; 38:503–511. Madoff RD, Parker SC, Varma MG, et al. Faecal incontinence in adults. Lancet 2004; 364:621–632. Mander BJ, Wexner ML, Williams NS, et al. Results of a multicentre trial of the electrically stimulated gracilis neoanal sphincter. Br J Surg 1999; 86:1543– 1548. Norton C, Chelvanayagam S, Wilson-Barnett J, et al. Randomized controlled trial of biofeedback for fecal incontinence. Gastroenterology 2003; 125:1320– 1329.

17 Loss of appetite and loss of weight

Case A 64-year-old man presents with a 3-month history of upper abdominal pain associated with weight loss and mild diarrhoea. He describes the pain as a dull ache and, on specific questioning, says it radiates straight through to the back. The pain is sometimes made worse by eating, and comes and goes. He has lost about 8 kilograms in the last 3  months. He has had, up to three times daily, loose stools which are more smelly than normal, but are not pale and flush away without difficulty. He has lost his appetite. He has not noticed dark urine or pale stools. There is no history of arterial or venous thrombosis or embolism. An upper endoscopy 1 month ago was normal based on the report brought by the patient. He is an ex-smoker, having ceased 10 years ago. He has otherwise been in good health. There is no family history of gastrointestinal disease. Physical examination is unremarkable. In particular, there are no palpable masses in the abdomen, no lymphadenopathy in any region, no jaundice, no signs of deep venous thrombosis, and no obvious skin lesions (specifically no nodular fat necrosis). Because of the alarm features (recent unexplained weight loss with anorexia, and new onset of abdominal pain), a computed tomography (CT) scan of the abdomen is ordered. A low-density solid mass in the head of the pancreas that is 3 cm in greatest dimension is identified, with dilatation of the pancreatic duct. The tumour does not appear to extend beyond the pancreas and does not involve the coeliac axis or superior mesenteric artery; no regional lymph nodes are identified. There is no evidence of distant metastases in the liver or elsewhere. A Ca-19-9 level is normal. Although the imaging is typical for pancreatic cancer, an IgG4 level is measured to test for autoimmune pancreatitis; this is not elevated. The patient is

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referred to a surgeon with special experience in pancreatic disease for consideration of resection. An endoscopic ultrasound is performed to ensure the patient is suitable for curative surgery and, following this test and full discussion of the risks and benefits, the patient undergoes a Whipple's procedure. Although the patient makes an excellent postoperative recovery, he expires 9 months later from metastatic pancreatic adenocarcinoma.

Introduction Body weight is normally constant despite changes in energy expenditure. The energy value of food is a measure of its capacity to produce heat and is expressed in terms of kilocalories per gram (kcal/g). The energy values of carbohydrates (4.1 kcal/g), proteins (5.6 kcal/g), and fats (9.4  kcal/g) differ significantly. Body mass index (BMI, in kg/m2) is calculated by the weight (in kilograms) divided by the square of the height (in metres). Someone with a BMI below 18.5 is considered underweight. Anorexia refers to a loss of appetite. Appetite is a desire or inclination to satisfy one's natural need for food. This is different from hunger, which is an uneasy or painful sensation caused by lack of food. Hunger may persist despite a loss of appetite. Satiation or satiety is a sensation of satisfaction experienced after adequate intake of food. Weight loss is defined as a state when the caloric output (from the basal metabolic rate and voluntary activities) exceeds the input. Weight loss that equals or exceeds 5% of body weight (or 4.5  kg) over a 6-month period is arbitrarily defined as clinically significant. Most individuals can sustain a loss of 5–10% of their body weight without any significant health consequences. In a hospital or institutional setting, patients who have lost weight have increased morbidity and mortality, particularly elderly patients and cancer

17 Loss of appetite and loss of weight patients. Those who have lost 5 kg or more in the preceding 6 months also have an increased postoperative morbidity and mortality.

Pathophysiology of Anorexia and Weight Loss Anorexia Food intake is regulated by complex central and peripheral mechanisms. The central mechanisms act via the hypothalamus. There are two hypothalamic centres: 1. the hunger or feeding centre, situated in the lateral hypothalamus; 2. the satiety centre, situated in the ventromedial hypothalamus. Destruction of the brain's feeding centre can result in failure of the person to eat, leading to starvation and death. Conversely, injury to the satiety centre can lead to hyperphagia (exaggerated appetite) and obesity. Satiation signals that are multiple (and redundant) help lead to the cessation of food intake. During meals, signals arising from the gastrointestinal tract (from gastric distension and intestinal hormone release including cholecystokinin [CCK], glucagon-like peptide [GLP-1] and peptide YY) help lead to meal cessation by inducing satiation, probably acting via sensory nerves travelling to the hindbrain. Additional adiposity signals (from body fat itself such as leptin, and hormones released in response to a meal such as insulin) circulate to the brain and interact with these other signals to regulate meal size. On the other hand, there are few known signals that control the initiation of meals (orexigenic signals) although increased ghrelin (from the stomach and duodenum) precedes increased food intake, and probably acts via the vagus nerve and directly on the brain. Anorexia alone is not a symptom of diagnostic value and can occur in many gut and systemic diseases (Box 17.1). Anorexia should be differentiated from ‘sitophobia’, which is a term used to describe a fear of food because of subsequent abdominal pain. Sitophobia can occur with chronic mesenteric vascular insufficiency (abdominal angina) or small intestinal Crohn's disease with partial obstruction. Anorexia should also be distinguished from early satiation (a feeling of fullness after eating a small amount such that a normal meal cannot be finished), such as occurs after a partial gastrectomy and in patients whose gastric fundus fails to relax

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Box 17.1  Selected causes of anorexia Gastrointestinal tract/liver Gastric outlet obstruction or small bowel obstruction ll Gastric cancer ll Hepatic metastases ll Acute viral hepatitis Metabolic ll Addison's disease ll Hypopituitarism ll Hyperparathyroidism Functional ll Extremely unpleasant sight/smell Systemic ll Chronic pain ll Renal failure ll Severe congestive heart failure ll Respiratory failure Psychiatric ll Depression ll Anorexia nervosa Medications ll Digoxin ll Narcotic analgesics ll Diuretics ll Antihypertensives ll Chemotherapeutic agents ll Amphetamines Miscellaneous ll Excessive smoking ll Excessive alcohol intake ll Oral cavity disease ll Thiamine deficiency ll Early pregnancy ll Hypogeusia or dysgeusia ll

(e.g. after a vagotomy, and in some patients with functional dyspepsia).

Weight loss Involuntary weight loss is a common manifestation of a variety of disease processes (Table 17.1). Although the precise pathophysiological mechanisms inducing weight loss are unclear, multiple factors have been implicated. Cancer patients may be unable to eat or may not feel like eating (secondary to treatment or depression). Failure to down-regulate energy expenditure in the face of decreased caloric intake can lead to energy imbalance, which may be one of the main mechanisms of weight loss in some

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Table 17.1 Selected causes of weight loss Cause

Examples

Medical conditions Malignancy

Carcinoma of the pancreas, stomach, oesophagus, colon, liver, lung, breast, kidney

Gastrointestinal and liver disease

Malabsorptive states, inflammatory bowel disease, secondary to dysphagia, pancreatitis, hepatitis

Cardiovascular disease

End-stage heart failure

Respiratory disease

End-stage respiratory failure

Renal disease

Chronic kidney disease

Endocrine disease

Hyperthyroidism (and hypothyroidism-induced anorexia in elderly patients), hyperparathyroidism, diabetes mellitus, panhypopituitarism, Addison's disease, phaeochromocytoma

Connective tissue Scleroderma, rheumatoid arthritis disease Infections

HIV, tuberculosis, pyogenic abscess, infective endocarditis, atypical Mycobacterium, systemic fungal infections

Neurological disease

Stroke, dementia, Parkinson's disease

Drugs

Amphetamines, cocaine, opiates, serotonin reuptake inhibitors

Psychiatric conditions Depression Anorexia nervosa Bulimia nervosa Alcoholism Neurolepticwithdrawal Miscellaneous conditions Oral disorders

Ill-fitting dentures, candidiasis, gingivitis

Hyperemesis gravidarum

cancers. Increased caloric utilisation by tumour tissue may also be a factor, although increases in resting energy expenditure have not been shown to occur in all patients with tumours. In the acquired immune deficiency syndrome (AIDS), poor oral

intake, malabsorption, tumour development and repeated infections coupled with a relatively high resting energy expenditure may all have a role. In elderly people, preferential oxidation of fatty acids and an increase in anaerobic glucose metabolism result in inefficient expenditure or wastage of adenosine triphosphate. At a molecular level, various mediators may be important in promoting loss of weight. Tumour necrosis factor (TNF) is a cytokine produced from activated lymphocytes and macrophages in cancer patients or in patients with emphysema or severe heart failure; in animal studies it gives rise to anorexia and weight loss. Pentoxifylline, an inhibitor of TNF, can reverse the above effects in animal studies. Interleukin-1, IL-1-beta and IL-6 are potent anorexic cytokines, increasing resting energy expenditure and promoting skeletal wasting. Although reductions occur from both adipose tissue and muscle (lean mass) in weight loss, the extent from each source can differ. Obese people lose less lean mass than those who are not obese. In uncomplicated starvation, fat tissue is selectively depleted to spare muscle proteins. However in patients with AIDS or cancer, weight loss occurs predominantly from the muscle compartment.

Clinical Approach to Anorexia and Weight Loss The differential diagnosis is extensive (Box 17.1 and Table 17.1), but investigations should be directed by the history and physical examination.

History Determine whether the problem is acute or chronic and when it began. Enquire about any loosening of the patient's clothes or changes in belt size. Also ask whether weight loss is ongoing. Previous records or photographs may be helpful for comparison. There are rare situations in which patients claim to have lost weight without having done so. Next, determine the patient's appetite and eating habits. Ask about the number of meals per day and their composition, and usual daily physical activity. About one-third of patients with involuntary weight loss plus anorexia have a cancer; up to a quarter have no cause uncovered by tests. Depression is a common cause of weight loss. Weight loss does not always accompany anorexia. Patients may actually have weight loss with an increase in appetite in malabsorption, hyperthyroidism, uncontrolled diabetes mellitus,

17 Loss of appetite and loss of weight phaeochromocytoma or occasionally with lymphoma or leukaemia. Ask about other gastrointestinal symptoms. For example, recurrent vomiting may indicate bowel obstruction, while dysphagia may suggest oesophageal cancer. The occurrence of diarrhoea immediately after eating can occur in patients with a high intestinal fistula or malabsorption. Ask whether the patient is afraid to eat because eating precipitates pain or other gastrointestinal symptoms. Abdominal pain that usually occurs after eating suggests peptic ulcer disease, chronic pancreatitis or chronic mesenteric ischaemia (abdominal angina). Pain after eating may also occur in patients with the irritable bowel syndrome or functional dyspepsia (Chs 6 and 7). In elderly patients, poor dentition is a common but often overlooked problem. Oral disease resulting from conditions such as vitamin deficiencies, candidiasis or gingivitis can affect mastication. Ask about alterations in taste (dysgeusia), which may make food seem unpalatable. Zinc deficiency may sometimes be responsible for dysgeusia (Ch 3). A detailed current drug history is important. Various medications, including digoxin (especially in toxic doses), amphetamines, chemotherapeutic agents and narcotic analgesics, can cause anorexia and associated nausea and vomiting, which may lead to subsequent weight loss. It is important to look up the side effects of drugs being taken if you are unsure. Ask about previous medical conditions (e.g. pulmonary tuberculosis, renal disease, previous cancer, cardiac disease) and past surgery. Postgastrectomy syndromes can cause malabsorption (Ch 6). Prior abdominal surgery causes adhesions that can lead to chronic incomplete intestinal obstruction. Cigarette smoking and alcohol use may be important (e.g. due to the associations with lung and other cancers and cirrhosis, respectively). The patient's involvement in high-risk behaviour may be relevant (e.g. acquisition of HIV infection). Ask about social isolation and symptoms of depression (including depressed mood, apathy, insomnia, fatigue, feelings of worthlessness, diminished ability to think and suicidal ideation). Depression, not malignancy, is the most common cause of weight loss in elderly patients and institutionalised patients, and is often missed. It may not always present in its ‘typical’ form. Ask about body image and self-induced vomiting; anorexia nervosa and bulimia nervosa are important causes of weight loss in young people.

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Physical examination Weigh the patient and measure the patient's height, then calculate the BMI. Milder degrees of weight loss can exist with little or no wasting. In severe weight loss, muscle wasting will usually be obvious—look particularly at the temporalis, deltoid and quadriceps muscles. Body fat loss is suggested by hollowness of the cheeks and buttocks, and by subcutaneous fat content on pinching a fold of skin. Measure the waist circumference—locate the upper hip bone and the top of the right iliac crest. Place the tape in a horizontal plane around the abdomen at the level of the iliac crest; make sure it is snug (but not too tight), is parallel to the floor and the patient has expired normally before taking the reading. In overweight adults (BMI 25 to 34.9 kg/m2), a waist circumference greater than 102 cm for men (or 88 cm for women) is associated with a greater risk of heart disease and metabolic syndrome. Assess hydration status and look for fluid overload (oedema). Examine for specific features of vitamin and mineral deficiencies (Table 17.2). Glossitis, cheilosis or perioral dermatitis can result from deficiency of vitamins such as riboflavin, pyridoxine or niacin, whereas peripheral neuropathy or ataxia can occur due to lack of thiamine or vitamin B12. Next, conduct a careful gastrointestinal examination. For instance, in a patient with weight loss and jaundice (Ch 23), a pancreatic cancer with biliary obstruction may be the explanation. If stigmata of chronic liver disease are present and abdominal examination reveals a liver mass with or without a bruit, cirrhosis with development of a hepatoma should be considered. Large abdominal masses can occasionally compress the stomach or small bowel, inducing anorexia (Ch 19). Look for other clues on the general examination. Although usually not pathognomonic, they can help direct investigations of a particular organ system. For instance, clubbing may suggest the presence of co-existing chronic lung infection or cancer, whereas lymphadenopathy could point towards a possible lymphoma, metastatic cancer or chronic infection. In a febrile patient, the presence of a newly detected murmur may suggest a diagnosis of infective endocarditis, whereas localised bony tenderness could occur in osteomyelitis or with bone metastases.

Investigations The diagnostic work-up needs to be directed towards defining the extent of malnutrition and detecting the underlying cause of weight loss.

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Last name: First name: Middle initial: Sex: Date: Age: Weight (kg): Height (cm): Complete the form by writing the points in the boxes. Add the points in the boxes, and compare the total assessment to the malnutrition indicator score.* Points Anthropometric assessment Points 12. Selected consumption markers 1. Body mass index for protein intake: (weight in kg ÷ (height in m)2): a. < 19 = 0 points a. At least one serving of dairy products b. 19 to < 21 = 1 point (milk, cheese, yogurt) per day: c. 21 to < 23 = 2 points yes no d. > 23 = 3 points b. Two or more servings of legumes or eggs per week: 2. Midarm circumference: yes no a. < 21 cm = 0 points c. Meat, fish or poultry every day: = 0.5 point b. 21 to 22 cm yes no c. > 22 cm = 1 point 0 or 1 yes answers = 0 points 3. Calf circumference: 2 yes answers = 0.5 point a. < 31 cm = 0 points 3 yes answers = 1 point = 1 point b. ≥ 31 cm 13. Consumes two or more servings of fruits 4. Weight loss during past 3 months: or vegetables per day: a. > 3 kg = 0 points a. No = 0 points b. Does not know = 1 point b. Yes = 1 point c. 1 to 3 kg = 2 points d. No weight loss = 3 points 14. Decline in food intake over the past 3 months General assessment 5. Lives independently (not in nursing home or hospital): a. No = 0 points b. Yes = 1 point

because of loss of appetite, digestive problems, or chewing or swallowing difficulties: a. Severe loss of appetite = 0 points b. Moderate loss of appetite = 1 point c. No loss of appetite = 2 points

6. Takes more than three prescription drugs per day: a. Yes = 0 points b. No = 1 point

15. Cups of fluid (eg, water, juice, coffee, tea, milk) consumed per day (1 cup = 8 oz): a. < 3 cups = 0 points b. 3 to 5 cups = 0.5 point c. > 5 cups = 1 point

7. Has suffered psychologic stress or acute disease in the past 3 months: a. Yes = 0 points b. No = 1 point

16. Mode of feeding: a. Needs assistance to eat b. Self-fed with some difficulty c. Self-fed with no problems

8. Mobility: a. Bed-bound or chair-bound b. Able to get out of bed or chair, but does not go out c. Goes out

Self-assessment 17. Does the patient think that he or she has nutritional problems? a. Major malnutrition = 0 points b. Moderate malnutrition or does not know = 1 point c. No nutritional problem = 2 points

= 0 points = 1 point = 2 points

9. Neuropsychologic problems: a. Severe dementia or depression = 0 points b. Mild dementia = 1 point c. No psychological problems = 2 points 10. Pressure sores or skin ulcers: a. Yes b. No

= 0 points = 1 point

Dietary assessment 11. How many full meals does the patient eat daily? a. One meal = 0 points b. Two meals = 1 point c. Three meals = 2 points

= 0 points = 1 point = 2 points

18. How does the patient view his or her health status compared with the health status of other people of the same age? a. Not as good = 0 points b. Does not know = 0.5 point c. As good = 1 point d. Better = 2 points

Assessment total (maximum of 30 points):

*

*Malnutrition indicator score: ≥ 24 points = well nourished; 17–23.5 points = at risk for malnutrition; < 17 points = malnourished.

Figure 17.1  Mini nutritional assessment. Reproduced with permission from Guigoz, Y, Vellas, B, Garry, PJ. Assessing the nutritional status of the elderly: The Mini Nutritional Assessment as part of the geriatric evaluation. Nutr Rev 1996; 54(1 Pt 2):S59. Copyright © 1996 International Life Sciences Institute.

17 Loss of appetite and loss of weight Tests to estimate nutritional status Nutritional assessment helps to identify patients who are more likely to develop complications from their malnutrition and, hence, likely to benefit from supportive nutritional therapy. Assessment can be either clinical or based on laboratory tests and measurements. Calculate the BMI (Box 17.2). Other anthropometric measurements include triceps skin-fold thickness and mid-arm muscle circumference to assess the fat reserve and the muscle mass of the body, respectively. These quantitative measurements are useful for follow-up of nutritional status. The subjective global assessment is based on the history and clinical findings. The degree of recent weight loss, dietary alterations, symptoms, the level of physical activity and stress due to illness (metabolic demand) is gauged from the history. Examination subjectively assesses the amount of fat reserve, muscle mass and oedema or ascites. Patients are then classified into one of three groups:

A—well-nourished: eating well and gaining weight again even if there is muscle wasting; B—mild to moderate (or suspected) malnutrition: moderate (5–10%) weight loss that continues, continued low intake, progressive functional impairment, and moderate stress due to illness; C—severe malnutrition: severe weight loss (over 10%), poor intake, progressive functional impairment, and muscle wasting.

Laboratory tests that detect decreases in serum albumin or lymphocyte count (under 1.5 × 109/L (under 1500/mm3)) are crude but helpful estimates of nutritional status. Estimation of proteins with a shorter half-life, such as transferrin or prealbumin, should be undertaken if enteral or parenteral nutrition is being considered. Vitamin levels (e.g. fat-soluble vitamins A, D and K) need to be checked in patients with suspected severe malabsorption (e.g. pancreatic insufficiency). To determine adequate protein intake, nitrogen balance can be assessed by estimating the protein intake and urinary urea nitrogen excretion. To assess adequate caloric intake, energy expenditure can be calculated using the Harris-Benedict equation, if weight, height and age are known. To determine lean body mass and total body fat, body composition can be simply measured using bioelectrical impedance. The prognostic nutritional index predicts the likelihood of developing postoperative complications in patients undergoing gastrointestinal surgery. It is based on a simple

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Box 17.2  Classification of nutritional status by body mass index (BMI) < 16.0 16–16.9 17–18.4 18.5–24.9

Severely malnourished Moderately malnourished Mildly malnourished Normal

linear equation incorporating measurements of serum proteins (albumin and transferrin concentration), subcutaneous fat (triceps skin fold), and immunologic function (delayed skin hypersensitivity). In the elderly, the mini-nutritional assessment is a valid tool that allows subdivision of patients into nourished, malnourished or at risk of malnutrition (Fig 17.1). Tests aimed at detecting the cause Diagnostic tests can be arbitrarily classified into those of a screening nature and those that target specific abnormalities detected by the history, physical examination or initial screening test results (Table 17.3). The tests are most successful in finding the cause when they are directed by the history and examination findings. Routine tests are inexpensive, and may help to identify the basic nature of the problem. A full blood count can detect evidence of iron deficiency anaemia, which may suggest blood loss from a gastrointestinal tract cancer. A high erythrocyte sedimentation rate or C-reactive protein may suggest inflammation or malignancy. Electrolyte and creatinine tests can identify chronic kidney disease as a cause of anorexia. Liver function tests can be helpful (e.g. elevated transaminase levels in hepatitis, obstructive jaundice due to pancreatic cancer or hypoalbuminaemia in malignancy or chronic liver disease). A serum calcium may detect hypercalcaemia caused by a malignancy. A bedside urine analysis may detect proteinuria (e.g. nephrotic syndrome) or haematuria. In the absence of infection or stones, persistent haematuria may indicate renal or bladder cancer. A positive result of a stool occult blood test may indicate colorectal neoplasia or inflammatory bowel disease, but this test has low sensitivity and specificity and is less often done (Ch 10). If malabsorption is suspected, then an appropriate work-up should be done (Ch 14). A thyroid-stimulating hormone test will detect hyperthyroidism and fasting blood sugar level test, diabetes mellitus. Tumour markers may occasionally help point towards a correct

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Table 17.2  Clinical findings associated with vitamin and mineral deficiencies Findings on physical examination

Associated vitamin deficiencies

Mucocutaneous Dermatitis/cheilosis/glossitis

Riboflavin (B2), pyridoxine (B6), niacin

Bleeding/swollen gums

Vitamin C

Petechiae/ecchymoses

Vitamins C and K

Perifollicular haemorrhages/ keratitis

Vitamin C

Rash (face/body: pustular, bullous, vesicular, seborrhoeic, acneiform), skin ulcers, alopecia

Zinc

Neurological Peripheral neuropathy

Thiamine/vitamin B12, chromium, vitamin E

Dementia/confusion

Thiamine/niacin, zinc, manganese

Night blindness

Vitamin A

Ophthalmoplegia

Thiamine

Haematological Pallor (anaemia)

Vitamin B12/folic acid, iron, copper

Miscellaneous Dysgeusia

Zinc

Fractures

Vitamin D

Loosening of teeth, periosteal haemorrhages

Vitamin C

Cardiac failure/cardiomyopathy

Thiamine, selenium

Hypothyroidism

Iodine

diagnosis in difficult cases but are of most use in following response to treatment (Box 17.3). A chest x-ray examination is relatively inexpensive and an adjunct to the clinical examination. It is mandatory in the presence of pulmonary symptoms (e.g. to detect pulmonary tuberculosis or primary lung cancer) or if routine tests are unhelpful. A silent mass lesion, infiltrative process or lymphadenopathy may be detected on the chest x-ray film. CT scans of the chest and abdomen provide excellent anatomical definition and objective

assessment which is not operator dependent. They are extremely useful for defining mediastinal and retroperitoneal pathologies. Mediastinal widening seen on chest x-ray films in small cell lung cancer, lymphoma or thymoma can be delineated further with a chest CT scan. Similarly, metastatic lymph notes in the mesentery or in the retroperitoneum, or organomegaly detected on clinical examination can be accurately defined by an abdominal CT scan. Although CT should be reserved for localising a suspected lesion, this test is increasingly used for screening when no diagnosis is forthcoming. Ultrasound examination can provide valuable information about biliary anatomy or pelvic pathology (Ch 19). Mammography should be done in women if breast cancer is a consideration. Gastroscopy and colonoscopy have replaced barium examination as the gold standard for visualising the upper and lower gastrointestinal tract. In patients with altered bowel habits or microcytic anaemia thought to be due to chronic gastrointestinal blood loss, endoscopy is the procedure of choice for detection of underlying pathology (e.g. gastric or colorectal cancer). Barium examinations still have a role to play in screening the small bowel (e.g. Crohn's disease). Fine needle aspirations are useful for pathological confirmation of suspected lesions in organs such as the liver. Test yield Evaluation will reveal a cause for weight loss in 75% of cases. The most common causes are depression and cancer. In one-quarter of patients, despite detailed examination and exhaustive tests, the aetiology remains elusive. In such cases, it is prudent to adopt a wait-and-see approach since the diagnosis may become obvious within the next 6–12 months.

Management of Patients with Weight Loss A summary of an approach is presented in Figure 17.2. Identification and treatment of the underlying medical or psychiatric cause remains the cornerstone of management. It is also important to provide patient support and education; cancer is a feared diagnosis and late-stage cancer even more so. Revision of dentures may be required in older patients. Treatment of infection or review and cessation of unnecessary medication may be all that is required in individual cases. Chemotherapy for malignancy may help to alleviate anorexia and cachexia secondary to cancer. Adequate pancreatic enzyme supplements should be prescribed

17 Loss of appetite and loss of weight

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Table 17.3 Investigations for weight loss and examples of diseases to consider Diagnostic test

Examples of diseases screened

Bedside tests Urine analysis

Renal cell cancer

Laboratory tests Routine Full blood count and iron studies

Iron deficiency anaemia from gastrointestinal blood loss

Folate/vitamin B12

Macrocytic anaemia in bacterial overgrowth

Electrolytes

Chronic kidney disease, Addison's disease

Liver function tests

Chronic liver disease

Calcium/phosphate

Hyperparathyroidism, bony metastases

Erythrocyte sedimentation rate or C-reactive protein

Autoimmune disease, inflammatory bowel disease, malignancy

Specific Anti-nuclear antigen

Autoimmune disease, e.g. systemic lupus, scleroderma

Rheumatoid factor/anti-cyclic citrullinated peptide

Rheumatoid arthritis

Thyroid function tests

Hyper/hypothyroidism

Tumour markers

(See Box 17.3)

Imaging tests Chest x-ray

Lung cancer, tuberculosis

Barium studies of small bowel/small bowel capsule/ enteroscopy

Crohn's disease

CT scan chest/abdomen/pelvis Magnetic resonance cholangio-pancreatography

Empyema, lung/ovarian/liver cancers Bile duct/pancreatic cancer

Invasive tests Gastroscopy, colonoscopy

Peptic ulcer, oesophagus/stomach/colon cancers

Endoscopic retrograde cholangiopancreatography

Pancreatic cancer, cholangiocarcinoma, ampullary tumour

Laparoscopy, laparotomy

Crohn's disease, internal malignancies

Fine needle aspiration

Liver/breast/thyroid/lymph node cancers

for patients with pancreatic insufficiency. Optimal control of underlying colitis as well as improvement in nutritional status are required in patients with inflammatory bowel disease. Occasionally, it may be useful to admit a patient to hospital for medical and nursing supervision in order to observe the individual's eating habits closely. Self-induced vomiting in bulimic patients, surreptitious laxative abuse in patients with difficult to diagnose ‘diarrhoea’ or food faddism, and avoidance of food in anorexic patients may only then become obvious. Empiric therapy has a place in stimulating appetite and increasing weight in patients with

end-stage cancer and AIDS. Cyproheptadine, a serotonin antagonist, has been extensively used in both adults and children and may be of benefit in a few cases. Corticosteroids have an established role in stimulating appetite and improving the sense of well-being in patients with malignancies. However, steroids have side effects and do not usually result in non-fluid weight gain (e.g. increased muscle bulk). Megesterol is a synthetic progestin that is an antiemetic with an appetitestimulating effect. It is helpful in increasing oral food intake and non-fluid weight gain in patients with AIDS. This medication is usually well tolerated but is expensive.

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Box 17.3  Causes of elevated levels of tumour markers Carcinoembryonic antigen Colon cancer (higher levels if the tumour is more differentiated or is extensive, or has spread to the liver) ll Lung cancer, breast cancer, seminoma ll Cigarette smokers ll Cirrhosis, inflammatory bowel disease, rectal polyps, pancreatitis ll Advanced age Alpha fetoprotein ll Hepatocellular cancer: very high titres or a rising titre is strongly suggestive, but over 10% of patients do not have an elevated level (and not usually elevated in fibrolamellar carcinoma, a variant of hepatocellular cancer) ll Hepatic regeneration e.g. cirrhosis, acute or chronic viral hepatitis (especially hepatitis C) ll Cancer of the stomach, colon, pancreas or lung ll Testicular germ cell cancer (non-seminoma, not ever elevated in a seminoma), ovarian germ cell cancer ll Pregnancy ll Ataxia telangiectasia ll Normal variant Cancer-associated antigen (CA-19-9)* ll Pancreatic carcinoma (80% with advanced, well-differentiated cancer have an elevated level) ll Other gastrointestinal cancers: colon, stomach, bile duct ll Acute or chronic pancreatitis ll

Nutritional Support In patients who cannot or will not eat, nutrition can be provided by enteral or parenteral feeding. Malnourished patients who cannot maintain an adequate intake, especially those already with a significant negative nitrogen balance, require nutritional support. Although it is possible to adequately replenish nutrition with total parenteral nutrition (TPN), the associated higher costs, increased medical and nursing needs and complications make the enteral route the preferred choice in all circumstances. Enteral nutrition also has a beneficial effect on intestinal cells, providing the necessary fuel (e.g. glutamine, volatile fatty acids) for promoting intestinal integrity. A specific indication for enteral feeding is to establish early small bowel adaptation following massive resection. Hence, the enteral route is physiological

Chronic liver disease Biliary tract disease or acute cholangitis CA-125 ll Ovarian cancer ll Endometrial cancer ll Pancreatic or colon cancer ll Benign diseases e.g. cirrhosis, colitis, diverticulitis, endometriosis, uterine leiomyoma, pelvic inflammatory disease ll 1% of healthy women Beta-hCG (human chorionic gonadotrophin) ll Choriocarcinoma and embryonal cell carcinoma ll Seminoma (uncommon) ll Ovarian germ cell cancer ll Trophoblastic differentiation of a lung or gastric primary cancer ll Pregnancy or gestational trophoblastic disease (females) ll Hypogonadal state (false positive due to luteinising hormone cross-reactivity) ll Marijuana use Prostate-specific antigen ll Prostate carcinoma (localised disease) ll Prostatic hyperplasia ll Prostatitis ll Prostatitic infarction ll ll

*Patients who cannot synthesise Lewis blood group antigens (~5% of the population) do not produce CA-19-9 antigen.

and allows greater flexibility: if the gut works, use it.

Enteral feeding Enteral feeding is achieved by means of feeding tubes placed either transnasally or percutaneously with the distal end lying in the stomach or the small intestine. Feeding via a nasogastric tube, which can be placed easily at the bedside, is the preferred route for short-term enteral feeding. However, on account of local irritation, it is often inadvertently or deliberately removed by patients. The mode of nutrient delivery can either be continuous (constant rate over 24 hours) or intermittent (boluses of 300–400 mL over 5– 10 minutes, every few hours). The entire feeding can be done over 12–16 hours during the night allowing freedom during the day.

17 Loss of appetite and loss of weight

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Document weight loss (4.5 kg [10 lb] or > 5% in ≤ 12 months)

Appraisal of biopsychosocial factors Chief complaints Medications Systems review Diet Medical history Social factors Surgeries Mental status* Tobacco/alcohol use

Physical examination Appearance Cardiovascular Mood/affect Pulmonary Skin/lymphatics Abdomen/rectum Musculoskeletal Genital/pelvic Breasts/prostate Neurology (+ MMSE)

Targeted diagnostic studies Stop if aetiology identified Pursue standard screening tests if indicated

Laboratory: Chest radiograph Stool haemoccult

Laboratory : Stool: Other:

Standard tests CBC/diff, MCV, chemistries (electrolytes, glucose, calcium, phosphorus), BUN, creatinine, AST ALT, Alk Phos, bilirubin, ESR/CRP, TSH, UA

Additional considerations Iron studies, B12, folate, serum protein electrophoresis, zinc, endomysial antibody, fat-soluble vitamins, HIV Fat collection, leukocytes, etc. Pap smear, mammography, PSA

Gastroenterologic evaluation Consider investigation of upper and lower gut (based on symptoms) Radiographic contrast studies vs upper and lower endoscopy Clinical situation dictates testing (e.g. diarrhoea or anaemia → endoscopy + biopsies)

Assess test results and re-evaluate patient

Treat patient based on specific findings/diagnoses

Perform specialised tests if clinically indicated (see Table 17.3)

For negative evaluations, establish follow-up in 3–6 months

Figure 17.2  Stepwise approach to patients with unintentional weight loss. Alk Phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood cell count; CRP = C-reactive protein; diff = white blood cell count differential; ESR = erythrocyte sedimentation rate; HIV = human immunodeficiency virus; MCV = mean corpuscular volume; MMSE = Mini-Mental State Examination; Pap = Papanicolaou; PSA = prostate-specific antigen; TSH = thyroid-stimulating hormone; UA = urinalysis. * Depression inventories may be useful. Adapted from Bouras E, Lange S, Scolapio J. Rational approach to patients with unintentional weight loss. Mayo Clinic Proceedings 2001; 76(9):923–929 with permission.

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Nasoduodenal/jejunal tubes have the added advantage of bypassing the stomach, thereby overcoming problems related to delayed gastric emptying. It is also useful when avoiding pancreatic stimulation is required, for example in patients recovering from severe acute pancreatitis. Placement of a nasoenteric tube beyond the pylorus may require pharmacological assistance (e.g. intravenous metoclopramide or erythromycin) or endoscopic/fluoroscopic assistance (e.g. over the wire placement). With nasoduodenal/jejunal tubes, continuous feeding is usually required to avoid diarrhoea and discomfort from small bowel distension. Percutaneous enteric gastrostomy (PEG) tubes, placed via an upper endoscopy, are well tolerated. They are indicated for long-term enteric feeding in patients unable to eat long term, such as those with a defective swallowing apparatus from neurological disease (e.g. stroke, advanced Parkinson's disease or motor neurone disease) or occasionally with oesophageal disease (e.g. advanced oesophageal carcinoma). A PEG is relatively contraindicated in patients with a previous gastrectomy and may be difficult in a patient with a midline abdominal scar from other surgery. The procedure-related mortality is approximately 1%; major procedure complications occur in 3% (e.g. perforation of a viscus, sepsis or haemorrhage) and minor procedure complications in 15% (e.g. local infection post procedure, tube dislodgment, blockage, gastrointestinal bleeding, epistaxis and nasal mucosal ulceration). Operative placement (surgical jejunostomy) is considered only when other methods are not possible or complications supervene. Diarrhoea is a common complication of enteral feeding. Causes include high osmotic load, sorbitol-based compounds, and use of antibiotics leading to altered bacterial flora. Decreasing the osmolality and infusion rate, avoiding sorbitol or magnesium-based compounds, increasing dietary intake of lactobacillus, stopping antibiotic therapy, or regularly using diphenoxylate or loperamide may be helpful in individual cases. Another specific problem associated with nasogastric or nasoenteric feeding is gastrooesophageal reflux. Aspiration is also an important complication. Patients with symptomatic aspiration (e.g. aspiration pneumonia) may benefit from elevation of the head end of the bed during and post feeding, and the avoidance of bolus feeding. If aspiration occurs with a PEG despite the incorporation of the above regimen, a revision to jejunostomy tube feeding should be considered. Placement of the tube beyond the pylorus reduces,

but does not overcome, this complication. The main indications for use of jejunostomy feeding over gastrostomy include tracheal aspiration, gastroparesis and a partial or total gastrectomy.

Total parenteral nutrition While the enteral route is always preferable, total parenteral nutrition (TPN) is required when anatomical or physiological abnormalities of the gut preclude enteral feeding. In clinical practice, the most common indications are protracted periods of non-functioning bowel (e.g. major abdominal sepsis). Short gut syndrome occurs infrequently, but requires long-term TPN. Preoperative TPN is of no benefit in healthy patients or even those with mild-to-moderate malnutrition. Indications for TPN are summarised in Box 17.4. TPN formulae contain a mixture of proteins (4.5–10% amino acids), carbohydrates (25–70% dextrose), fat (lipid emulsions), electrolytes, vitamins and trace elements. The daily protein requirement is around 1.5–2.0 g/kg/day. Glucose is the main energy substrate used, providing approximately 50% of daily calorie requirement. Lipids can be infused 2–3 times per week (500 mL; 10% lipids) as a source of essential fatty acids, or infused daily as a calorie source delivering about 40% of the patient's non-nitrogen calorie requirement. The latter form of infusion minimises catabolism of endogenous proteins and provides an alternative source of calories. It also avoids the metabolic complications that may result from the usage of a higher concentration of glucose (e.g. hepatic steatosis and hyperglycaemia). The usual requirement for sodium is 1–2 mmol/kg/ day and potassium is 1 mmol/kg/day. Electrolyte requirements are guided by serum concentrations. Box 17.4  Indications for total parenteral nutrition ll

ll

ll

ll

ll ll

Postoperative (bowel surgery, protracted recovery) Severe inflammatory bowel disease (complicated ulcerative colitis, severe Crohn's disease with malabsorption) Acute radiation enteritis or chemotherapy enteritis Enterocutaneous fistula involving the small bowel Short gut syndrome Preoperative (severely malnourished patients only when enteral nutrition is not possible)

17 Loss of appetite and loss of weight Diarrhoea, vomiting or high output fistulae necessitate additional supplementation. Multivitamins and trace elements are usually provided in standard amounts on a daily to weekly basis. Additional care must be exercised in patients with specific organ failure (e.g. hepatic or renal failure). Complications related to TPN can be either local (related to insertion and maintenance of the central venous catheter) or systemic (related to the infusion itself). In patients receiving TPN, local defence barriers may break down, allowing bacterial colonisation and systemic seeding. Strict asepsis and insertion by experienced personnel, followed by patient education in the care of the line, should minimise local complications. Long (peripherally inserted central catheter) lines placed through, for example, the brachial vein to just above the right atrium can be left in place up to a year before needing replacement. As metabolic derangements are frequent, close monitoring by a dedicated TPN team is preferable. The complications are summarised in Box 17.5. The refeeding syndrome occurs with overly aggressive nutritional replacement. Severe hypophosphataemia occurs because carbohydrates given enterally or intravenous glucose stimulates insulin, leading to phosphate shifts into cells. Irritability and hyperventilation followed by profound muscle weakness, acute rhabdomyolysis, seizures and respiratory failure (from diaphragm paralysis) then death can occur. Box 17.5  Complications of total parenteral nutrition Local (central vein catheter) Pneumothorax/haemothorax ll Venous thrombosis ll Air embolus ll Local infection and septicaemia ll Thrombophlebitis Systemic ll Hyper/hypoglycaemia ll Electrolyte disturbances Refeeding syndrome ll Azotaemia and hyperosmolarity ll Liver dysfunction (hepatocellular or cholestatic) and fatty liver ll Acalculous cholecystitis ll Cholelithiasis (long-term therapy) ll Vitamin or mineral deficiency (rare) ll Metabolic bone disease (rare) ll

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Alcoholics who are malnourished are at particular risk; the refeeding syndrome can then occur after starting a normal diet. It is therefore very important to give adequate supplemental phosphate in these settings unless renal function is impaired.

Diseases Associated with Weight Loss Some common gastrointestinal cancers, and anorexia and bulimia nervosa are discussed here. Other diseases are covered elsewhere (e.g. malabsorption: Ch 14).

Adenocarcinoma of the pancreas Adenocarcinomas arising from ductal cells constitute 90% of all cases of pancreatic cancer. Islet cell tumours, acinar cell tumours, and cystadenocarcinomas account for most of the remaining 10% of cases (see Ch 26). The incidence appears to be on the increase, with carcinoma of the pancreas being the second most common gastrointestinal malignancy (after colon cancer). Pathogenesis The exact aetiopathogenesis is unclear. It is rare before age 45 years and is more common in men and people of African descent. Increasing age (over 60 years) is a risk factor. Chronic pancreatitis and hereditary chronic pancreatitis (autosomaldominant due to a mutation in the cationic trypsinogen gene (PRSS1), Ch 6), and some familial cancer syndromes (e.g. Peutz-Jeghers syndrome) are of established importance. Smoking, diabetes mellitus, obesity, increased dietary fat, partial gastrectomy and Helicobacter pylori are also risk factors. There is no convincing evidence that coffee intake is a causal factor. Clinical features It usually manifests in elderly people and, unfortunately, often at an advanced stage. The initial symptoms and signs can be non-specific, but anorexia, weight loss and upper abdominal pain are common features. Pain occurs in 75% of patients and weight loss is present in almost all patients. The pain is usually an epigastric dull ache, which may radiate through to the back. Weight loss is primarily due to anorexia, although malabsorption may also contribute. Gastric outlet obstruction with vomiting may occur. With the exception of jaundice, other symptoms are often insidious and delay diagnosis. Jaundice due to biliary obstruction is found in the majority of patients with cancer of the

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pancreatic head. Pruritus is often associated. The gall bladder is usually enlarged in patients with cancer of the pancreatic head, but is impalpable in more than 50% (Courvoisier's law: if the gall bladder is enlarged and the patient is jaundiced, the cause is unlikely to be gallstones) (Fig 17.3). New onset diabetes mellitus, migratory thrombophlebitis (Trousseau's sign), venous thrombosis and acute pancreatitis are uncommon presentations of carcinoma of the pancreas. Upper gastrointestinal haemorrhage can rarely result from direct invasion of stomach or duodenum, or from varices due to compression of the portal venous system or involvement of the splenic vein. Diagnosis The diagnosis is initially suggested by demonstrating a mass in the pancreas or by dilated bile ducts. On ultrasound scan, this is characteristically hypoechoic. On CT scan, the mass is usually of reduced density compared with the rest of the pancreas. If the tumour is in the head of the pancreas, it commonly produces dilatation of the common bile duct and the main pancreatic duct (the double-duct sign). Lymphatic metastases may be apparent as masses in the porta hepatis. Liver metastases may also be apparent. Helical CT combined with intravenous contrast (CT angiograph) helps evaluate for resectability.

Figure 17.3  Enlarged palpable gallbladder in a patient with carcinoma of the head of the pancreas.

Endoscopic ultrasound (EUS) is useful to make a tissue diagnosis of a small tumour and to assess resectability. While tissue diagnosis can be achieved by CT or ultrasound-guided needle biopsy it has the disadvantage that the tumour might seed the needle track and this track will not be excised by subsequent surgery. This is not the case for an EUS-guided biopsy. If the tumour is obviously unresectable (e.g. obvious vascular involvement of a portal vessel or superior mesenteric artery or vein, or metastases), the issue of seeding the track is irrelevant. Magnetic resonance cholangiopancreatography will define the pancreatic duct anatomy non-invasively. Look for a long extrinsic compression of the common bile duct; the pancreatic duct may also be compressed. An endoscopic retrograde cholangiopancreatography (ERCP) can be done to stent biliary obstruction if surgery is to be avoided. A tissue diagnosis at ERCP is possible for ampullary carcinoma by biopsy and for cholangiocarcinoma by brush cytology. Histological diagnosis is mandatory for confirmation of the tumour and to rule out focal pancreatitis, autoimmune pancreatitis or other neoplasms, such as lymphoma, islet cell tumours and cystadenocarcinoma, where the prognosis and therapeutic options are significantly different (Ch 26). The cancer-associated antigen (CA-19-9) is often elevated in advanced disease. Occasionally, a small (under 2 cm) tumour is demonstrated without evidence of lymphatic or liver metastases in a patient who is young and fit enough to be considered for a major pancreatic resection. Further evaluation is warranted to show that the tumour is resectable and that there are no metastases that have failed to be demonstrated by CT and ultrasound scan. A contrast-enhanced helical CT scan with thin cuts may detect small liver metastases, or encasement of the gastroduodenal artery or superior mesenteric vein or portal vein, demonstrating that the tumour is not resectable. Laparoscopy may demonstrate small peritoneal or liver metastases. If the mass appears resectable after all imaging, many surgeons will operate without a preoperative tissue diagnosis. Treatment Curative surgical resection (e.g. pancreaticoduodenectomy, i.e. a ‘Whipple’ resection) is the only effective treatment for the disease. Operative mortality in experienced hands is low (2–5%). Unfortunately, fewer than 15–20% of all tumours are resectable at the time of diagnosis. The 5-year

17 Loss of appetite and loss of weight survival rate after curative operation is below 30% for node-negative and 10% for node-positive patients. Even in patients who eventually have tumour recurrence, the survival is prolonged threeto fourfold (to a median of 17–20 months) compared with patients not undergoing resection. Untreated non-metastatic pancreatic cancer has a median survival of about 8–12 months (and 3–6 months if there are metastases). Adjuvant chemotherapy alone after resection may improve survival. The main aim of palliative therapy should be relief of jaundice. This can usually be achieved by endoscopic insertion of a biliary stent. This is attractive because it avoids an operation. If the patient seems likely to survive for more than 6 months, an expanding metal stent (internal diameter 10 mm) can be used rather than conventional 3-mm plastic stent, which tends to block with sludge and needs changing every 3 months. Surgical biliary bypass (choledochojejunostomy) is rarely performed these days except in patients operated on with curative intent who are found at operation to be unresectable. In that circumstance a gastroenterostomy can be performed at the same time. Otherwise the 10% of patients who develop gastric outlet obstruction will usually be palliated with an expanding metal uncovered duodenal stent. Chemotherapy and radiotherapy have not been shown to be very effective, increasing median survival by only a few months in locally advanced cancer. In those with hereditary chronic pancreatitis, screening for pancreatic cancer is recommended from age 35 years. Similarly, those with a family history of pancreatic cancer can be offered screening 10 years before the age at which the cancer was diagnosed. Spiral CT or EUS are recommended in these cases, but the tests are not very sensitive in this setting. Cystic lesions of the pancreas found by crosssectional imaging that have a high potential for malignancy include the following: 1. intraductal papillary mucinous neoplasm (dilated ductal segments usually seen in the head of the pancreas with thick mucus; these need close follow-up and surgical resection is indicated if the lesion is causing symptoms, the main pancreatic duct is dilated (10 mm or over), the cyst size is 30 mm or over, or cyst fluid cytology is positive for malignancy); 2. mucinous cystadenoma (most often found in middle-aged women in the body or tail of the pancreas—the treatment is surgery); 3. serous cystadenoma (often a large lesion but low malignant potential—resect if enlarging or symptomatic);

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4. papillary cystic neoplasm (often young women but rare; locally aggressive).

Islet cell pancreatic neoplasms A gastrinoma will cause peptic ulcer disease as part of the Zollinger-Ellison syndrome (Ch 6), and can be found in the pancreas (25%) or duodenum (50%). Two-thirds of cases with a vasoactive intestinal polypeptide secreting tumour occur in the pancreas and over 50% are malignant; this causes a severe secretory diarrhoea (‘pancreatic cholera’). An insulinoma causes hypoglycaemia, but is very rare (insulin and C-peptide are both high during hypoglycaemic episodes). A glucagonoma is also very rare but has a distinctive presentation: it causes weight loss, hyperglycaemia and a scaly red rash (necrolytic erythema).

Carcinoma of the oesophagus Squamous cell carcinoma and adenocarcinoma account for more than 90% of all cases of oesophageal tumour. Smoking, excess alcohol and ingestion of nitrites and fungal toxins have been causally linked to the development of squamous cell carcinoma. Achalasia, Plummer-Vinson syndrome (cervical and oesophageal web and iron deficiency anaemia) and previous lye ingestion also increase the risk. Adenocarcinomas arise from the distal oesophagus in metaplastic segments of columnar epithelium (Barrett's oesophagus). The incidence of adenocarcinoma of the distal oesophagus has risen sixfold in the past 20 years. Gastro-oesophageal reflux disease and obesity are risk factors. Clinical features Weight loss and progressive dysphagia for solids are the initial symptoms in most patients. Dysphagia progresses later on to include semisolids and liquids. Progressive dysphagia is, therefore, always an alarm symptom and mandates appropriate investigation, usually upper endoscopy (see Ch 2). Unfortunately, however, diagnosis at this stage often indicates incurable disease. Diagnosis Endoscopy helps to delineate the nature and the extent of the lesion, and biopsies will usually confirm the diagnosis. The tumour spreads initially through the wall of the oesophagus and then via lymphatics to adjacent lymph nodes. Once the diagnosis is confirmed histologically, tumour extent is ascertained by a CT scan of the chest and upper abdomen and subsequently by positron emission tomography (PET) scanning. PET whole-body

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scanning is more sensitive for distant metastases than CT, detecting bony as well as liver and lung metastases and also metastases in totally unexpected positions. EUS is being used increasingly for additional regional staging. Thus, it is possible to assess how far through the oesophageal wall the tumour has penetrated and whether enlarged local perioesophageal lymph nodes have been infiltrated by the tumour. Nodal involvement is more reliably ascertained by fine needle aspiration biopsy of one or more of those nodes. Treatment Apart from early oesophageal cancers (e.g. those detected during Barrett's screening [see Ch 1] that are treated by curative surgery), the prognosis is generally poor (the 5-year survival rate is about 5% for all patients, but as high as 20% for patients selected for surgical resection). Nevertheless, surgery offers the only hope of cure and, as long as the tumour can be resected with clear margins, this achieves the best palliation. Preoperative chemoradiotherapy has been shown to improve the disease-free interval and possibly survival. Unfortunately, many patients are too old or frail to tolerate this approach. In those unsuitable for surgery by a specialist oesophageal surgeon, palliation of dysphagia can be achieved by placement of an expandable metal stent. Palliative chemotherapy and radiotherapy have limited roles.

Gastric carcinoma There has been a significant decline in the incidence of gastric carcinoma in many Western countries, yet overall it remains one of the most common causes of cancer-related deaths in the world. The incidence is highest in Japan, followed by China, South America and countries in Eastern Europe. It is rare under the age of 40 years. Pathology Adenocarcinoma accounts for the majority (over 90%) of gastric carcinomas (Fig 17.4). Lymphomas account for most of the remainder. Adenocarcinomas can be further classified histologically into intestinal and diffuse types. The intestinal type is characterised by cohesive neoplastic cells, which form gland-like structures and are frequently polypoid. The diffuse cancers lack cohesion, are usually ulcerative and develop throughout the stomach. Adenocarcinomas are also staged into early and advanced cancers. In early cancers, the depth of invasion is limited to the submucosa; if detected early, gastric cancer is potentially curable with resection.

Figure 17.4  Gastric adenocarcinoma of the stomach.

Aetiology Chronic atrophic gastritis, which begins as a multifocal process, can progress in those predisposed to intestinal metaplasia and dysplasia. This sequence can ultimately lead to cancer. H. pylori is classified as a class I carcinogen by the World Health Organization; it causes chronic atrophic gastritis and is linked to gastric adenocarcinoma, mucosa-associated lymphoid tissue (MALT) lymphoma and B-cell lymphoma. Patients with H. pylori infection have a higher risk (three- to sixfold) of developing noncardia gastric adenocarcinoma. Other risk factors for gastric cancer are listed in Box 17.6. Changes in multiple oncogenes and tumour suppressor genes (e.g. MCC, APC and DDC) have been identified in gastric cancer. Clinical features Gastric cancer in its early stages is asymptomatic and is diagnosed either incidentally or through a screening program. With symptomatic presentation, advanced disease is often already present. The key symptoms are upper abdominal pain and weight loss. Anorexia and nausea also occur in about one-third of patients. Lesions around the cardia can present with dysphagia as the predominant symptom. Typically gastric carcinomas spread to local lymph nodes and/or the liver. Diagnosis Gastroscopy with biopsy is the standard method for diagnosing gastric cancer. To increase the accuracy, multiple biopsies (more than 5) are recommended.

17 Loss of appetite and loss of weight Box 17.6  Risk factors for gastric adenocarcinoma Genetic factors ll Blood group A ll Family history ll Hereditary non-polyposis colon cancer syndrome Environmental factors ll Low socioeconomic status ll Decreased consumption of fresh fruits and vegetables, and vitamin C ll Increased consumption of salted or smoked foods Precursor conditions ll H. pylori gastritis ll Pernicious anaemia (autoimmune chronic atrophic gastritis) ll Ménétrier's disease ll Gastric polyps (usually adenomatous, occasionally hyperplastic) ll Previous partial gastrectomy

All gastric ulcers should be biopsied to rule out the presence of neoplasm. The tumour is staged prior to surgery first by CT scanning looking for lymph node metastases, liver metastases and ascites, then by laparoscopy to detect smaller liver and peritoneal metastases. PET is also used as an adjunct, as it is in assessment of oesophageal tumours. Treatment Complete surgical resection of the tumour (and adjacent lymph nodes) is the only chance for a cure. In distally located tumours, the distal stomach is removed. For proximally located tumours, the whole stomach and sometimes the distal oesophagus are removed. Adjuvant chemoradiotherapy has recently been shown to be beneficial. Surgery may also afford a means of palliation in patients with gastric outlet obstruction or significant gastrointestinal bleeding. Combination chemotherapy can be used to palliate some nonsurgical candidates with advanced gastric cancers. However, the medial survival with combination chemotherapy is only 6–10 months, and is toxic. Prognosis The most important determinant of prognosis is stage. In early gastric cancer, the incidence of lymph node involvement is about 10%, and the 5-year survival is about 75%. On the other hand, advanced gastric cancer (with serosal involvement)

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will have spread to lymph nodes in about 70% of cases and has a dismal 5-year survival rate of 5%.

Other gastric tumours Gastric carcinoid These are rare. They grow slowly, rarely metastasize, and rarely cause the carcinoid syndrome. The aetiopathogenesis is related to any chronic high gastrin state. Carcinoids are classified as follows: type 1 is found in association with pernicious anaemia (autoimmune gastritis); type 2 in Zollinger-Ellison syndrome (gastrinoma); and type 3 is spontaneous (associated with vitiligo). Proton pump inhibitors have not been found to be a cause. Gastrointestinal stromal tumours Gastrointestinal stromal tumours (GIST) are rare mesenchymal tumours that may cause mass effects, or lead to bleeding, pain or obstruction. They can occur anywhere in the gastrointestinal tract, but the stomach is most often involved; they most often metastasise to the liver. ‘Carney's triad’ comprises a gastric GIST with a paraganglioma, and a pulmonary chondroma, usually in young women. At upper endoscopy, a submucosal mass bulging into the gastric lumen with smooth margins and normal overlying mucosa is typically seen; EUS and fine needle aspiration or biopsy are often needed to make the diagnosis. All GISTs 2 cm in size or larger should be resected if possible. Approximately 80% of GISTs have mutations in the KIT proto-oncogene; tyrosine kinase inhibitors such as imatinib halt tumour proliferation, and this is used as adjuvant therapy for lesions at high risk of metastatic disease.

Anorexia nervosa While usually affecting young women, anorexia nervosa can also affect men. It is characterised by a distortion of body image. The disorder has been increasing over the last few decades with a prevalence in Western society of approximately 3%. It has been noted that patients with anorexia, over time, may exhibit symptoms of bulimia (see below). Clinical features Young females in the pubertal age group are at the greatest risk. Amenorrhoea is usually present. A history of food fads, food avoidance, excessive use of purgatives or diuretics and selfinduced vomiting is common. Mental irritability, depression or agitation can co-exist. The menstrual cycle is absent for three or more cycles. These patients typically manifest an extreme loss of fat and muscle bulk, leading to gaunt faces, atrophic

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breasts and loss of body contour. Hypotension, hypothermia and bradycardia may also be evident. Lanugo (soft, down-like hair), dry skin and brittle nails are common. Pathogenesis Distorted body image is a central abnormality; even extremely thin and emaciated patients consider themselves to be overweight, inducing them to self-starvation. There exists an association between anorexia and major depressive illnesses, as well as obsessive-compulsive behaviour, personality disorders and substance abuse. There is a tendency for these patients to be high achievers and perfectionists. Complications The medical complications arise from starvation. Hypokalaemia, hypochloraemia and metabolic alkalosis are typical (Table 17.4). Cardiac complications are the most frequent cause of death in these patients. Prolongation of the Q-T interval is thought to predict the onset of serious cardiac arrhythmias. As glucose metabolism and insulin secretion are disturbed, hypoglycaemia is common and potentially lethal. Osteopenia from oestrogen deficiency is common and can lead to debilitating fractures. Treatment A multidisciplinary approach is required. Outpatient therapy is increasingly employed. Intense cognitive therapy and psychotherapy Table 17.4  Laboratory findings that may occur in patients with anorexia nervosa Investigation

Finding

Endocrine investigations

Low gonadotrophin (FSH and LH) levels Low oestrogen and testosterone levels Sick euthyroid state Increased cortisol level

Metabolic investigations

Hypokalaemia, metabolic alkalosis Hypocalcaemia, hypomagnesaemia, hypophosphataemia Hypoglycaemia Prerenal azotaemia

Haematological investigations

Anaemia, pancytopenia Low plasma protein levels

are the mainstays of treatment. Oral feeding is usually commenced in small amounts but occasionally parenteral nutrition may be needed in dire circumstances. Patients may resort to vomiting, purging, or surreptitious disposal of food or medications. Hospitalisation and a supervised feeding program are needed in patients with moderate to severe disease (where the body weight is below 75% of ideal weight). Such patients mostly require prolonged hospital admission (average: 60–90 days) to achieve full nutritional rehabilitation. Malnourished patients are less responsive to tricyclic antidepressants and more likely to develop side effects, especially arrhythmias and hypotension; they should be used only when depression is not improving despite weight gain. Selective serotonin reuptake inhibitors are useful for reducing relapse. Cyproheptadine, an appetite stimulant, is of little benefit. Antipsychotics may have a role in some patients. Approximately 20% of patients have a relapse and 10–20% die as a result of ventricular arrhythmias, opportunistic infections, suicide or starvation. An equal number remain chronically ill. Prognosis is worst in those with later onset of disease.

Bulimia nervosa Bulimia nervosa is the most common eating disorder. Self-induced vomiting follows excessive gorging. Women outnumber men by about 20:1. They have a sense of a lack of control over their eating behaviour, and are overly concerned with their weight and shape. For diagnosis, a minimum of two bulimic episodes per week for 3 months is required, with regular purging behaviour, such as self-induced vomiting or the use of laxatives and diuretics. Unlike anorexic patients who are cachectic, these patients have fluctuations in body weight due to alternately bingeing and fasting. Gastro-oesophageal reflux and Mallory-Weiss tears can occur. Abuse of laxatives or diuretics is common. Clinical features Bulimic patients have a tendency to hide their illness. Body weight is usually near normal and only about 50% of patients have amenorrhoea. The following signs may sometimes be present: ll Russel's sign: repeated mechanical trauma to the skin over the dorsum of fingers and metacarpophalangeal joints, leading to erosions and callused knuckles due to self-induced vomiting; ll painless swelling of salivary glands (sialadenosis); and

17 Loss of appetite and loss of weight dental caries and erosion of enamel caused by high acid content in vomit. Hypokalaemia and metabolic alkalosis (from vomiting or laxatives) may be present. ll

Treatment As with anorexia nervosa, a similar multidisciplinary approach is necessary. Pharmacotherapy has a greater role to play and often higher doses of medications are required. Fluoxetine (up to 60 mg/day) has been best studied, but only one-third of patients go into remission. A combination of an antidepressant plus cognitive behavioural therapy appears to be better (up to 50% remission). Individuals who have milder symptoms at the commencement of treatment tend to have a better prognosis than those individuals who are disabled and functioning poorly at the start of treatment. Additionally, other indicators of poor prognosis include premorbid personality disturbance, low self-esteem, impulsiveness and persistent body image dissatisfaction.

Key Points ll

ll

ll

ll

ll

ll

ll

ll

Body mass index (BMI, in kg/m2) is calculated by the weight (in kilograms) divided by the square of the height (in metres). A person with a BMI below 18.5 is underweight. ‘Sitophobia’ describes a fear of food because of subsequent abdominal pain. This occurs with chronic mesenteric vascular insufficiency (abdominal angina). About one-third of patients with involuntary weight loss plus anorexia have a cancer; up to a quarter have no cause uncovered by tests. Causes of weight loss with an increase in appetite include malabsorption, hyperthyroidism, uncontrolled diabetes mellitus, lymphoma and phaeochromocytoma. Depression, not malignancy, is the most common cause of weight loss in elderly patients and institutionalised patients. In the elderly, the mini-nutritional assessment is a valid tool that allows subdivision of patients into nourished, malnourished or at risk of malnutrition. Empiric therapy for stimulating appetite and increasing weight with end-stage cancer and AIDS includes cyproheptadine, a serotonin antagonist, corticosteroids and megesterol. In patients who cannot or will not eat, the enteral route is the preferred choice in all circumstances: if the gut works, use it.

ll

ll

ll

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Percutaneous enteric gastrostomy (PEG) tubes are indicated for long-term enteric feeding in patients unable to eat long term, such as those with a defective swallowing apparatus from neurological disease. Diarrhoea is a common complication of enteral feeding. Decreasing the osmolality and infusion rate, avoiding sorbitol or magnesiumbased compounds, increasing dietary intake of Lactobacillus spp., stopping antibiotic therapy, or regularly using diphenoxylate or loperamide may be helpful. Aspiration is an important complication of any tube-based enteral feeding including PEG. Patients may benefit from elevation of the head end of the bed during and post feeding, and the avoidance of bolus feeding.

Further reading Attia E, Walsh BT. Behavioral management for anorexia nervosa. N Engl J Med 2009; 360:500–506. Bouras EP, Lange SM, Scolapio JR. Rational approach to patients with unintentional weight loss. Mayo Clin Proc 2001; 76:923–929. Fuccio L, Zagari RM, Eusebi LH, et al. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann Intern Med 2009; 151:121–128. Hernandez JL, Matorras P, Riancho JA, et al. Involuntary weight loss without specific symptoms: a clinical prediction score for malignant neoplasm. QJM 2003; 96:649–655. Katz MH, Mortenson MM, Wang H, et al. Diagnosis and management of cystic neoplasms of the pancreas: an evidence-based approach. J Am Coll Surg 2008; 207(1):106–120. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340:825–831. Madeddu C, Macciò A, Panzone F, et al. Medroxyprogesterone acetate in the management of cancer cachexia. Expert Opin Pharmacother 2009; 10(8):1359–1366. Messing B, Joly F. Guidelines for management of home parenteral support in adult chronic intestinal failure patients. Gastroenterology 2006; 130(2 Suppl 1): S43–S51. Penman ID, Henry E. Advanced esophageal cancer. Gastrointest Endosc Clin N Am 2005; 15:101–116. Rolland Y, Kim MJ, Gammack JK, et al. Office management of weight loss in older persons. Am J Med 2006; 119:1019–1026. Steinhausen HC, Weber S. The outcome of bulimia nervosa: findings from one-quarter century of research. Am J Psychiatry 2009; 166:1331–1341. Visvanathan R, Chapman IM. Undernutrition and anorexia in the older person. Gastroenterol Clin North Am 2009; 38(3):393–409. Yager J, Andersen AE. Clinical practice. Anorexia nervosa. N Engl J Med 2005; 353:1481–1488.

18 Food allergies and intolerance

Case A male aged 16 years presents complaining of abdominal bloating and diarrhoea for 1 month. This commenced following an outbreak of what was described as viral gastroenteritis in his boarding school. All the other pupils have completely recovered. His symptoms occur soon after eating or drinking. Specific inquiry reveals that milk or milk products appear to exacerbate his symptoms of bloating and diarrhoea. He has lost approximately 2 kg weight. Physical examination was normal. A lactose tolerance test was positive. This was confirmed by a positive lactose breath hydrogen test. Following a consultation with a dietician he commenced on a lactose-free diet using soy products to substitute for milk. He has remained symptom-free.

Introduction Many patients who present with gastrointestinal symptoms—particularly abdominal pain, diarrhoea and abdominal distension—complain of food-induced symptoms and believe that they are ‘allergic to food’. In some of these individuals there is food intolerance secondary to an underlying disease such as lactose malabsorption. However, the majority of patients have a functional gastrointestinal disorder, in which the mechanism of the perceived food intolerance is obscure. Only a minority of the apparently food-intolerant individuals will subsequently be found to be truly reacting adversely to components of the food they eat and rarely will this reaction be of an immunological (allergic) nature. Adverse food reaction can be broadly based into two categories. The first category is

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immunologically mediated adverse reactions to foods. These particular reactions are unrelated to any physiological effect of the food or food additive, and are mediated by immunoglobulin E (IgE) antibodies and others result from non-IgEmediated mechanisms. The second category is food intolerance. These reactions include any adverse physiological response to a food or food additive that is not immunologically mediated, such as lactose intolerance or pharmacologically related adverse food reactions. The mainstay of management of food allergies and adverse reactions remains focused on avoidance of the allergenic or reactive foods. There have been recent multiple advances to various therapies that may eventually complement or even replace the main therapeutic approach, which is food avoidance.

A Clinical Approach History and physical examination The relationship of the gastrointestinal symptoms to meals needs to be determined. In true food allergy this commonly occurs soon after ingestion. Excessive bloating and diarrhoea suggests lactose intolerance. In functional gastrointestinal disorders, symptoms after meals are common but symptoms between meals are also frequent and often no food can be consistently blamed. The specific symptoms of irritable bowel syndrome should be sought (Ch 7). Individuals may react to the nutrients in food, such as protein, carbohydrate, fat, vitamins or minerals or to food additives. Foods that commonly cause reactions are summarised in Table 18.1. A physical examination is generally unhelpful, unless the patient is currently experiencing symptoms. Occasionally skin rashes or signs of

18 Food allergies and intolerance Table 18.1  Main foods that commonly cause gastrointestinal disturbances Food type

Common examples of trigger foods

Cereal grains

Wheat

Dairy products

Milk, cheese

Fruit

Citrus Fruit

Vegetables

Onions, capsicum

Miscellaneous foods

Coffee, eggs, chocolate

asthma are detected. It may be helpful in excluding other disorders. There are multiple approaches to elicit a history from individuals with adverse food reactions that are possibly due to an allergen. The suggested approach is to elicit three main elements from the history: 1. symptoms associated with adverse food reaction such as nausea, bloating, vomiting, itch; 2. possible reactive or triggering foods—peanuts, for example; 3. possible contributing factors that may have exacerbated the adverse reaction such as associated with concomitant drug therapy or associated with exercise. Note that allergic reactions to food have the potential for serious, even fatal, outcomes. Thus the highest priority is to elicit the symptoms of the allergic reaction if they can be identified. What are the symptoms involved with the allergic reaction? These can include the following common presentations: ll systemic symptoms—palpitations, dizziness, fainting and collapse; ll gastrointestinal symptoms—nausea, vomiting, diarrhoea and cramping abdominal pains; ll dermatological—urticaria, angio-oedema, flu­ shing, swelling or itching a few minutes after food; ll respiratory symptoms—stridor, wheeze, cough and dyspnoea. What was the onset of symptoms like? Was the onset acute or subacute? How rapidly did the symptoms occur after the ingestion of the allergen? IgE allergic reactions can typically occur within minutes, whereas non-IgE

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(cell-mediated) reactions tend to develop more gradually over hours to days. How severe was the allergic reaction on this occasion? All of the symptoms experienced should be documented and their severity explored. Did the patient require hospital admission with severe cardiorespiratory symptoms? If this is the case, this is usually an acute IgE-mediated reaction. Has this reaction occurred in the past? If so what was the severity grade then? If the patient had anaphylaxis requiring intramuscular adrenaline and treatment in an intensive care unit, this is likely to be a severe IgEmediated reaction. The patient's medical records should be requested and reviewed to confirm symptoms such as wheezing, flushing, stridor and collapse as patients may not be fully aware of these events.

Identification of Food Allergens It is important to accurately document the potential food allergens and their previous effects and reactions. Such documentation includes the following points: ll Develop a list of foods that may have caused the symptoms. Eggs, nuts and seafood are the usual suspects. ll Discuss the minimum quantity of food required to produce the symptoms. ll Explore the preparation of the relevant foods (raw, cooked, contaminated with another food additive, spices and so on). ll Explore the characteristic symptoms that the patient experiences on exposure to the relevant food.

Identification of contributing factors The questions below are potentially less helpful in identifying the offending allergen, but they may also provide the clinician with some additional information regarding the exacerbating factors to the allergic response: ll Did the patient receive any concurrent medications at the time of the allergic reaction? It has been reported that alcohol or anti-inflammatory agents may exacerbate the allergic reaction. ll Was the patient involved in any physical exertion before the reaction? Some reactions may be severe after physical exercise.

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Physical examination in the emergency department The initial examination to a patient presenting to an emergency department is to assess the severity of the condition and includes careful assessment of: A  Airway B  Breathing C  Circulation. To assess signs of severe anaphylaxis it is important to observe for cardiorespiratory compromise and dermatological manifestations, which include the following: ll acute respiratory complications: bronchospasm, stridor, wheeze, cyanosis; ll acute cardiovascular complications: tachycardia, hypotension, delayed capillary refill time, drowsiness; ll acute dermatological signs: angio-oedema, urticaria. If these features are present, immediate treatment should be instituted; see the sections on management below. The majority of food allergies present subacutely or chronically, so the preferred approach is to identify any possible manifestations of their allergy, for example dermatological symptoms, along with a detailed history as above. There are various symptoms of chronic diseases where a food allergy may be responsible; for example, atopic dermatitis has been associated in approximately 40% of infants or children with moderate to severe atopic disease.

Investigations Appropriate investigations may be needed to exclude other relevant diseases such as coeliac disease and inflammatory bowel disease or to confirm a suspicion of lactose intolerance. This is particularly important if there is evidence of weight loss or gastrointestinal tract bleeding. The specific features of immunologically mediated adverse food reactions and food intolerance are discussed below. Pathophysiology True allergic reactions of the hypersensitivity type are rare. In these circumstances, the offending agent is a specific food, such as eggs, nuts, milk or seafood. Food allergy reactions may be IgE-mediated, nonIgE-mediated or both. IgE-mediated antibodies are the most widely recognised mechanism of food hypersensitivity. Atopic patients can produce IgE antibodies to specific epitopes of the food allergen, which can then bind to high-affinity receptors in

the skin, gastrointestinal tract and respiratory tract. These then cause the release of inflammatory mediators including histamines, leukotrienes, prostaglandins and cytokines. These can then produce various tissues effects, including mucus production, vasodilatation, and smooth muscle contraction, thereby producing the symptoms associated with food allergen exposure. Most IgEmediated reactions are immediate reactions, so produce effects such as acute cutaneous symptoms or anaphylaxis. Non-IgE-mediated food allergies (mainly delayed Th2-type cell-mediated responses) are usually manifest by chronic skin or gastrointestinal complaints. The absence of reliable testing for nonIgE-mediated allergies has contributed to a poorer understanding of its pathogenesis. Those allergies that are associated with several diseases, such as eosinophilic oesophagitis, are not always due to primarily an IgE or non-IgE reaction but may be a combination of both. Food allergens are water-soluble glycoproteins resistant to heating and proteolysis with molecular weights of 10–70 kDa. These small proteins can be absorbed across mucosal surfaces, and many are well classified such as the common peanut allergens Ara h1, Ara h2 and Ara h3. Closely related foods frequently contain allergens that cross-react immunologically but less frequently cross-react clinically. There has been recent evidence that cross-reactive allergens have been identified in certain foods and airborne pollens. Incidence General surveys report that as many as 30% of households consider at least one family member to have an adverse food reaction. It has been estimated that between 20% and 30% of people report food allergies in themselves or their children. However ‘true’ food allergy is present in only 6% of children and in approximately 3% of adults. Morbidity and mortality associated with food allergies The symptoms of adverse food reactions are typically manifest in the gastrointestinal tract, skin and respiratory tract. The majority of symptoms of food allergies are mild and include various gastrointestinal symptoms such as bloating, abdominal pains and nausea. However, there have been multiple reports of severe anaphylactic reactions and death following the ingestion of certain foods. Fatalities can result from severe laryngeal oedema, bronchospasm, hypotension or a combination of all of these signs.

18 Food allergies and intolerance Investigations for food allergies There are several objective approaches to testing for food allergens which vary between clinicians and institutions. The following are brief descriptions of the main investigations used in an attempt identify food allergies. Skin-prick tests are performed with fresh fruits and vegetables by inserting the test device into the relevant fruit or vegetable and then pricking the patient's cleaned skin. This has been shown to be a more reliable method to detect allergies to fresh foods (apples, tomatoes and so on) than commercial testing with food extracts. Testing with fresh fruit and vegetables has a sensitivity of 95% and specificity of 50%. Skin testing with commercial food extracts may be more useful for sensitisation to peanuts or legumes which contain stable allergens. They are also useful to assess the systemic reactions to certain allergens, as they have been shown to be better to demonstrate systemic reactions than fresh extracts. IgE immunoassays are in vitro tests to detect foodspecific IgE, for example IgE radioallergosorbent testing. They can be useful in circumstances where IgE-mediated reactions are thought to be likely, such as in life-threatening anaphylaxis. This can provide similar information to skin-prick testing, but it is more expensive and less specific. As there are significant false positives and negatives, the test results should be considered in conjunction with a detailed clinical history. IgE immunoassays have a sensitivity of 95% and a variable specificity. Availability is limited to several major allergens: including egg, milk, fish and peanuts. Acute management of severe food allergic reactions If these features are present immediate treatment should be instituted with high flow oxygen, intravenous (IV) hydrocortisone, IV antihistamines, and/or intramuscular adrenaline (in cases of severe anaphylaxis with hypotension, laryngeal oedema or severe bronchospasm). The patient may need to be managed in an intensive care setting depending on the severity of their reaction and their recovery with the above management. Individuals who have been diagnosed with significant allergic reactions should be taught how to use a self-administered adrenaline injection and advised to always carry it with them. Pharmacological management of food allergies There have been recent developments in use of monoclonal antibodies to IgE in the management of suspected IgE-mediated food allergies.

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A randomised controlled trial found that an anti-IgE antibody can confer protection against unintended peanut ingestion in those with IgEmediated allergies in 75% of patients. This drug has been discontinued due to consensus agreements among pharmaceutical companies, but in the future anti-IgE antibodies may prove to be beneficial in those with moderate to severe food allergies. Oral immunotherapy has been the target of several studies as it may reduce the risk of side effects that are associated with subcutaneous route of administration. A randomised controlled trial that used the sublingual administration of hazelnut extracts demonstrated effectiveness with only minor systemic side effects. A similar study administered increasing doses of food allergens to children who had wheat, apple, milk, egg and fish allergies. This resulted in an 86% success rate in those patients who completed the treatment protocol, with only minor side effects. This therapeutic approach requires further study. The benefit appears to be achieved with a regular intake of the drug. Compliance may be a problem. There is also need for long-term outcome data with these therapies. Non-IgE-mediated food allergies are more difficult to diagnose and manage than IgEmediated allergies for several reasons. They are cell-mediated allergies and have a slow disease course compared to IgE-mediated reactions. The established tests of skin-prick testing and serum measurements of food-specific IgE levels are less sensitive in these allergies. This dictates that the overall management is different to IgEmediated allergies. The most widely studied nonIgE-mediated food allergy has been eosinophilic oesophagitis. This is characterised by oesophageal intraepithelial eosinophilic infiltration (Ch 2). Several therapeutic approaches have been studied for the management of eosinophilic oesophagitis. One of these is the use of an aminoacid-based formula. Several studies have shown that this can induce clinical symptomatic and histological remission in a paediatric population with eosinophilic oesophagitis. An elemental diet is an effective treatment for eosinophilic oesophagitis in children and adolescents. The limiting factor associated with this form of therapy may be compliance. Its taste is described as unpleasant and the volume required to be consumed is large. It imposes a dramatic change that is difficult for older children. Corticosteroids are the current mainstay of treatment in eosinophilic oesophagitis. Oral

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methylprednisolone was given for 4 weeks to 20 children with eosinophilic oesophagitis and resulted in a dramatic histological and clinical improvement in the vast majority of patients. However, systemic side effects of corticosteroids limit their use in this disease, particularly in a paediatric population. A different route of administration of corticosteroid, which involves ‘topical’ administration consisting of swallowed aerosolised fluticasone propionate, has been developed. A recent published randomised controlled trial performed over 3 months in paediatric patients with eosinophilic oesophagitis resulted in 50% histological remission in those who were treated with fluticasone, compared with 9% remission in placebo-treated patients. Troublesome side effects have been noted with this therapy. They include oesophageal candidiasis. Disease relapse was observed on their discontinuation. Dietary manipulation appears to have some success in treating eosinophilic oesophagitis. When food elimination based on skin-prick testing alone proved to be non-beneficial, one study demonstrated that elimination diets based on a combination of skin-prick testing and patch testing had a success rate of 77%. In an observational study, six foods thought to be highly allergenic were removed from the diet of patients with eosinophilic oesophagitis. These included egg, soy, wheat, peanut, milk and seafood. Improvement in oesophageal eosinophilia was observed in 74% of patients. Dietary manipulation may need to be considered in the future as a form of therapy, but failure to thrive in a paediatric population may preclude the use of this management.

Food Intolerance The non-allergenic intolerances to food are heterogeneous and can be divided into two main groups: lactose intolerance and pharmacologicallyrelated adverse food reactions as opposed to true ‘allergic food reactions’.

Lactose intolerance Lactose intolerance is a very common precipitant of food intolerance. Lactase is a brush border enzyme that splits the milk sugar, lactose, into glucose and galactose. Absence of this enzyme results in osmotic diarrhoea due to presence of unabsorbed lactose in the small bowel and colon. In the colon lactose is converted to hydrogen and short-chain fatty acids by the bacterial flora. There are three forms of lactase deficiency: 1. congenital lactase deficiency, which is present from birth and is very rare;

2. acquired lactase deficiency, which occurs in most non-milk-consuming populations around the world and develops in late childhood; and 3. secondary lactase deficiency, which occurs in situations where small bowel mucosal damage is present, such as postgastroenteritis and coeliac disease. Intolerance to lactose-containing foods is a common problem. In Europe and the United States it has been estimated that the prevalence is 7–20%, and is as high as 95% in Native Americans, 75% among Africans and African Americans, and 50% in Hispanics. Clinical symptoms of lactose intolerance include abdominal pains, diarrhoea and flatulence after ingestion of milk or milk-based products. These symptoms have been attributed to low intestinal lactase levels, which may be secondary to mucosa injury, or reduced genetic expression of the enzyme lactase-phlorizin hydrolase. Lactose intolerance can also co-exist with irritable bowel syndrome and their symptoms can be similar. The term ‘lactose malabsorption’ is generally reserved for those patients with typical symptoms in whom the intestinal malabsorption of lactose has been confirmed by a test of absorption or malabsorption. The lactose tolerance test measures the capacity for lactose absorption after the oral administration of a 50 g test dose in adults and sequential measurement of blood glucose levels. False-negative results can be seen in diabetes, bacterial overgrowth and abnormal gastric emptying. The lactose breath hydrogen test measures lactose malabsorption, by giving the patient oral lactose and measuring breath hydrogen at serial intervals. Both false-negative and positive results can occur with this test. A genetic test for the polymorphism associated with lactose intolerance has been developed with an acceptable sensitivity and specificity. Management of lactose malabsorption generally takes the form of three approaches: 1. reduced dietary lactose intake. The patient should be instructed to avoid lactose and in particular milk, ice-cream and cheese, which have high concentrations of lactose, for at least 2 weeks or until the symptoms resolve. Most patients can tolerate a daily intake of 240 mL of 2% fat milk, although spreading the lactose load throughout the day may be beneficial. 2. substitution of alternative nutrient sources to maintain energy and protein intake. The patient should consult with an appropriate

18 Food allergies and intolerance ­dietician for dietary advice to maintain an adequate lactose-free food intake. 3. administration of a commercially available enzyme substitute. This is a bacterial or yeast beta-galactosidase. It can reduce symptoms and breath-hydrogen values after ingestion of lactose-containing foods in lactose-intolerant patients.

Pharmacologically related adverse food reactions In many individuals there is no evidence of an allergic reaction or a specific enzyme-deficiency but the gut and other organs appear to react to one or more ingredients in the food ingested. In these situations reactions to food are often delayed from between 1 hour and 48 hours after ingestion. It is likely that reactions occur to more than one food, and reactions to each constituent may exhibit a dose-response relationship with a triggering threshold that depends partly on recent intake. Thus an individual food does not necessarily produce the same reaction on each occasion. This can result in a delay in diagnosis. Recurrent aphthous ulceration is infrequent but is characteristically found in salicylate-sensitive individuals. Upper respiratory tract symptoms such as nasal congestion, excessive mucus production, recurrent sore throats or sinusitis are common in those who react to dairy products. In some individuals these foods can precipitate asthma. Neurological symptoms are commonly present and are sometimes bizarre including headaches, general lethargy and myalgia. Patients may describe the sensation of feeling ‘drugged’ or ‘hungover’. When challenged by these foods they may note confusion, dizziness, paraesthesia, sweating, palpitations and flushing. Objective impairment of memory and concentration may be documented. These reactions cannot be diagnosed accurately by any available skin or blood test. The chemicals in the responsible foods are best identified by systematic diets and oral challenge: ll Diet diary: This can be helpful irrespective of the putative cause of the food reaction. The diary consists of a detailed record of all foods consumed and any perceived food reaction experienced. This can be useful to identify culprit foods that are potentially responsible for symptoms. It helps patients focus on the foods consumed, but it is not usually diagnostic and may be misleading, as many symptoms due to adverse food reactions are delayed or infrequent.

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Elimination diets and challenge: The responsible food chemicals are best identified by systematic elimination diets and oral challenge. Since each component compound is often present in many foods and each patient is usually sensitive to several compounds, the elimination diet must be comprehensive. This approach can be used to determine the diagnosis as well as the treatment and prevention of adverse food reactions whether allergy or not. When this is used as a diagnostic tool, it generally requires complete avoidance of suspected foods for a given time period (usually 1–2 weeks) while monitoring for a decrease in symptoms. These diets can be difficult to follow as more foods that commonly occur in the diet are eliminated. Additional limitations of this method include possible patient or physician biases, which may limit interpretation of results and treatment and variable patient compliances. Challenges should be spaced by at least 48 hours to allow for delayed reactions. Any response to a challenge should be followed by a pause of at least three symptomfree days because patients often experience a temporary refractory period during which they are unresponsive to that particular food. When designing an elimination diet for individuals with potential food-induced problems, it is usually wise to remove cereals, dairy products, citrus fruits, beverages and food additives. A standard exclusion diet should avoid these but be nutritionally adequate and contain meat (usually lamb), fruits (particularly pears) and vegetables. If an individual has not improved after 2 weeks on an exclusion diet, as a general rule symptoms are not due to food intolerance, and it is likely that they have a functional gastrointestinal disorder. Thus diagnosis of food intolerance can be confirmed by the use of an elimination diet to determine whether symptoms remit and re-emerge on a subsequent challenge with suspected ‘trigger foods’ versus a placebo (preferably double-blind). This means of diagnosis is time-consuming and difficult. Compliance by poorly motivated patients is low. However, the results are dramatic and sustained in some individuals when long-term dietary modifications are undertaken based on the results of individual oral provocation results. ll

Summary Education is of paramount importance to patients with food allergies. Patients should be given information to contact their local food

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Table 18.2 Summary of the characteristics, investigations and management of the main food reactions IgE-mediated food allergy

Non-IgE-mediated food allergy

Lactose intolerance

Pharmacologicallybased reactions

Triggering factors

Certain foods, e.g. eggs, fish, nuts, milk

Unknown

Lactose-containing foods

Can occur with many food items

Prevalence

Overall uncommon, although common in Atopic patients

Rare

Common in non-Caucasians

Uncommon

Age group Affected

All age groups

Usually young children, occasionally adults

All age groups

All age groups

Symptoms/signs Gastrointestinal Respiratory Dermatological

Nausea, vomiting ­abdominal pain, ­cramping Stridor, wheeze, cyanosis, dyspnoea Urticaria, angioedema

Nausea, abdominal pains, weight loss, failure to thrive (in infants and young children)

Abdominal pain, bloating, flatulence, diarrhoea, failure to thrive (in infants)

Diarrhoea, nausea, ­bloating, vomiting; often associated with ­respiratory and ­neurological ­symptoms

Investigations

Skin testing ­(sensitivity 95%/specificity 50%) Serum testing for specific IgE antibodies ­(sensitivity 95%) Commercial food extracts

Oral challenge test Endoscopy or colonoscopy with biopsy (finding eosinophils is suggestive of diagnosis)

Lactose tolerance test (sensitivity 75%/specificity 96%) Genetic testing

Nil confirmatory laboratory investigations Elimination diet with challenge testing to support diagnosis

Treatment

Emergency treatment Epipen® and acute hospital care Allergen avoidance In development; ­monoclonal antibodies and oral immunotherapy

Elemental diet Systemic or topical steroids

Avoid lactose. Use commercially available lactose substitutes.

Elimination diet

allergy organisation and the International Food Information Council. The patient should be referred to an immunologist in cases where IgE-mediated reactions are suspected. The diagnosis and management of non-IgE-mediated allergies is more complex and should involve a gastroenterologist and an immunologist. Once a food allergy has been diagnosed, it is important that the trigger allergen is strictly avoided whether by ingestion, skin contact or inhalation. Patients with likely IgE-mediated allergies that appear mild should be given a prescription for antihistamines to take as required. However, where there is a strong suspicion of anaphylaxis or moderate to severe symptoms the patient should receive and be educated in the use of epinephrine autoinjectors. For lactose intolerance and pharmacologically related reactions, the main treatments which appear to be useful are food avoidance and an elimination diet respectively (see Table 18.2).

Key Points ll

ll

ll

ll

ll

ll

ll

Complaints of adverse reactions to food are common. Irritable bowel syndrome has many similar symptoms. Foods commonly associated with adverse reactions include wheat, milk, citrus fruit, eggs and chocolate. Some reactions are immunologically mediated (allergic), for example fish and eggs. Some reactions are pharmacologically related adverse food reactions, for example wheat and food additives. Elimination diets with challenge often need to be performed to support a diagnosis of pharmacologically related food reactions. True allergic reactions (e.g. IgE mediated and non-IgE mediated), while rare, can be lifethreatening.

18 Food allergies and intolerance

Further reading Burks AW, James JM, Hiegel A, et al. Atopic dermatitis and food hypersensitivity reactions. J Pediatr. 1998; 132(1):132–136. Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol 2005; 116(5):1073–1079. Jansen JJ, Kardinaal AF, Huijbers G, et al. Prevalence of food allergy and intolerance in the adult Dutch population. J Allergy Clin Immunol 1994;93(2):446–456. Kagalwalla AF, Sentongo TA, Ritz S, et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin Gastroenterol Hepatol 2006; 4(9):1097–1102. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995; 109(5):1503–1512. Konikoff MR, Noel RJ, Blanchard C, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology 2006; 131(5):1381–1391. Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 2003; 348(11):986–993. Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol 2005; 3(12):1198–1206.

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Markowitz JE, Spergel JM, Ruchelli E, et al. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol. 2003; 98(4):777–782. Patriarca G, Nucera E, Pollastrini E, et al. Oral specific desensitization in food-allergic children. Dig Dis Sci. 2007; 52(7):1662–1672. Rasinpera H, Savilahti E, Enattah NS, et al. A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut 2004; 53(11):1571– 1576. Sampson HA, Anderson JA. Summary and recommendations: classification of gastrointestinal manifestations due to immunologic reactions to foods in infants and young children. J Pediatr Gastroenterol Nutr 2000;30(suppl):S87–S94. Sicherer SH, Sampson HA. Food hypersensitivity and atopic dermatitis: pathophysiology, epidemiology, diagnosis, and management. J Allergy Clin Immunol 1999;104(3 Pt 2):S114–S122. Spergel JM, Andrews T, Brown-Whitehorn TF, et al. Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol 2005; 95(4):336–343. Young E, Stoneham MD, Petruckevitch A, et al. A population study of food intolerance. Lancet 1994; 343(8906):1127–1130.

19 Palpable asymptomatic abdominal masses

Case Mrs PA, a 45-year-old previously well woman presented to her general practitioner for a health check as part of a life insurance renewal. She denied any current illness or symptom, but when her general practitioner carried out an abdominal examination a mass was palpated in the right upper quadrant. The mass was smooth, slightly tender and moved with respiration, suggesting it arose in the liver. Following first principles, her doctor first of all revisited her medical history and noted that Mrs X had been on the oral contraceptive pill for more than 20 years. Furthermore, on close questioning she admitted to intermittent low grade abdominal discomfort in the right upper quadrant over several years, but a little more frequently over the last few months. However, her general practitioner could not identify any other hepatic disease risk factor in her history, such as intravenous drug use or other exposure to hepatitis B or C infection, or exposure to hydatid disease, and could find no other physical abnormality, in particular no evidence of chronic liver disease. Mrs X was referred for liver function tests, viral screens and an abdominal ultrasound scan. Her transaminase levels were mildly elevated, hepatitis B and C serology were negative and there was a solid mass seen on ultrasound scanning. Mrs X was referred to a multidisciplinary hepatology unit and, after more detailed investigation, was eventually found to have a 12-cm mass protruding from the inferior margin of hepatic segment 5. The imaging characteristics including the presence of a central scar were consistent with focal nodular hyperplasia, thought to be unrelated to her oral contraceptive pill consumption. After discussion with a hepatologist, with a hepatic surgeon and with her general practitioner and family, Mrs  X elected to undergo surgery for removal of the

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mass. Subsequent histopathology confirmed the diagnosis of focal nodular hyperplasia. Her recovery was uneventful.

Introduction The aim of this chapter is to give guidelines to assist clinicians in the five most common clinical scenarios within which palpable asymptomatic abdominal masses are detected: 1. asymptomatic patient + asymptomatic abdominal mass: an abdominal mass, found unexpectedly during routine clinical examination of an asymptomatic patient. The mass becomes the presenting feature of the disease that has caused it—for example, a right iliac fossa mass due to an asymptomatic carcinoma of the caecum; 2. staging examination + asymptomatic abdominal mass: an asymptomatic abdominal mass found during the evaluation of a patient presenting with related primary pathology in another site—for example, asymptomatic hepatomegaly due to haematogenous metastases from a breast carcinoma. The pathologies are clearly related. The clinician performed a staging clinical examination, looking for evidence of metastatic spread from the primary breast carcinoma; 3. patient with an unrelated disease + asymptomatic abdominal mass: a patient may have two unrelated pathologies—for example, a renal mass due to asymptomatic hydronephrosis found during the examination of a patient presenting with decreasing visual acuity due to cataracts. It is initially appropriate to try to relate all the clinical features of a particular case to the presenting symptoms—to try to attribute all findings to a single causative process (the principle of Ockham's razor). However, when there are two pathologies that are unrelated one finding will not explain the other;

19 Palpable asymptomatic abdominal masses 4. self-detected palpable asymptomatic abdominal mass: an abdominal mass found by the patient. This is an unusual situation that most commonly occurs with masses of the abdominal wall, less commonly with large intraabdominal masses; 5. scan-detected palpable asymptomatic abdominal mass: an unexpected abdominal mass demonstrated on an abdominal scan performed for some other reason. The organ of origin is often identified on the scan and the pathological process may also be apparent on the scan. The clinician will then go back to the patient to seek symptoms or signs that may be attributable to the mass itself or to the pathological process that caused it. Other chapters in this book are orientated to evaluation of symptomatic abdominal masses, abdominal distension and lumps in the groin. Chapter 26 discusses masses detected as incidental findings on abdominal imaging (incidentalomas).

Examination of the Abdomen Abdominal examination is performed from the right-hand side of the bed with the patient supine. The presence of a friend or relative may help the patient relax. The environment should be quiet, warm and private. The examination must be gentle as discomfort results in protective contraction of the abdominal muscles (voluntary guarding). If an abdominal mass is detected, it is reasonable to go back through its evaluation in the standard sequence used in physical examination (inspection, palpation, percussion and auscultation) to ensure that no important features are overlooked.

Documenting the Finding of an Abdominal Mass How was the mass detected, who detected it and when? These will be the first features noted and recorded, describing how the mass was found and the characteristics noted at the time. Abdominal masses may be visible, palpable and audible: ll visible masses: there may be generalised abdominal distension or a localised deformity of abdominal wall contour. Anterior abdominal masses may be visible and palpable when quite small. Visible intraabdominal masses usually imply large lesions and are most easily seen in elderly, thin patients—for example, a visible right iliac fossa mass caused by a caecal carcinoma. A mass that was not revealed by inspection or palpation may be detected on cross-sectional

ll

ll

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imaging (ultrasound, computed tomography [CT] or magnetic resonance imaging [MRI]); palpable masses: abdominal masses that cannot be seen on abdominal inspection may be detected by palpation. Features noted on palpation may help narrow the diagnostic possibilities; audible masses: a bruit heard on auscultation over a mass or an adjacent vessel may yield information about the perfusion of the mass or about its effect on local blood flow.

What were the features noted on physical examination? Physical examination features that would be documented about any mass at any site in the body are also used to describe abdominal masses: size, the presence or absence of any of the cardinal signs of inflammation, tenderness, shape, consistency, surface features, edge definition and mobility on palpation. However, while examining an abdominal mass and reporting on it the following questions should be asked: ll What is the position within the abdomen? Refer to the nine regions of the abdomen (Fig 19.1). ll What is the depth of the mass? Is it in the body wall or within the abdominal cavity? ll Is the mass painful at rest or tender to palpation? ll Does the mass move with palpation or with respiration? ll Can a pulsation be seen or felt? Is the pulsation transmitted or expansile? ll Are the bowel sounds normal, increased, decreased or absent? ll Can a bruit or rub be heard?

Masses within the Abdominal Wall The different types of abdominal wall hernias and their features are listed in Box 19.1. Abdominal wall hernias are generally easy to characterise as a cough impulse is usually present, the hernia may present in a characteristic position and it may be possible to reduce the hernia. To separate other masses found within the abdominal wall from masses within the abdominal cavity, ask the patient to contract the anterior abdominal muscles by lifting his or her head from the examining couch with hands behind head, or to straight leg raise both legs simultaneously while keeping the head on the bed. This may help to define the mass as follows: ll A mass within the abdominal cavity (the peritoneal cavity) will be made less distinct, less easy to palpate and may disappear altogether until the abdominal wall muscles are relaxed again.

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1

2

3

4

5

6

7

8

9

1. Right hypochondrium 2. Epigastrium 3. Left hypochondrium 4. Right lumbar region 5. Umbilical region 6. Left lumbar region 7. Right iliac fossa 8. Hypogastrium 9. Left iliac fossa

Figure 19.1  Schematic illustration of the nine abdominal regions.

Unexpected abdominal masses right and left upper quadrants. Mobile with respiration. Within abdominal cavity. Slightly tender. No bruit or pulsation. Patient complained of nausea. Detailed history revealed history of skin lesion removed 10 years prior. Needle cytology diagnosis metastatic melanoma.

Figure 19.2  Unexpected palpable metastatic melanoma. Patient presented for assessment of dementia.

19 Palpable asymptomatic abdominal masses Box 19.1  Causes of abdominal wall masses Lumps that could occur anywhere on the body These arise in the skin and subcutaneous fat and include: ll lipoma; ll sebaceous cyst; and ll neurofibroma. Lumps specific to the anterior abdominal wall Arising from a process elsewhere (metastatic) ll Tumour: metastatic nodule in umbilicus secondary to intraperitoneal malignancy (known eponymously as a Sister Mary Joseph nodule) Arising in the abdominal wall fascia and muscle ll Rectus sheath haematoma (usually painful) ll Desmoid tumour (associated with Gardiner's syndrome; Ch 22) Herniae ll Incisional: previous abdominal surgery. Mass in line of scar. Sac and apparent mass may be much larger than hernia neck. ll Umbilical: hernia through umbilicus. Congenital umbilical herniae commonly resolve in infancy. ll Paraumbilical: the neck of the hernia is just lateral to the umbilical scar. Usually present later in life. ll Epigastric: knuckle of extraperitoneal fat extrudes through a small linea alba defect, between xiphoid process and umbilicus. Usually small (under 2 cm), commonly irreducible, no cough impulse. ll Spigelian: rare. Found along linea semilunaris at lateral edge of rectus sheath. Usually a third of the way between the umbilicus and the pubis. Divarication of the rectus muscles ll Supraumbilical elliptical bulging of attenuated linea alba between the recti when the patient strains. Not a true hernia and no cough impulse.

ll

ll

A mass within the abdominal wall muscle layers becomes less easy to define when the abdominal wall muscles are contracted, but is less likely to disappear altogether than the type above. A mass that is within the abdominal wall but that is superficial to the abdominal wall muscles will be made more obvious when the

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abdominal wall muscles are contracted, as it is then palpated against the tightened abdominal wall muscles.

Retroperitoneal Masses The retroperitoneal region is subdivided into five regions: ll a central column containing the great vessels and surrounding lymph nodes and the pancreas and duodenum overlying them; ll two lateral upper regions containing the kidneys and adrenals, plus the ascending colon on the right and the descending colon on the left; and ll two lateral lower regions that lie below the posterior brim of the pelvis and contain the right ureter and caecum on the right, and the left ureter and the lower descending colon on the left.

Palpation features of retroperitoneal masses Retroperitoneal masses are fixed by their retroperitoneal attachments and do not move on palpation or with respiration. Retroperitoneal masses in the upper lateral regions may be ballotable on bimanual palpation. This sign is elicited by dipping the fingers of one hand into the renal angle while palpating the corresponding point on the anterior abdominal wall with the other hand. The mass is then held forward by pressure from the posterior hand and may be felt by the other hand palpating through the anterior abdominal wall. The classic ballotable mass is an enlarged kidney. A mobile but normal right kidney is sometimes ballotable in thin patients. Other laterally placed masses, such as cancers of the ascending and descending colon, are rarely ballotable. Adrenal masses are not ballotable because they are situated above the posterior-inferior chest wall margin. An enlarged spleen is not ballotable. As the spleen enlarges, the lower pole of the spleen expands downwards and forwards into the abdomen while the upper pole remains covered by the posterior rib cage. Masses in the central column are covered behind by the spine and the erector spinae muscles whereas masses in the lower lateral regions are protected by the pelvis.

Intraabdominal Masses Site On the basis of position (Fig 19.1), we can start to define the likely organ of origin of an intraabdominal mass as shown in Table 19.1. However, we cannot be certain of the organ

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of origin of a palpable mass on the basis of its position alone. Organs do not necessarily enlarge concentrically from a fixed point. The pattern of enlargement may be determined by surrounding structures, by retroperitoneal attachments and by the pathological process responsible for the organ enlargement. The liver, for example, is limited by the diaphragm along the superior surface and by the diaphragm and ribs along the lateral surface and so tends to enlarge downwards and inwards. The uterus and bladder are limited by the pelvic walls laterally and below and so tend to enlarge upwards in the midline. The kidneys, aorta and pancreas are retroperitoneal and limited behind by the posterior abdominal wall and so tend to expand from their original site in all directions except posterior. An enlarged segment of small bowel is usually not found in the upper reaches of the abdomen because the transverse mesocolon, the transverse colon and the greater omentum are attached to retroperitoneal tissues along a horizontal line at the level of the inferior border of the pancreas. These three organs tend to form a barrier restricting upward migration of small bowel masses. A single pathological process may have focal or diffuse effects in a given organ and may have different effects on the different organs involved.

A cancer of the sigmoid colon may become fixed to the posterior abdominal wall by local invasion. Omental metastatic deposits from the same sigmoid colon cancer will not move with respiration but may be relatively mobile on palpation. Hepatic metastatic deposits from the same cancer may move with respiration as the liver moves, but will not move on palpation. An enlarged organ may come to fill several adjacent abdominal regions if the degree of enlargement is great. Thus, in the third trimester of pregnancy, an enlarged pregnant uterus can be expected to fill the hypogastrium, the periumbilical region and part of the epigastrium. The likely organ of origin may be defined by the position of the mass as in Table 19.1. Discriminating clues that may be found on examination and that the patient may report on closer questioning may help establish the causative process. See Table 19.2 and Box 19.2.

Movement with respiration The diaphragm moves inferiorly with inspiration and back up to its neutral position with expiration. Immediately below the diaphragm are the liver and the spleen. An enlarged liver or spleen will move inferiorly with each inspiratory effort. As well as moving inferiorly, the liver edge and the

Table 19.1 Organ of origin of intraabdominal masses by region Right hypochondrium

Epigastrium

Left hypochondrium

Right lobe of liver

Stomach

Spleen

Gall bladder

Left lobe of liver

Pancreas*

Pancreas*

Stomach

Lymph nodes* Aorta* Right lumbar region

Periumbilical

Left lumbar

Ascending colon*

Omentum

Descending colon*

Right kidney*

Transverse colon

Left kidney*

Aorta* Retroperitoneal nodes* Right iliac fossa

Hypogastrium

Left iliac fossa

Appendix

Bladder

Sigmoid colon

Caecum*

Uterus

Iliac aneurysm*

Iliac aneurysm*

Right and left ovary*

Left ovary*

Right ovary Iliac nodes* *Strictly retroperitoneal in position

Iliac nodes*

19 Palpable asymptomatic abdominal masses

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Table 19.2 Clinical clues that may be present with an apparently asymptomatic abdominal mass Mass position

Discriminating features on clinical examination

Clinical clues that may have been overlooked

Clinical examples that may fit the picture

Right hypochondrium

Hard, irregular, moves with respiration, can't get above it

Vaguely unwell Pain or other symptoms referable to primary tumour Episodes of asthma, allergy History of exposure to farm dogs Previous attack of cholecystitis

Metastatic liver disease (e.g. breast, pancreas, stomach, colon, lung, melanoma) Hydatid disease

Hard, no movement with respiration, mobile or fixed to palpation Hard, fixed (no movement with respiration or on palpation), can't get above it Hard, fixed (no movement with respiration or palpation)

Anorexia, nausea, weight loss, symptomatic anaemia, mild dyspepsia Anorexia, nausea, weight loss, vague epigastric or back pain

Carcinoma of the stomach

Lymphoma B symptoms Primary tumour elsewhere

Para-aortic lymphadenopathy

Left hypochondrium

Moves with respiration, can't get above it

Malaria exposure Haemolytic anaemia Alcohol abuse Non-specific lymphoma symptoms

Splenomegaly

Right lumbar

Ballotable

Symptoms of renal failure, vague ache in loin Symptomatic anaemia

Massive hydronephrosis, polycystic kidney Carcinoma of ascending colon

Lassitude, weight loss, symptoms attributable to primary tumour elsewhere Symptomatic anaemia

Metastatic omental tumour

Firm, smooth, moves with respiration, can't get above it Globular, moves with respiration, may get above it Epigastric

Mobile or fixed on palpation but no movement with respiration Periumbilical

Single/multiple mobile ± ascites Mobile/fixed, no movement with respiration Pulsatile, immobile Hard, fixed (no movement with respiration)

Left lumbar

Ballotable Mobile/fixed, no movement with respiration

Vague back ache Vaguely unwell

Gall bladder mucocoele

Carcinoma of the pancreas

Transverse colon carcinoma Aortic aneurysm Metastatic lymph nodes

Symptoms of renal failure, vague ache in loin Per rectum bleeding, change in bowel habit, symptoms of anaemia

Massive hydronephrosis, polycystic kidney Carcinoma of descending colon

Right iliac fossa

Mobile/fixed Mobile, indentable

Symptomatic anaemia Dull ache right iliac fossa Constipation

Carcinoma of caecum Constipation (stool)

Hypogastrium

Globular, smooth, immobile, not palpable bimanually, pressure over it may induce desire to micturate Palpable bimanually, ± lobulated

Difficulty with micturition

Chronically obstructed bladder

Irregular cycles, menorrhagia, vague hypogastric pain, backache Vague lower abdominal ache

Fibroids

Palpable bimanually, perhaps slightly off midline Globular, smooth, immobile, palpable bimanually Left iliac fossa

Mobile, fixed Mobile, indentable

Missed menstrual period Per rectum bleeding, change of bowel habit Constipation

Benign or malignant ovarian cyst Pregnancy Sigmoid colon carcinoma Constipation (stool)

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Box 19.2  Features of an abdominal mass that should be defined on clinical examination ll

ll ll ll ll ll

ll ll ll

ll

ll ll ll ll

ll ll

Is it superficial or deep to the anterior abdominal wall? Is there a cough impulse? Is it single or multiple? What is the position of the mass? What are the shape and dimensions? Can all of the margins be palpated? Are the margins sharp, blunt or indistinct? Is the surface texture smooth or irregular? Is the consistency hard, firm or soft? Does it appear to descend from behind the costal margins (can't get above it) or arise from the pelvis (can't get below it)? Does the mass move with respiration or does it move on palpation? Is it indentable? Is there tenderness? Is there pulsation? (transmitted or expansile) Is the inferior margin palpable per rectum or per vagina? Is the mass resonant or dull on percussion Is there a bruit on auscultation?

inferior pole of the spleen move medially relative to the costal margin. Other organs in the upper abdomen do not move with respiration. Retroperitoneal organs (the pancreas, aorta, kidneys and lymph nodes) are relatively fixed to the posterior abdominal wall, so that they are not displaced inferiorly with each movement of the liver and spleen, which slide over them. Intraabdominal pressure rises during inspiration, compressing hollow organs such as the stomach, transverse colon and small bowel, and limiting the movement of these organs. An enlarged gall bladder moves inferiorly with respiration as it is firmly attached to the liver. Similarly an inflammatory mass or a neoplastic mass just inferior to the liver but attached to the inferior surface of the liver, though not to retroperitoneal structures, will also move inferiorly with respiration. Hepatic masses or perihepatic masses may not move with respiration if attached to the body wall in front, laterally or behind.

Relation to costal margin and brim of pelvis Palpation of the upper reaches of the abdominal cavity is prevented by the costal margins. Thus, the full extent of hepatomegaly and splenomegaly

is not appreciated by abdominal palpation. Unlike a mass in the transverse colon or omentum, a superior edge of an enlarged liver or spleen by palpation cannot be defined. Palpation of the pelvic cavity is restricted by the pubis in front and by the rest of the pelvic ring laterally and behind. Accordingly, the examiner cannot rely on anterior abdominal examination to define an inferior margin of enlarged organs that lie in the pelvis (bladder and uterus). However, rectal or vaginal examination may allow palpation of the inferior margin of pelvic masses.

Mobility Most abdominal masses are relatively immobile. Neoplastic masses involving the omentum, transverse colon, sigmoid colon and small bowel are the most likely to display some mobility. All of these organs are anteriorly placed and loosely attached to the posterior abdominal wall by a mesentery. Inflammatory masses of the bowel (which are usually painful) tend to be less mobile because inflammatory adhesions tend to fuse these masses to adjacent structures. So a carcinoma of the small bowel may well result in a mobile mass whereas a mass due to Crohn's disease of the small bowel will be tender and will usually be adherent and immobile.

Shape, edge and consistency The most common asymptomatic intraabdominal mass is caused by faecal loading of a segment of colon (Fig 19.3), usually caecum or sigmoid colon. A loaded colon tends to be tubular or sausage-shaped with a lobular surface contour. The orientation of a caecum loaded with faeces is vertical, while that of sigmoid colon is oblique, parallel to the inguinal ligament. Pressure on the surface of the mass by pressing a finger or thumb into it through the anterior abdominal wall may result in indentation of the surface of the mass. This is an uncommon but characteristic diagnostic feature of constipation with faecal loading. Malignant tumours tend to be vaguely nodular to palpation; benign tumours usually have a smooth contour. Malignant tumours tend to be hard in consistency, whereas benign tumours may be soft.

Single or multiple If more than one mass is found, the differential diagnosis is narrowed. The most common cause of multiple abdominal masses is constipation. The next most common cause is multiple peritoneal secondaries.

19 Palpable asymptomatic abdominal masses

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Figure 19.3  Faecal loading in the transverse colon.

Tender or non-tender An asymptomatic abdominal mass is unlikely to be tender. Tenderness implies inflammation, which may be due to infection, infarction or haemorrhage into the mass (Table 19.3).

Pulsatile or non-pulsatile Aneurysms can develop in any large artery in the abdomen, but the aorta is the most commonly affected artery and palpable abdominal aneurysms are almost always in the abdominal aorta. The mass caused by an aneurysm of the abdominal aorta is found in the midline just above the umbilicus and displays expansile pulsation, expanding laterally in both directions with each pulsation. Expansile pulsation is detected by bimanual pulsation over the mass to distinguish it from transmitted pulsation. Transmitted pulsation arises from a mass situated between the aorta and the anterior abdominal wall. This will transmit the aortic pulsation anteriorly, but not laterally. If there is any doubt and the patient is well enough, ask the patient to crouch on hands and knees while the mass is palpated again. If an overlying mass is mobile with respect to the posterior abdominal wall, then the mass may fall away from the aorta and will no longer

transmit the pulsation. If the patient is not able to cooperate with this and diagnostic doubt remains an urgent abdominal ultrasound scan or CT scan may be indicated. If the haemodynamic status of the patient is unstable urgent operation may be indicated without resort to scanning.

Percussion note Solid abdominal tumours are dull to percussion and this technique may help in approximating tumour dimensions. The upper level of liver is not palpable as it is behind the ribs. The level of the superior hepatic margin may be determined by percussion over the lower thorax on the right in the midclavicular line. This, along with palpation of the inferior margin should allow determination of the liver span (its normal span is under 12.5 cm). If this is not done a ptosed liver may be mistaken for hepatomegaly.

Bruit or silent Auscultation over a mass may reveal a bruit. Bruits are most commonly limited to systole and are caused by turbulent (non-laminar) flow in a narrowed artery. A continuous or machinery bruit may be heard over an extremely vascular tumour. It

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Table 19.3 Tender abdominal masses* Position of mass

Features on examination

Diagnosis

Right hypochondrium

Localised, moves with respiration, can't get above it

Acute cholecystitis, empyema of the gall bladder Haemorrhage or infarction in a liver tumour (or cyst)

Right hypochondrium

Enlarged liver

Cholangitis Portal pyaemia Hepatic metastases Acute severe right heart failure

Epigastric

Immobile

Pancreatic pseudocyst Pancreatic phlegmon Dissection in abdominal aortic aneurysm

Left hypochondrium

Enlarged spleen

Splenic infarct

Right loin

Enlarged kidney

Pyonephrosis Renal cell carcinoma

Periumbilical

Pulsatile

Dissection in abdominal aortic aneurysm

Right iliac fossa

Immobile

Appendix phlegmon/abscess Crohn's disease

Hypogastrium

Enlarged bladder Enlarged uterus Enlarged ovary

Acute urinary retention Haemorrhage or infarction in a fibroid Haemorrhage or infarction in an ovarian tumour/cyst Acute pyosalpinx

Left iliac fossa

Immobile, sometimes palpable bimanually

Acute diverticular phlegmon Diverticular abscess

*Usually symptomatic

signifies the presence of significant arteriovenous shunting within the tumour. A bruit over the liver may also occur in acute alcoholic hepatitis or with an arteriovenous malformation.

Bimanually palpable on rectal or vaginal examination Masses within the lower half of the abdomen, particularly those in the hypogastrium (inferior to the umbilicus), may arise from the pelvic organs, in particular the bladder, uterus or ovaries. Origin from within the pelvis may be suspected if the lower margin of a mass cannot be palpated because of the bony pubis. The mass should be further characterised by bimanual palpation from above and below. This is achieved by palpating the superior edge of the mass with one hand on the abdomen, while attempting to palpate the inferior edge with either the index finger of the other hand in the rectum or the index and middle fingers in the vagina. For a bimanual rectal examination, the patient is positioned in the left lateral decubitus position with the hips and knees flexed. For bimanual vaginal examination, the patient is positioned supine with hips and knees flexed and hips externally rotated.

If a mass arising from within the pelvis can be palpated bimanually its size, surface characteristics and relationship to the uterus may be ascertained using this technique. The lower edge of the bladder cannot be appreciated per rectum or per vagina. An ovarian mass should be distinguishable from the uterus bimanually; the circular indentation of the cervix is used to help identify the uterus. Several other important observations may be made during a rectal examination. First, the rectum may be loaded with faeces. This is consistent with the presence of one or more abdominal masses caused by constipation. Secondly, there may be evidence of peritoneal spread of a malignant tumour of the stomach, colon or ovary. The sign to seek is the presence of a hard, irregular and relatively fixed tumour mass anterior to the rectum at the tip of the examining finger on rectal examination (Blumer's shelf), though this is rare. Finally, there may be blood on the glove from a previously unsuspected colon cancer or the hard irregular mass of a rectal tumour (Ch 22). Having defined the features of the mass, the clinician should review the clinical history with

19 Palpable asymptomatic abdominal masses a focus on symptoms possibly associated with the provisional diagnoses. On specific questioning, symptoms that were previously overlooked by the patient might be recalled (see Box 19.3).

Other signs on general physical examination The physical examination is completed mindful of the working diagnosis, based on the finding of an abdominal mass. Specific examples of relevant positive findings are listed in Table 19.4.

Office Tests The finding of occult blood in the faeces provides supportive evidence that an abdominal mass might be due to a gastrointestinal malignancy and guides further examination and testing to the gastrointestinal tract. But, as faecal occult blood testing is neither sensitive nor specific (Ch  10), definitive examinations will be required, for instance by colonoscopy and biopsy. Similarly, the finding of blood or protein in the urine, while also non-specific, may focus attention on the urinary tract. Box 19.3  Examples of vague symptoms that may be revealed only after the mass is uncovered Non-specific symptoms Mild abdominal discomfort ll Lethargy, easy fatigueability ll Weight loss, anorexia ll Nausea, vomiting ll Bloating Symptoms indicating an extraabdominal consequence of the disease process ll Worsening angina due to cardiac decompensation caused by occult blood loss and iron deficiency anaemia ll Dyspnoea from a pleural effusion due to pulmonary spread of an abdominal malignancy ll Superficial thrombophlebitis due to paraneoplastic phenomena Symptoms suggesting the disease process or organ ll Upper gut—heartburn, dyspepsia, dysphagia, early satiety ll Lower gut—altered bowel habit, blood, mucus or pus in stools, colicky abdominal pain ll Pancreas/biliary tree—pruritus, jaundice, steatorrhoea ll

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Imaging Plain radiology Plain abdominal x-rays are of limited value in the assessment of abdominal masses. Consequently, this step is often omitted in favour of more powerful imaging tools, particularly cross-sectional imaging such as ultrasound and CT scanning. Plain abdominal x-ray is useful in the detection of pathological calcification including: ll calcification in the wall of an arterial aneurysm; ll plate-like or curvilinear calcification in the wall of a liver hydatid cyst (Fig 19.4); ll calcification due to chronic pancreatitis; ll calcification in an ovarian mass suggestive of ovarian teratoma. A plain chest x-ray examination should also be performed and may reveal: ll rounded shadows due to pulmonary metastases; or ll pleural effusion due to pulmonary metastases.

Ultrasound and CT These modalities should allow definition of the abdominal organ involved and often, the pathologic process responsible for a palpable mass. Each scanning technique has particular advantages. Ultrasound scanning discriminates well between cystic and solid lesions. CT scanning is better in obese people as adjacent structures can be Table 19.4  Examples of extraabdominal signs that may be associated with an asymptomatic abdominal mass Sign

Associated abdominal mass

Pallor

Gastrointestinal malignancy with occult bleeding

Wasting

Advanced malignancy

Signs of chronic liver disease (palmar erythema, spider naevi, gynaecomastia, testicular atrophy, ascites, caput medusae)

Splenomegaly associated with portal hypertension Hepatic mass due to hepatocellular carcinoma in cirrhosis

Hard, fixed irregular breast lump Hard supraclavicular lymph node Signs of pleural effusion

Hepatomegaly due to metastatic breast cancer Epigastric mass due to stomach cancer Mass of malignant origin or benign ovarian tumour (Meigs’ syndrome)

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separated visually by intervening lucent fat planes. Ultrasound images are often suboptimal in obese patients. Further, if the space between the anterior abdominal wall and the palpable mass contains gas-filled loops of bowel, these will cast posterior shadows and distortions on the ultrasound scan images but not the CT scan images, making CT scanning the preferred technique for imaging of unexpected abdominal masses (Ch 26). In practice, if the overall information yielded is inadequate to complete a management plan after the first examination, whether ultrasound or CT, then the other scan is usually performed as well.

Confirmation of an abdominal mass or an enlarged abdominal organ on imaging

in detail in Chapter  26. Cystic hepatic lesions are most commonly due to simple cysts. These may be quite large, may be multiple and are frequently discovered incidentally (Fig 19.5A and 19.5B). Though rare, hepatic neoplastic cysts (cystadenomas) should be excluded. Hydatid cysts are not infrequent in Echinococcus spp. endemic areas but are generally easy to diagnose on ultrasound or CT scans, which usually reveal daughter cysts within the main cyst. If the hepatic lesion is single and solid, it is likely to be a solitary secondary deposit but may be a primary hepatoma, particularly if there is a history of chronic liver disease. The other single

The next investigations depend on the results from ultrasound or CT scans.

Box 19.4  Causes of hepatomegaly

Liver First, ask yourself: is the enlargement uniform or irregular? The possible causes of a diffuse, uniform enlargement are listed in Box 19.4. If CT has detected small, low density but nonspecific lesions or if liver enlargement is irregular or patchy, ultrasound scanning is useful to determine whether the lumps are solid or cystic. Evaluation of lumps in the liver is discussed

Diffusely enlarged but smooth Massive ll Metastatic disease ll Alcoholic liver disease with fatty infiltration ll Myeloproliferative diseases (e.g. polycythaemia rubra vera, myelofibrosis) Moderate The above causes plus: ll haemochromatosis; ll haematological disease (e.g. chronic myeloid leukaemia, lymphoma); ll fatty liver (e.g. diabetes mellitus, obesity); ll infiltrative disorders (e.g. amyloid). Mild The above causes plus: ll hepatitis (viral, drugs); ll cirrhosis; ll biliary obstruction; ll granulomatous disorders (e.g. sarcoid); ll HIV infection. Diffusely enlarged but irregular ll Metastatic disease ll Cirrhosis ll Hydatid disease ll Polycystic liver disease Localised swellings ll Riedel's lobe (a normal variant—the lobe may be palpable in the right lumbar region) ll Metastasis ll Large simple hepatic cyst ll Hydatid cyst ll Hepatoma ll Liver abscess (e.g. amoebic abscess)

Figure 19.4  Abdominal x-ray. Incidentally found curved, plate-like calcification (circled) consistent with a hydatid cyst.

From Talley NJ, O'Connor S. Clinical examination. 6th edn. Sydney: Elsevier Australia; 2010.

19 Palpable asymptomatic abdominal masses solid lesions discussed in Chapter 26 tend to be less massive and are less likely to cause hepatomegaly. If hepatomegaly is due to multiple solid lesions, metastatic liver disease is the likely explanation. The next step will then be to establish the primary tumour site. The common sources are colon,

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pancreas, stomach, breast and lung. Histological confirmation of the diagnosis should usually be sought, provided this does not risk compromising the treatment and chances of cure by seeding along the biopsy track or by rupture of the tumour. A biopsy of the primary tumour is preferred as the

Thin walled, large and small, homogeneous, low density collections consistent with simple hepatic cysts

Figure 19.5  CT scans. Massive hepatic cyst detected on abdominal exam. Elderly patient admitted with a stroke.

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histology from the liver may well be consistent with malignancy but still be non-discriminatory about the primary site. Furthermore, biopsy of a primary tumour, whether by gastroscopy, colonoscopy, bronchoscopy or needle biopsy, is generally safer than liver biopsy. If the primary tumour cannot be found, then ultrasound or CT-guided biopsy of the hepatic mass may be indicated to secure a diagnosis of metastatic disease but, even then, the primary site may remain enigmatic. Gall bladder Gall bladder enlargement due to obstruction of the common bile duct (e.g. carcinoma of the head of the pancreas or ampulla of Vater) will usually be associated with jaundice (Ch 23). A gallbladder mucocele usually forms a smooth, globular swelling in the right upper quadrant and may be relatively painless and non-tender. Enlargement due to carcinoma of the gall bladder is unusual. Stomach If the mass is thought to be gastric on CT, then gastric carcinoma or gastric lymphoma is the likely diagnosis. Gastroscopy and biopsy should confirm

the diagnosis. Visualisation of the stomach by ultrasound scanning, and to a lesser extent by CT, is poor. Management of an asymptomatic tumour of the stomach will depend on the patient's age and comorbidity as well as on the stage of the disease. Preoperative staging of gastric carcinoma includes a search for lymphatic, haematogenous and transcoelomic metastases and involves physical examination, CT scanning of the chest and abdomen and frequently, positron emission tomography (PET) scanning (Ch 17). Pancreas On the basis of the ultrasound or CT scans, the clinician should know whether a pancreatic lesion is cystic or solid. If cystic it is likely to be either a pseudocyst of the pancreas or a neoplastic cyst (cystadenoma or rarely cystadenocarcinoma) (see Fig 19.6). For the diagnosis of pseudocyst, there should have been a definite prior episode of pancreatitis. The management of pancreatic pseudocyst is discussed in Chapter 4. The treatment of cystadenoma is surgical resection (Ch 26).

Stomach. Note fluid level at gastric gas/fluid interface

Pseudocyst filling lesser sack Thick wall (inflammatory) Fluid in pseudocyst

Figure 19.6  Unexpected epigastric mass on examination for renewal of life insurance. Subsequent CT revealed intraabdominal fluid-filled mass consistent with pancreatic pseudocyst and unexpected radiolucent gallstone in gallbladder. On subsequent questioning patient admitted an episode of abdominal pain and malaise after alcohol binge drinking 8 weeks prior.

19 Palpable asymptomatic abdominal masses If the lesion is solid, then pancreatic cancer is likely. On ultrasound scanning pancreatic cancers often have a characteristic hypo-echoic appearance. The CT scan should be examined for evidence of spread to the liver, to peripancreatic and portal lymph nodes, encasement of the portal vein or superior mesenteric vein and dilatation of the pancreatic duct. Most malignant pancreatic tumours that have grown to the point where they are palpable on physical examination will be unresectable. Many of these tumours will also have caused obstructive jaundice by obstructing the common bile duct in the pancreas (see Ch 23). Primary tumours of the body and tail of the pancreas may also cause jaundice indirectly, when Box 19.5  Causes of splenomegaly and hepatosplenomegaly Massive splenomegaly Haematological disease (e.g. chronic myeloid leukaemia, myelofibrosis) Moderate splenomegaly The above cause plus: ll portal hypertension (hepatic and prehepatic causes); ll haematological disease (e.g. lymphoma, leukaemia, thalassaemia); ll storage disease (e.g. Gaucher's disease). Small splenomegaly The above causes plus: ll infective (hepatitis, leptospirosis, malaria, bacterial endocarditis) ll haematological disease (e.g. haemolytic anaemias, essential thrombocythaemia, polycythaemia rubra vera) ll connective tissue diseases or vasculitis (e.g. rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa) ll solitary cyst, polycystic syndrome, hydatid cyst ll infiltration (amyloid, sarcoid) Hepatosplenomegaly ll Chronic liver disease with portal hypertension ll Haematological disease (e.g. myeloproliferative disease, lymphoma) ll Infection (e.g. acute viral hepatitis, infectious mononucleosis) ll Infiltration (e.g. amyloid, sarcoid) ll Connective tissue disease (e.g. systemic lupus erythematosus) ll

From Talley NJ, O'Connor S. Clinical examination. 6th edn. Sydney: Elsevier Australia; 2010.

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metastatic portal lymph nodes obstruct the hepatic ducts at the porta hepatis. The management of pancreatic cancer is considered in Chapter 17. Lymph nodes Enlarged para-aortic lymph nodes producing an epigastric mass are likely to have arisen from a primary tumour elsewhere. The common sites of origin are the stomach, colon, pancreas and testis. The origin of the lymphadenopathy should be established by investigation of the likely primary site (see above). If no primary site is found, then an imaging guided percutaneous biopsy is reasonable. Cytology from a percutaneous needle aspiration biopsy may be non-diagnostic or inadequately specific for full tumour typing if the lymphadenopathy is due to malignant lymphoma (Ch 26). Core biopsy or an open biopsy may still be needed for histology. Spleen Truly incidental splenomegaly is a very uncommon finding. The spleen has to be enlarged to several times its normal size to be palpable so most patients with splenomegaly will have symptoms from the causative process before the spleen is palpable. The causes of splenomegaly include infections, inflammatory diseases and haematological diseases liver diseases (Box 19.5). The most important gastroenterological cause of splenomegaly is portal hypertension (see Ch 24). The spleen may be reported as enlarged on CT scanning but if the spleen is not palpable and there is no apparent cause, the radiological finding of slight splenic enlargement is often misleading. Kidneys The common causes of an enlarged kidney include obstructions, cysts, tumours and infections as shown in Box 19.6. If there is congenital or

Box 19.6  Causes of unilateral kidney enlargement ll

ll

ll ll ll ll

Hydronephrosis (may be bilateral and may be symmetrical or asymmetrical) Polycystic kidney (may be bilateral and may be symmetrical or asymmetrical) Simple cyst of kidney Renal cell carcinoma Pyonephrosis (may be bilateral) Renal vein thrombosis

From Talley NJ, O'Connor S. Clinical examination. 6th edn. Sydney: Elsevier Australia; 2010.

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acquired absence of a kidney or if renal disease has resulted in unilateral renal atrophy, the remaining kidney will undergo compensatory hypertrophy and may become palpable. A careful clinical history and an ultrasound scan should clarify this situation. Colon Asymptomatic masses arising in the colon are most likely to be due to constipation or to tumours, usually malignant. Smaller benign tumours of the colon may cause intussusception, when the key presenting feature is usually colicky abdominal pain. Faecal masses (Fig 19.3) are quite firm but should be indentable and should disappear with purgation. Neoplastic masses arising in the colon are usually firm to hard. They may or may not be mobile, but do not indent. As is also the case for masses in the stomach, colonic masses are poorly imaged by ultrasound. By the time colonic neoplastic masses are palpable, the origin in colon can usually be determined by CT scan. However, conclusive diagnosis requires a tissue biopsy for histopathology. Biopsy usually requires a colonoscopy. Staging of malignant tumours is described in Chapter 22. Small bowel A palpable small bowel mass will be apparent on CT. The causes of asymptomatic small bowel masses are shown in Table 19.5. Unlike the stomach and the colon, endoscopy of the small Table 19.5 Causes of small bowel masses Cause

Pathology Comment

Cyst

Mesenteric cyst

Congenital Fluid collection in the mesentery derived from remnants of reduplicated bowel

Tumour

Benign Malignant

Lipoma Hamartoma (e.g. Peutz-Jeghers syndrome) Adenocarcinoma Carcinoid tumour Lymphoma

Intussusception

Inflammation

May have a polyp or tumour at its leading edge Crohn's disease

Inflammatory mass therefore usually fixed and often tender Check for anal/ perianal signs and for extraabdominal signs

bowel is difficult. If further radiological imaging of a small bowel mass is required after CT, it is usually achieved by small bowel series, often carried out as a small bowel enema or CT enterography. If radiological imaging has not been adequate and there is no suggestion of an obstructing lesion in the small bowel, capsule endoscopy may be indicated. Small bowel enteroscopy is available in highly specialised centres. Preoperative biopsy of a small bowel tumour may not be possible. However, a PET scan may reveal a glucose avid tumour in the small bowel, suggesting malignancy, either adenocarcinoma or lymphoma. If the neoplastic process is confined to the small bowel, histological confirmation may not be achieved until small bowel resection has been carried out. If there is disease outside the small bowel, for instance in lymph nodes or in the liver, biopsy of these may yield definitive histopathology. Omentum Normal omentum is never palpable. Omentum becomes palpable only when it is infiltrated by tumour, usually by transperitoneal spread (transcoelomic metastases). The common sites of origin of transcoelomic metastases are colon, ovary, stomach and pancreas. Melanoma is the most common extraabdominal primary malignancy causing metastases to the omentum and small bowel. Omental secondaries are usually associated with some degree of ascites. Tapping the ascites, with ultrasound guidance if the amount is subclinical, provides a specimen for cytology (Ch 20). If ascitic fluid is not available for cytology, transcutaneous needle biopsy of omental masses is usually possible under imaging guidance. Metastatic disease in the omentum always denotes advanced disease, whatever the organ of origin. Once cytology or histopathology is available, medical oncology advice should be sought though further treatment, while possibly providing worthwhile palliation, is unlikely to be curative. A gynaecological opinion should also be sought if an ovarian source seems likely. Aorta An abdominal aortic aneurysm may present as an asymptomatic mass detected on clinical examination or as an unexpected finding on abdominal imaging. After an abdominal aortic aneurysm has been detected, it is important to measure its width (side to side), as the risk of sudden rupture of the aneurysm is related to aneurysm width. While a reasonable estimate of the width of an aneurysm can be made on clinical

19 Palpable asymptomatic abdominal masses examination, ultrasound or CT scanning is more accurate. If the proximal extent of the aneurysm cannot be defined it may involve the renal arteries, making subsequent repair more difficult. This may be difficult to ascertain on physical examination and the width and proximal extent should always be checked on an abdominal ultrasound or CT scan. The management decision should be made by a vascular surgeon, but operative graft replacement or endoluminal grafting is usually indicated if the aneurysm is greater than 5.5 cm in diameter. If the aneurysm is 3–4 cm, monitor with ultrasound every 2–3 years; if 4–5.4 cm, monitor every 6 months. An expansion of over 0.5 cm in 6 months is another indication for surgery. Bladder An enlarged bladder is nearly always an obstructed bladder and initially should be drained by urinary catheterisation. The abdomen should then be reexamined. Ovaries Ovarian enlargement may be suggested by a mass arising from the pelvis with the lower margin palpable on bimanual examination as outlined above. Ultrasound scanning is useful for sorting solid masses from cysts or cystic neoplasms, but full assessment of suspected ovarian neoplasms usually requires abdominal and pelvic CT scanning. Specialist gynaecological opinion should be sought when an enlarged ovary is discovered incidentally or is suspected.

Other Investigations

more appropriate selection of specific diagnostic tests can be made (see Table 19.6).

Nuclear medicine With the exception of PET, the use of radionuclide scanning in the anatomical and functional assessment and the diagnosis of abdominal masses has declined with the advent of crosssectional imaging (ultrasound, CT and MRI scans). PET scanning is very useful in disease staging, in assessing responses to treatment and sometimes, when biopsy is impossible or inadvisable, for diagnosis. Radionuclide imaging still has an occasional place in the assessment of incidentally detected liver lesions (see Ch 26). Table 19.6  Further evaluation of abdominal masses by blood tests Clinical diagnosis

Further blood test and rationale

Possible gastrointestinal malignancy

Tumour markers (Ch 17) including: ll lower gut—­ carcinoembryonic antigen (CEA); ll upper gut—CA 19-9.

Possible hepatoma

Tumour marker: alphafetoprotein (Ch 17) Risk factors for hepatoma/ indicators of chronic viral liver disease: hepatitis B and C serology

Significant liver replacement

Coagulation studies should be checked prior to any intervention (e.g. liver biopsy) that might be complicated by excessive bleeding

Possible hydatid disease of the liver

Hydatid serology—to confirm the diagnosis and to ensure that biopsy is not attempted as leakage from the cyst might cause intraperitoneal spread of the disease (Ch 26)

Pancreatic mass

Tumour marker: CA-19-9 Endocrine screen depending on symptoms (insulin, gastrin, vasoactive intestinal peptide, glucagon) Endocrine tumour prognosis better than prognosis for adenocarcinoma of the pancreas and management is different (Ch 26)

Blood tests An abdominal mass, whether truly asymptomatic or not, usually denotes a significant clinical problem. A faeces-loaded colon is an exception, though severe constipation can still be a significant clinical management issue. Simple haematological and biochemical screening is usually done early in the process of investigating an abdominal mass and usually includes a full blood count, liver function tests and serum levels of urea, creatinine and electrolytes. While these often provide useful information about systemic consequences of the mass and the process that has caused it, they are not diagnostic tests. More specific blood tests may be indicated once the organ of origin and the likely pathological process are better defined from the history and examination and the ultrasound or CT scans. With the diagnostic possibilities narrowed, a

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Tissue diagnosis A definitive tissue diagnosis should be sought for any abdominal mass that is or that might be neoplastic. This information is essential for a secure final diagnosis, to establish prognosis and in the selection of treatments, such as surgery, radiotherapy, chemotherapy or other interventions. Furthermore, patients and their families also require accurate information about diagnosis, prognosis, management plans and possible outcomes for informed consent to treatments and to organise personal, family and business affairs. An accurate tissue diagnosis is a fundamental requirement. As indicated above, a biopsy should be taken from the primary tumour if possible. This is especially so for tumours of the stomach, colon, lung, breast, pancreas and skin. For stomach, colon and lung, the biopsy is usually taken using an endoscopic technique. For breast and pancreas, it is by direct puncture (needle biopsy), guided radiologically if the primary is impalpable. Most liver masses can be accessed for percutaneous biopsy utilising imaging guidance. However, bleeding, bile leakage, tumour rupture and biopsy track dissemination can occur as a result of the procedure. Hepatocellular carcinomas extending to the liver surface are at particular risk for these consequences of needle biopsy. Thus, specialist liver surgery opinion should always be sought before a radiologist is asked to perform a biopsy of a primary or metastatic liver neoplasm, especially if there is any chance at all that the lesion may be surgically resectable. Tumour biopsy by laparoscopic or open abdominal operation may occasionally be required to finalise a diagnosis if fine needle biopsy is unsafe (e.g. some hepatocellular carcinomas), or unlikely to yield diagnostic material (e.g. liposarcoma of the retroperitoneum).

Key Points ll



There are five basic scenarios in which an asymptomatic abdominal mass is detected incidentally: – asymptomatic patient + asymptomatic abdominal mass; – staging examination for malignancy + asymptomatic abdominal mass;

ll

ll

ll

ll



– patient with an unrelated disease + asymptomatic abdominal mass; – self-detected palpable asymptomatic abdominal mass; – scan-detected palpable asymptomatic abdominal mass. An abdominal mass may be detected because it may be: – v isible; – palpable; – audible. Features recorded about an abdominal mass should include: – position within the abdomen (refer to the nine regions of the abdomen); – depth (in the body wall or abdominal cavity); – pain (at rest) or tenderness (to palpation); – mobility (with respiration or on palpation); – pulsation (transmitted or expansile); – bowel sounds (normal, increased, decreased or absent); – bruit or rub (on auscultation). Unexpected abdominal masses may also be associated with extraabdominal signs. Relate site and characteristics of a mass to potential tissues of origin to help: – narrow the field of possible diagnoses; – g uide initial (non-invasive) investigations; – suggest direction of specialist referral; – i ndicate possible subsequent invasive investigations.

Further reading Grover SA, Barkuyn AN, Sackett DL. The rational clinical examination. Does this patient have splenomegaly? J Am Med Assoc 1993; 270:2218–2221. McGee S. Evidence-based physical diagnosis. 2nd edn. Philadelphia: Saunders; 2007. Naylor CD. The rational clinical examination. Physical examination of the liver. J Am Med Assoc 1994; 271:1859–1865. Talley NJ, O'Connor S. Clinical examination. A systematic guide to physical diagnosis. 6th edn. Sydney: Churchill Livingstone; 2010.

20 Abdominal distension

Case A 32-year-old woman presents with a 6-day history of progressive abdominal distension and nausea. She had recently been an inpatient with an episode of acute pancreatitis. The aetiology of the pancreatitis was familial pancreatitis, with her grandmother, father and one brother having episodes of recurrent pancreatitis. She looked well, was afebrile and was not jaundiced or pale. Abdominal examination revealed a moderately distended abdomen that was tense but not tender. The bowel sounds were normal. There was evidence of shifting dullness and a fluid thrill. A provisional diagnosis of ascites was made. Laboratory blood tests were all normal in particular the amylase, lipase, liver function tests and albumin. A CT scan confirmed marked ascites. The pancreas was slightly enlarged but well perfused with a slightly prominent pancreatic duct. There were no loculated fluid collections or evidence of pseudocyst formation. A diagnostic aspiration of the fluid revealed it was straw-coloured. Analysis confirmed it was an exudate with no cells and an amylase of over 100 000 I/U (serum ascites– albumin gradient < 11 g/L). This confirmed the clinical suspicion of pancreatic ascites. The following day an ERCP was performed. The pancreatic duct was dilated at 4 mm with no obvious stricture. There was a leak of contrast from the region of the distal body into the peritoneal cavity. An endoscopic pancreatic stent was inserted with good drainage noted. Over the next 3 days the abdominal distension resolved and she was discharged home. Three weeks later a follow-up CT scan confirmed complete resolution of the ascites and a relatively normal pancreas with the stent in situ. She remained well and the stent was removed after 6 months. Unfortunately, she had further episodes of recurrent acute pancreatitis over the next 4 years and is likely to develop chronic pancreatitis.

Preliminary Examination of the Abdomen The traditionally taught five causes of generalised abdominal distension (the ‘five Fs’) are: flatus, fluid, faeces, fetus and fat. To this list should be added a sixth: massive organomegaly or ‘filthy big tumour’. For the patient presenting with generalised abdominal distension, a preliminary abdominal examination is worthwhile before a detailed history is taken to determine which of the ‘six Fs’ is the most likely cause. The reason for this departure from the usual sequence of history followed by examination is that history taking can be greatly simplified if the clinician has some prior idea of the underlying problem.

1. Flatus The cause of flatus is gaseous distension of the bowel often secondary to a bowel obstruction or paralytic ileus. There is generalised hyperresonance to percussion. Any fluid contained within the distended bowel associated with a bowel obstruction or ileus is clinically undetectable. It lies posteriorly with the patient lying supine and is not percussible. It is contained within bowel loops and cannot shift. Auscultation of the abdomen may reveal hyperactive bowel sounds with mechanical obstruction and absent or just a few ‘tinkly’ bowel sounds with paralytic ileus.

2. Fluid or ascites Intraperitoneal fluid collection is associated with dullness to percussion in the flanks with the patient lying supine. The dullness is described as shifting dullness because the upper limit of the dullness moves in relation to the abdominal wall as the patient is rolled onto the side. Massive ascites is also associated with a fluid thrill felt in one flank after tapping in the other. The distension is less globally distributed with ascites than with

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gaseous distension of the abdomen, with the effect that the flanks tend to sag.

3. Faeces Stool can accumulate in the colon to produce abdominal distension. This can cause gaseous distension of more proximal bowel. The degree of distension tends to be less than can occur with ascites or bowel obstruction. The faeces can be recognised as firm to hard lumps that are indentable when prodded with the tip of the examining finger (Ch 11). The segments of colon overlying the brim of the pelvis on the left and right sides may be more prominent to the examining hand.

4. Fetus Pregnancy and the associated enlarged uterus produce a globular firm mass, which arises out of the pelvis so that the examining hand cannot palpate an inferior border. In early pregnancy, the swelling is confined to the lower abdomen. The mass may reach as high as the epigastrium in late pregnancy. Further, bony fetal parts, such as the head and back, may be identifiable to palpation and fetal heart sounds may be heard on auscultation.

5. Fat Within the abdomen, fat commonly produces abdominal distension. It is known colloquially as ‘pot belly’ or ‘beer gut’. It does not have characteristic features on clinical examination except that other parts of the body are usually also obviously fat. Obesity is so prevalent that a previously obese patient may present with further distension due to one of the other ‘five Fs’. Evaluation by physical examination is always more difficult under these circumstances.

6. Filthy big tumour (massive organomegaly) Features of massive organomegaly are covered in Chapter 19.

History and Further Examination A classification of the causes of abdominal distension is presented in Table 20.1 and relevant symptoms are listed in Table 20.2. The duration of abdominal distension and its association with abdominal pain are key questions. Thus, abdominal pain should not usually be expected to be a feature, except with abdominal distension due to gas in bowel obstruction; with the other causes, there may be milder discomfort due to stretching of the parietal peritoneum or the capsule

of an organ. Localised pain can occur with organ swelling. Similarly, the speed of development for most causes is slow, except with abdominal distension from gas, in which case it can be fast. Tense swelling of the abdomen due to fluid or a large tumour can cause increased intraabdominal pressure leading to heartburn, nausea, vomiting or dyspnoea (from elevation of the diaphragm). The specific clinical features for each cause are described below.

Clinical Features Gaseous distension of the bowel (flatus) Mechanical obstruction of the bowel (small or large) The distension is usually acute in onset and develops over hours to days. The obstruction may be open or closed. Examples of open obstructions are a band adhesion occluding the lumen of the small bowel and a cicatrising carcinoma of the sigmoid colon. With these, the distension is generalised. Examples of closed obstructions are sigmoid and caecal volvulus. The time frame of development is similar. The abdominal distension with a sigmoid volvulus is directed from the pelvis towards the right hypochondrium, because the sigmoid mesocolon is attached to the left false pelvis. The abdominal distension with a caecal volvulus is directed from the pelvis towards the left hypochondrium, because of the attachment of the caecum to the right false pelvis. The distension is associated with other features of bowel obstruction, namely colicky abdominal pain, vomiting and constipation. The diagnosis and management of bowel obstruction is discussed in Chapter 4. Paralytic ileus This is often preceded by an abdominal operation. Operations involving retroperitoneal structures (e.g. repair of an aortic aneurysm), operations during which there is considerable handling of the bowel and prolonged operations are more prone to paralytic ileus. Irritation of the retroperitoneum as occurs with severe pancreatitis or a spontaneous retroperitoneal haemorrhage can precipitate an ileus. An intraabdominal inflammatory process such as acute diverticulitis and biochemical disturbances such as hypokalaemia, hypomagnesaemia and chronic kidney disease can also precipitate an ileus. In contradistinction to a mechanical bowel obstruction, there is no colicky pain with paralytic ileus, just the discomfort associated with distending the parietal peritoneum. The condition settles spontaneously

20 Abdominal distension

265

Table 20.1  Classification of causes of abdominal distension: the ‘six Fs’ Cause

Example

Distension

1. Flatus (gaseous distension) Bowel obstructed Open Closed

Generalised Sigmoid volvulus

Localised

Caecal volvulus

Localised

Paralytic ileus

Generalised

Pseudo-obstruction

Generalised

Irritable bowel syndrome

Generalised

Acute gastric dilatation

Localised

Gas bloat

Generalised

See Table 20.3 for detail

Generalised

Bowel not obstructed

2. Fluid (ascites) 3. Faeces

Localised

4. Fat

Generalised

5. Fetus

Localised

6. Filthy big tumour (organomegaly) Liver

See Chapter 19

Localised

Spleen

See Chapter 19

Localised

Ovary

Ovarian cyst

Localised

Uterus

Fibroids

Localised

Kidney

Polycystic kidney

Localised

Hydronephrosis



Localised

Bladder

Obstructed bladder

Localised

Mesentery

Tumour

Localised

Retroperitoneum

Tumour

Localised or generalised

Pseudo-obstruction The time course of pseudo-obstruction is more protracted than with mechanical obstruction; the degree of distension may fluctuate considerably. Pseudo-obstruction is discussed in Chapter 7.

Acute gastric dilatation This is most commonly seen soon after abdominal surgery or major trauma (not necessarily abdominal trauma). Diabetes mellitus is another cause. The key manifestation is copious vomiting of ‘coffee grounds’, a mixture of gastric secretions and old blood. Hypokalaemic alkalosis may result from the persistent vomiting. The condition is managed by decompression with a nasogastric tube and fluid replacement.

Irritable bowel syndrome This may be associated with chronic fluctuating abdominal distension of moderate degree. This condition is considered in detail in Chapter 7.

Gas bloat This particular chronic problem can occur as a complication of antireflux surgery for gastrooesophageal reflux (Ch 1). It results from air

with correction or resolution of precipitating factors. Gastric decompression and fluid replacement (and sometimes intravenous hyperalimentation) are required while resolution occurs.

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Table 20.2  Possible symptoms with abdominal distension Symptom

Relevance/significance

Abdominal pain: ll abdominal tightness/vague generalised ache; ll colicky (periumbilical or lower abdominal).

Non-specific Bowel obstruction

Nausea/vomiting

Bowel obstruction

Anorexia

Non-specific, malignancy, cirrhosis

Loss of weight

Non-specific, malignancy, cirrhosis

Bowel habit (recent and usual)

Bowel obstruction, constipation

Respiratory symptoms

Secondary to elevation of the diaphragm

Previous history of malignant disease

As a possible cause of ascites

Alcohol or drug abuse

As a cause of liver disease and ascites

Jaundice

Associated with liver disease

Easy bruising/spontaneous bleeding

Associated with liver disease

Missed menstrual cycle(s)

Pregnancy

swallowing in a patient who has a diminished ability to belch because of their surgery. The degree of distension of stomach and bowel can vary considerably. It is generally worse postprandially. There is usually some degree of discomfort. This may vary from a vague feeling of fullness to a more localised epigastric discomfort to central abdominal colicky pain. It may be relieved to a degree by passage of flatus.

Ascites (fluid) This usually develops gradually and continuously, with the onset over weeks to months, and is relatively painless. When the ascites is gross, there may be a vague discomfort caused by stretching of the abdominal wall and the parietal peritoneum. When ascites is painful, infected ascites, hepatoma or pancreatitis should be considered. There may be respiratory symptoms due to respiratory embarrassment with gross ascites or development of a pleural effusion (usually on the right due to a leak of fluid through the diaphragmatic lymphatics). The main causes of ascites and their prevalence are listed in Table 20.3. These are: ll cirrhosis: 80% of patients with ascites have cirrhosis. The causes of cirrhosis are discussed in Chapter 24. Risk factors to enquire about include alcohol abuse, intravenous drug use, tattoos, blood transfusion and living in developing countries where the prevalence of hepatitis B and hepatitis C is high. These patients may have splenomegaly due to portal hypertension as well as other stigmata of chronic liver disease

Table 20.3 Causes of ascites Cause

Prevalence (%)

Cirrhosis

80

Malignancy

10

Heart failure

5

Tuberculosis

1

Other: hypoproteinaemia caused by starvation (kwashiorkor and malignancy) or excessive loss (protein-losing enteropathy, nephrotic syndrome); pancreatic ascites; chylous ascites

4

ll

ll

including spider naevi, palmar erythema, proximal muscle wasting, jaundice, fetor, flap, testicular atrophy and gynaecomastia; malignancy: 10% of patients have ascites secondary to malignancy. The three malignancies most commonly associated with ascites are gastric, colonic and ovarian carcinomas. Most of these patients have a past history of malignancy. In some, abdominal distension is the presenting feature. There may be hepatomegaly or lymphadenopathy or other evidence of tumour spread; cardiac ascites: cardiac ascites is secondary to severe right-sided heart failure, most commonly due to constrictive pericarditis. Other signs include an elevated jugular venous pressure, pulsatile tender hepatomegaly and peripheral oedema;

20 Abdominal distension ll

ll

ll

267

hypoproteinaemia: ascites due to hypoproteinaemia (e.g. from starvation, or excessive loss from protein-losing enteropathy or nephrotic syndrome) is minor in degree and associated with peripheral oedema; pancreatic ascites: this is only seen after severe acute pancreatitis or a blunt transacting injury to the pancreas. It is due to a persistent leak of pancreatic fluid from the pancreatic duct into the peritoneal cavity. The leak may be due to a side hole in the pancreatic duct or due to complete dissociation of the proximal and distal duct; chylous ascites: this results from surgical trauma to cisterna chyli or rarely due to obstruction by lymphatic spread of tumour.

Faecal impaction of the colon (faeces) This is a chronic problem caused by chronic constipation, and is most commonly seen in elderly people. The various causes of constipation are considered in detail in Chapter 11. Abdominal distension is an uncommon feature of the most severe end of the spectrum. A history of infrequent, usually hard bowel actions is expected. A history of laxative abuse is also very common. Lower abdominal colicky pain may be associated. When such pain occurs it should be relieved by the passage of flatus or a large evacuation of the bowel.

Pregnancy (fetus) This is associated with a menstrual-free period in women.

Abdominal distension due to obesity (fat) This is painless and longstanding. The deposition of fat is in the mesentery of the bowel and the omentum to a greater degree, and in the anterior abdominal wall to a lesser degree in men. In women there is a greater proportion of fat deposited in the abdominal wall, as compared to the mesentery of the bowel and omentum.

Figure 20.1  Plain abdominal x-ray film showing small bowel obstruction. There is dilatation of the small bowel. It is recognised as small bowel from its central position and its transverse mucosal bands—the valvulae conniventes (black arrow). Air-fluid levels are seen on the erect view. The supine view gives a better view of the distribution of the dilated loops. From the number and position of the displayed dilated loops, the obstruction would be at the level of the mid-small bowel. The round radio-opaque shadow in the left hypochondrium is a tablet (open arrow). From Talley NJ, O'Connor S. Clinical examination. 6th edn. Sydney: Elsevier Australia; 2010.

Organomegaly The presenting history of patients with organomegaly resulting in abdominal distension is covered in Chapter 19.

give a ‘ground glass’ appearance, a non-specific vague increased whiteness to the abdominal cavity.

Investigations

Ultrasound or CT of the abdomen

The appropriate investigations to evaluate abdominal distension are detailed below.

This will confirm the presence of ascites (Fig 20.3) and define organomegaly.

Plain radiology of the abdomen

Blood tests

This may demonstrate a small or large bowel obstruction and paralytic ileus (Figs 20.1 and 20.2) as well as faecal loading. The fluid of ascites may

Liver function tests may indicate underlying chronic liver disease (Ch 24). A pregnancy test will confirm the presence of pregnancy.

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Figure 20.3  Abdominal CT showing ascites.

The features of ascitic fluid are summarised in Table 20.4.

Appearance Figure 20.2  Plain abdominal X-ray film showing generalised ileus. The large bowel is filled with gas and is dilated except in the descending colon. Dilated small bowel is also seen in the right hypochondrium (arrow). As gas is seen around to the rectum (arrow), mechanical obstruction is excluded. From Talley NJ, O'Connor S. Clinical examination. 6th edn. Sydney: Elsevier Australia; 2010.

There is no specific relevant test for obesity. Measure the weight and height to calculate the body mass index (BMI = weight [kg] divided by height squared [m2]). A BMI of 30 or over indicates frank obesity; a BMI of 40 or over indicates severe obesity (Ch 26). The diagnosis can usually be made on clinical grounds. Of the various causes of abdominal distension, only ascites will be discussed in further detail in this chapter. Bowel obstruction is discussed in Chapter 4. Constipation is discussed in Chapter 11. Pregnancy is beyond the scope of this text.

Diagnosis of Ascites There are two clinical steps to determining the cause of ascites. First, the clinical history and examination need to be focused on elucidating which pathological process underlies the accumulation of ascites. Secondly, a sample of the ascites needs to be examined. The sample is aspirated and its appearance noted before it is sent to the laboratory for biochemical, cytological and microbiological analysis. Blood needs to be sent at the same time for estimation of the serum albumin level.

Blood staining suggests malignancy or a traumatic ascitic tap, either current or past; turbidity or white fluid suggests infected or chylous ascites.

Serum-ascites albumin gradient Calculate this by subtracting the ascitic fluid albumin from the serum albumin value; the serumascites albumin gradient (SAAG) correlates with portal pressure. If the SAAG is 11 g/L or more, then portal hypertension is the likely diagnosis (97% accurate). Peritoneal carcinomatosis, tuberculosis and pancreatic ascites have a gradient under 11 g/L (Table 20.5).

Other biochemistry If pancreatic ascites is suspected, the ascitic amylase level needs to be assessed; it is very high in pancreatic ascites. A low pH (under 7.35) suggests spontaneous bacterial peritonitis or systemic acidosis. The lactate level is elevated in spontaneous bacterial peritonitis. If chylous ascites is suspected, the diagnosis can be confirmed by staining the specimen for fat.

Cells Examination of the ascites for polymorphonuclear cells is important to diagnose spontaneous bacterial peritonitis. A cell count of 250 × 106 polymorphs/L (250 polymorphs/mm3) or more, or 500 × 106 white cells/L (500 cells/mm3) or more, is strongly suggestive of the diagnosis. The cause is usually a gram-negative organism sensitive to treatment with a third-generation cephalosporin (e.g. cefotaxime).

20 Abdominal distension

269

Table 20.4 Characteristics of paracentesis fluid Aetiology

Colour

SAAG (g/L)

RBC (10 6/L)

WBC (10 6/L)

Cytology

Other

Cirrhosis

Straw

≥ 11

Few

< 250





Infected ascites

Straw

≥ 11

Few

≥ 250 polymorphs or ≥ 500 cells



+ve culture

Neoplastic

Straw/ haemorrhagic/ mucinous

< 11

Variable

Variable

Malignant cells



Tuberculosis

Clear/turbid/ haemorrhagic

< 11

Many

> 1000 70% lymphocytes



Acid-fast bacilli + culture

Cardiac failure

Straw

≥ 11

0

< 250





Pancreatic

Turbid/ haemorrhagic

< 11

Variable

Variable



Amylase increased

Lymphatic obstruction or disruption

White

< 11

0

0



Fat globules on staining

RBC = red blood cell count; SAAG = serum-ascites albumin gradient; WBC = white blood cell count.

Cytology If the SAAG is less than 11 g/L or malignancy is otherwise suspected, a cytological examination looking for malignant cells should be performed after the sample has been centrifuged. Establishment of the primary site is usually not possible using this specimen.

Culture As spontaneous bacterial peritonitis is insidious in onset and may have few associated symptoms and signs, a sample of ascites is always cultured. It is advisable to insert the specimen into blood culture bottles after collection to maximise the chance of a positive result. At the same time, the ascites should be cultured for acid-fast bacilli to diagnose the occasional case of tuberculous peritonitis.

Management of Ascites This depends on the underlying diagnosis, as follows.

Liver disease The management of ascites in liver disease is covered in Chapters 24 and 25.

Malignant ascites It is important to try to establish the site of the primary tumour because systemic hormonal or chemotherapy can result in regression of the

Table 20.5  Classification of ascites by ­ serum-ascites albumin gradient (SAAG) SAAG: high (≥ 11 g/L)

SAAG: low (< 11 g/L)

Cirrhosis Alcoholic hepatitis Cardiac ascites Massive liver metastases Fulminant hepatic failure Cirrhosis plus another cause

Peritoneal carcinomatosis Tuberculous peritonitis Pancreatic ascites Bile leak

intraperitoneal tumour and the ascites, especially if the primary site is colonic, gastric, breast or ovary. Clinical re-examination of breasts and abdomen may be helpful. The investigations used to establish the common sites of the primary tumour, namely colon, stomach, pancreas, ovary and breast, are shown in Table 20.6. In the event that the primary site is colon, stomach or pancreas, local therapy may be required to palliate the discomfort of distension. The therapeutic options are limited and none is really satisfactory. They include (1) repeated major paracentesis, which is time-consuming and results in the development of hypoalbuminaemia and malnutrition; and (2) peritoneovenous shunting, which can block and can be complicated by coagulopathy. Frequently, the best option is analgesia and general support.

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Colon

Colonoscopy and biopsy

disruption of the main pancreatic duct. If the duct is intact with a leak from a side hole, the leak may resolve with endoscopic pancreatic stenting. If there is complete disruption of the duct a distal pancreatectomy is required.

Stomach

Gastroscopy and biopsy

Key Points

Pancreas

Ultrasound ± CT scan ± fine needle aspiration EUS ± needle biopsy CA-19-9

Ovary

Pelvic ultrasound ± CT scan CEA, CA125

Breast

Mammography or fine needle aspiration cytology if palpable lump Breast biopsy and oestrogen receptors

Table 20.6  Investigations for primary tumour in patients with malignant ascites Site of primary Relevant investigations

CEA = carcinoembryonic antigen; CT = computerised tomography; EUS = endoscopic ultrasound.

Cardiac ascites The management is directed at treating the cardiac cause. This may involve pericardectomy if constrictive pericarditis is the underlying problem.

Pancreatic ascites Pancreatic ascites may settle with conservative management. This includes ‘pancreatic rest’ with enteric nutrition via a nasojejunal feeding tube. If the ascites fails to resolve over 2 weeks, it is unlikely to resolve and therapeutic intervention is required. Endoscopic retrograde cholangiopancreatography should be performed to define the location of the

ll

ll

ll

ll

ll

The aetiology of diffuse abdominal distension can be defined with the ‘5 Fs’ rule: flatus, fluid, faeces, foetus or fluid. For flatus and faeces, consider obstructive lesions in the small or large bowel or a motility disturbance. For fluid consider hepatic, inflammatory, malignant or pancreatic causes. Foetus is usually self-evident but must be considered. Fat or obesity is diagnosed after the other 4 ‘Fs’ have been excluded.

Further reading Runyon BA, Montano AA, Akriviadis EA, et al. The serumascites albumin gradient is superior to the exudate/ transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992; 117: 215–220. Saadeh S, Davis GL. Management of ascites in patients with end-stage liver disease. Rev Gastroenterol Disord 2004; 4:175–185. Smith EM, Jayson GC. The current and future management of malignant ascites. Clin Oncol 2003; 15:59–72. Williams JW Jr, Simel DL. The rational clinical examination. Does this patient have ascites? How to divine fluid in the abdomen. J Am Med Assoc 1992; 267:2645–2648.

21 Lumps in the groin and hernia

Case A 69-year-old man presents with a mass to the left of his umbilicus. He had noted this would come up when he stood or if he coughed or strained. The mass was getting progressively larger over the previous 4 or 5 months. There was no recent history of abdominal pain, constipation, vomiting or abdominal distension. He did not have a chronic cough. Eighteen months earlier he had an anterior resection for a Dukes’ C carcinoma of the distal sigmoid colon, followed by a course of adjuvant chemotherapy. He was otherwise fit and well. Abdominal examination in the supine position revealed a well man with a midline laparotomy scar. There was a 6 by 8 cm mass that became apparent when he coughed or elevated his head. As soon as the abdominal straining ceased, the mass disappeared. Palpation revealed a 3 cm defect close to the midline with an associated cough impulse. When standing, an obvious mass appeared, but remained soft. The clinical assessment was of an incisional hernia. A CT of the abdomen was performed to ensure there was no unexpected metastatic disease. This confirmed the hernia and excluded metastatic disease. He proceeded to an open incisional hernia repair using an underlay mesh technique.

Introduction The complaint of ‘a lump in the groin’ is commonly encountered in general clinical practice. The causes of this complaint are listed in Box 21.1. In the vast majority of cases, the cause is a hernia. The key clinical differentiation usually required is between a hernia and an enlarged inguinal lymph node. If a hernia is the problem, the clinician then has to decide whether it is inguinal or femoral.

One should be aware that patients do not always mean the inguinofemoral region when they refer to the groin. Thus, in the parlance of cricket, being ‘hit in the groin’ may mean the scrotum.

History The painless lump The lump in the groin may have been a chance finding by the patient and may not be associated with symptoms. Each of the conditions listed in Box 21.1 may present as a painless lump. Indeed, pain does not occur with a saphena varix, lipoma of the cord, encysted hydrocoele of the cord, hydrocoele of the canal of Nuck, or testicular maldescent. Hernias, inguinal lymphadenopathy and femoral aneurysms may or may not be associated with pain. Historically, the development of a hernia may have been preceded by groin pain after a heavy lift or ‘strain’. However, many hernias appear without any such antecedent history.

Box 21.1  Causes of a lump in the groin Common causes Inguinal hernia ll Femoral hernia ll Lymph node Other causes ll Saphena varix ll Femoral artery aneurysm/pseudoaneurysm ll Psoas abscess ll Lipoma of the cord ll Encysted hydrocoele of the cord (male) ll Testicular maldescent (male) ll Hydrocoele of canal of Nuck (female) ll

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The painful lump Hernias can be associated with several types of pain. First, there may be a dull ache in the groin experienced when the hernia is filled with intraabdominal contents, such as bowel or omentum. This ache is relieved by spontaneous reduction of the hernia, such as often occurs when the patient lies down. In these patients, the ache is typically worse at the end of a long, physically active day when the intraabdominal contents have filled and distended the hernial sac. Secondly, there is the pain secondary to venous congestion of the intraabdominal contents of the hernial sac, caused by the constrictive effect of the neck of the hernia on venous outflow of the contents. This is a more severe, constant pain that may increase in intensity should venous congestion progress to arterial insufficiency (strangulation). In this circumstance, the hernia will not be reducible and will be locally tender to palpation. These symptoms and signs are related to inflammation in the tissues around the hernial sac. Incarceration of the contents of a hernia within a hernial sac may be associated with intestinal obstruction, which is more commonly small bowel than large bowel. Small bowel obstruction is associated with central abdominal colicky pain, vomiting, abdominal distension and constipation (Ch 4). A painful enlarged lymph node is always inflamed. An inflamed lymph node is associated with a constant ache without abdominal symptoms. Not uncommonly, the cause of the inflamed lymph node, such as an infected ulcer or boil on the foot, will also be a source of pain. A femoral artery aneurysm, or pseudoaneurysm, is rarely painful. This is because the rate of expansion of the aneurysm is usually slow. Rapid expansion is more common with a pseudoaneurysm than a true aneurysm, and can be associated with a dull ache. A false aneurysm is secondary to puncture or rupture of the artery, as can occur after angiography or penetrating trauma. If the puncture site does not close or seal, there is a communication between the lumen of the artery and the haematoma outside the artery. A true aneurysm is surrounded by attenuated arterial wall, while a false aneurysm is surrounded by a fibrous capsule.

Reducibility There are three causes of a reducible lump: an inguinal hernia (most common); a femoral hernia; and a saphena varix (least common). A saphena varix is always reducible as it always disappears when the patient lies down. An inguinal hernia

is commonly reducible, while a femoral hernia is less often reducible because the neck is usually narrow and rigid. An incarcerated hernia is where the contents of a hernial sac are irreducible. This may lead to intestinal obstruction or even strangulation of the hernial contents (as above).

Physical Examination Anatomical localisation of the lump The initial step in the physical examination is to stand the patient to define whether the lump is in the inguinal or femoral region, whether or not there is a cough impulse and also observe if there is bilateral swelling. The two regions are separated by the inguinal ligament, which stretches between the anterior superior iliac spine laterally and the pubic tubercle medially. Both of these bony prominences are readily palpable. The other useful landmark to determine the precise position of lumps in the femoral region is the femoral artery, located just below the midinguinal point and identifiable by its pulsatile nature. The midinguinal point is situated midway between the anterior superior iliac spine and the pubic symphysis. Figure 21.1 details the various groin lumps above and below the inguinal ligament.

Lumps in the inguinal region (above inguinal ligament) Inguinal hernias Inguinal hernias exit from the abdominal cavity and then pass along the inguinal canal together with the spermatic cord in the male. The inguinal canal passes medially from the deep inguinal ring, the surface marking of which is the midinguinal point (see above) to the superficial inguinal ring, which is just above and medial to the pubic tubercle (Fig 21.2). It is imperative to examine the patient complaining of a lump in the groin while the patient is standing because a hernia may be apparent only in this position. Having examined in the standing position, have the patient lie down and determine if the hernia is reducible—coughing should also cause it to return. By placing the fingers along the line of the inguinal canal and asking the patient to cough, a cough impulse may be elicited; this is a pathognomonic sign of an inguinal hernia. This sign refers to the sudden expansion of a bulge beneath the examining fingers, which occurs when the increase of intraabdominal pressure blows some of the intraabdominal contents out into the

21 Lumps in the groin and hernia

273

GROIN LUMP

Is the lump above/below inguinal ligament?

ABOVE INGUINAL LIGAMENT

BELOW INGUINAL LIGAMENT

INGUINAL HERNIA Encysted hydrocele of cord Testicular maldescent Cyst of canal of Nuck Lipoma of the cord Iliac lymph node

LYMPH NODE (femoral) FEMORAL HERNIA Saphena varix Femoral aneurism Psoas abscess

Figure 21.1  Groin lumps below and above the inguinal ligament.

hernial sac. If the examiner believes that the sign has been elicited, then it is worth trying to elicit the sign on the contralateral side for two reasons. First, inguinal hernias are not uncommonly bilateral. Secondly, the cough impulse of a hernia can be confused with a normal anterior movement of the whole of the lower anterior abdominal wall anteriorly with coughing. This anterior movement is not expansile.

of the hernia, with the neck of the funnel being opposite to the neck of the hernia. Pressure is then applied by the other examining hand on the distal end of the hernia in the direction of the neck of the hernia. If the hernia is painful and tender, taxis should not be attempted and urgent surgical consultation arranged. Reduction of ischaemic bowel complicates the surgical management of the clinical problem.

Direct and indirect inguinal hernias Inguinal hernias are defined as direct or indirect (Fig 21.2). With a direct hernia, the hernial sac enters the inguinal canal through a weakness in the tissues of the posterior wall of the inguinal canal. With an indirect hernia, the sac enters the inguinal canal through the deep inguinal ring. The distinction between the two types of inguinal hernias is of little practical importance. From the prognostic point of view, indirect hernias more commonly develop the complication of strangulation (a strangulated hernia is one in which the contents are ischaemic) as the neck is narrower. Indirect hernias more commonly pass down into the scrotum than do direct hernias. Direct inguinal hernias are more commonly bilateral and have a wider neck. Some inguinal hernias, particularly the larger ones, may not reduce spontaneously but can be reduced with assistance. This manoeuvre is called taxis (pronounced taksis). It is achieved by making a funnel of one hand around the neck

Reducible or irreducible? An irreducible inguinal lump may be an irreducible inguinal hernia; a lipoma of the cord; an encysted hydrocoele of the cord (in males); a hydrocoele of the canal of Nuck (in females); a maldescended (ectopic) testis. To sort out the diagnosis, it is imperative to first examine the scrotum to ensure that there are two testes present. If there is only one, then a maldescended testis is likely to be the diagnosis. The diagnosis can be confirmed with an ultrasound examination. The maldescended testis is most commonly located by palpation just superior to the pubic tubercle. An irreducible inguinal hernia is usually soft and may have a ‘squelchy’ feel to it. An encysted hydrocoele of the cord within the inguinal canal should be suspected if traction on the ipsilateral testis causes the lump to move medially along the inguinal canal. An encysted hydrocoele of the cord distal to the superficial inguinal ring should be suspected on clinical examination by

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Anterior superior iliac spine Abdominal crease Pubic tubercle Groin crease

External oblique aponeurosis External inguinal ring Femoral vessels and nerve Spermatic cord

Surface land marks

The external oblique muscle

An indirect inguinal hernia

A direct inguinal hernia

Sac begins at the internal ring and is inside the spermatic cord

Sac appears medial to the inferior epigastric artery and is outside the spermatic cord

Figure 21.2  Anatomy of the inguinal region and important landmarks. From Browne NL. An introduction to the symptoms and signs of surgical disease. 3rd edn. New York: Oxford University Press; 1977.

the presence of a transilluminable swelling in close proximity to the spermatic cord; this does not extend laterally into the superficial inguinal ring, making differentiation from an inguinal hernia relatively easy. If there is any doubt about the diagnosis of an encysted hydrocoele of the cord and a hydrocoele of the canal of Nuck, then the diagnosis can be confirmed by an ultrasound examination. A lipoma of the cord cannot be distinguished from an inguinal hernia on clinical examination. It is a diagnosis made by the operating surgeon. Lipomas of the cord are also frequently associated with indirect inguinal hernias. The only possibility that needs to be considered is that the lump is not in the inguinal canal, but rather deep into it. Thus an enlarged external iliac lymph node might be palpable through the anterior abdominal wall, but only in a very thin patient.

Lumps in the femoral region (below inguinal ligament) Figure 21.1 details the various groin lumps below the inguinal ligament. Anatomy of the femoral region The femoral region is inferior to the inguinal ligament. The reference point in the femoral region is the femoral artery, which is located inferior to the midinguinal point as a pulsatile longitudinal cord. Deep to the femoral artery is the psoas muscle, which passes posteriorly to attach to the lesser trochanter of the femur. Lateral to the femoral artery is the femoral nerve. Medial to it is the femoral vein into which drains the long saphenous vein. Medial to the femoral vein is the femoral canal through which a femoral hernia emerges from the abdominal cavity. The femoral canal usually contains just fatty tissue and a few

21 Lumps in the groin and hernia tiny lymph nodes. Within the femoral region are the inguinal lymph nodes. They are divided into two groups, deep and superficial, depending on whether they are deep or superficial to the deep fascia. The deep group lie around the femoral vein. The superficial group are placed horizontally just below and parallel to the inguinal ligament or vertically along the line of the long saphenous vein. Physical examination of the femoral region Evaluate for the following: ll single or multiple: the only cause of multiple lumps in the femoral region is multiple enlarged lymph nodes. The presence of a single lump in the femoral region does not exclude an enlarged lymph node as the cause, as lymph nodes can enlarge individually or can expand as a matted mass; ll reducible or irreducible: if the femoral lump is reducible, then it is either a femoral hernia or more likely a saphena varix. A saphena varix is always easily reducible. Pressure is not required if the patient goes from the standing to the supine position. Although a femoral hernia may be reducible, most are not reducible because the neck of this type of hernia tends to be small so that the contents easily become entrapped within the hernial sac; ll

ll

mobile or immobile: none of the common groin lumps is fixed to the underlying bony pelvis and hip joint, yet, as most are encased by the deep fascia of the thigh, they are relatively immobile. This is particularly so for a small irreducible femoral hernia, which is relatively fixed by bony and ligamentous structures around its neck. An enlarged inguinal lymph node is marginally more mobile than a femoral hernia in the transverse direction; the presence of a cough impulse: the presence of this physical sign limits the diagnostic possibilities to a femoral hernia or a saphena varix. A saphena varix is a varicosity of the most proximal section of the long saphenous vein. It is associated with incompetence of the valve between the saphenous vein and the femoral vein. When the patient coughs, a palpable jet of blood spurts through the incompetent saphenofemoral valve into the saphena varix. Tapping may be associated with the palpable transmission of the impulse to the saphena varix along the line of the long saphenous vein (a fluid thrill). A saphena varix is usually associated with incompetence of the

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long saphenous vein and, hence, the presence of varicose veins in the distribution of the long saphenous vein; ll

ll

pulsatile or non-pulsatile: if the femoral lump is pulsatile, then it is either an aneurysm or a pseudoaneurysm of the femoral artery; tender or non-tender: a femoral hernia may become tender if the vascularity of its contents is in any way impaired so that the contents and, subsequently, the neck and surroundings become inflamed. An inguinal lymph node will be tender if there is inflammation within the lymph node. A femoral artery aneurysm or pseudoaneurysm will be tender if there is inflammation in the surrounding tissues as a result of rapid expansion. A psoas abscess is not usually tender because the inflammation is typically chronic. This unusual lump more commonly lies lateral to the femoral artery and will often be associated with a flexion deformity of the hip because of chronic irritation and contracture of the major flexor of the hip, the psoas muscle. Further, there may be a pain in the flank as well as fever, and occasionally signs of femoral nerve irritation.

Diagnosis remains uncertain After the physical examination of the femoral region has been completed, the examiner may still not be sure whether the femoral lump is an enlarged lymph node or a femoral hernia. The next step is to carefully examine the area drained by the inguinofemoral nodes as well as the reticuloendothelial system in general, as the enlarged lymph node may be part of a more generalised disease (e.g. lymphoma). As part of such a ‘lymphatic look’ it is vital to look carefully for a focus of infection or neoplasia as well as for any old scars that may represent a previously excised tumour. Boxes 21.2 and 21.3 list all of the areas that should be included in your ‘lymphatic look’.

Box 21.2  General lymphatic look: reticuloendothelial system ll ll ll ll ll ll

Cervical lymph nodes Supraclavicular lymph nodes Axillary lymph nodes Para-aortic nodes Liver Spleen

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Clinical gastroenterology: a practical problem-based approach An ultrasound may help to further define the nature of the lump.

Box 21.3  Local lymphatic look ll

ll ll

ll ll

ll ll ll

Feet—including between the toes and on the sole of the foot Legs External genitalia—male: penis and scrotum; female: labia, vagina below level of hymen Perineal skin Anal canal—below level of mucocutaneous junction Buttocks Abdominal wall—to level of umbilicus Back—to level of umbilicus

Management of Groin Lumps Management of femoral and inguinal hernias The preferred method of treatment is surgical repair (either open surgery or laparoscopic), the only method to cure an inguinal or a femoral hernia (see Fig 21.3). This has the benefit of relieving the inconvenience or discomfort of the hernia and, at the same time, preventing complications. Technically speaking, the hernia is always better to repair when it is small.

History

Examine Multiple

Solitary

Cough impulse or reducible lump

Non- reducible lump

Hernia Saphena varix

Hernia Lymph node Maldescended testis Psoas abscess Lipoma cord Femoral aneurism

Examine: – Varicose veins?

Hernia

Haematology Serology Histology/ cytology

Saphena varix Examine: – Scrotum – Pulsatile? – Relationship to femoral artery

Elective repair

Hernia

Hernia/node?

Repair

Explore surgically

Complicated: urgent

Irreducible, non-tender: elective

Tender: urgent

Lymph node

Non-tender: non-urgent

Figure 21.3  Summary of management of a lump in the groin.

Biopsy/cytology Consider systemic illness

21 Lumps in the groin and hernia Questions that need to be addressed when an inguinal or femoral hernia is being considered for surgical repair are: ll Is the hernia symptomatic? ll What is the risk of strangulation? ll What is the risk of a surgical repair in this patient? The finding of a markedly tender lump in the groin is important. The differential diagnosis is usually between a strangulated hernia (inguinal or femoral) and an inflamed lymph node. For the clinician to decide that the cause is an inflamed lymph node, the primary focus of infection must be very apparent. Otherwise the diagnosis is an incarcerated hernia with contents of doubtful viability (strangulated) until proven otherwise. If there is any doubt about the viability of the contents of a hernia, surgical repair of the hernia must be performed urgently. The situation is less pressing if the tenderness is only minor. A minor degree of tenderness in enlarged inguinal lymph nodes is relatively common. Frequently, the cause of a minor degree of lymphadenitis is not apparent and the symptoms and signs settle spontaneously with observation. The repair of inguinal hernias in the very young (neonates and young children) should be performed electively but as soon as possible because, at least in males, there is a risk that strangulation of the hernia may be associated with testicular infarction. If the contents of a hernia are strangulated, then operative repair needs to be performed on an emergency basis. After initial fluid resuscitation, the hernia is opened and the viability of its contents is assessed. If the contents are viable, then the contents can be returned to the abdomen and the hernia repaired in a standard fashion. If the contents are non-viable, then they need to be resected and bowel continuity restored prior to the hernia repair. The alternatives to surgical repair are observation alone and fitting a surgical truss. Observation alone might be considered if the patient is frail, particularly if the hernial sac is small and its neck wide. A surgical truss may relieve the dull ache of a hernia by maintaining the hernia reduced. The patient needs to be aware that, even if the truss is worn regularly, the hernia itself can cause significant discomfort and that permanent reduction is not guaranteed. Indeed, strangulation of a hernia can occur while the truss is fitted. In view of the limitations and problems with surgical trusses, most patients should

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have the hernia repaired surgically, especially as the procedure can be performed under local anaesthesia in most cases.

Management of an enlarged lymph node An enlarged inguinal lymph node may be solitary, associated with other enlarged lymph nodes in the groin or associated with a more generalised process of the lymphatic system (see Fig 21.3). Lymphadenitis If the enlarged lymph node is secondary to a primary infection elsewhere, then it is appropriate to treat the primary infection. If the enlarged lymph node is suspected to be part of a neoplastic process, then biopsy is indicated. Biopsy is performed to diagnose and stage the tumour. A biopsy is also required of the lesion thought to be the causative primary lesion. Fine needle aspiration cytology is reasonable in the first instance. Thereafter, a whole lymph node may need to be excised if the diagnosis is thought to be lymphoma. If the diagnosis is metastatic tumour, then an ‘en bloc’ dissection of lymph nodes in the groin may be performed as part of the treatment of the tumour. The most common example of this is radical clearance of groin nodes for metastatic melanoma in the inguinal lymph nodes after the primary has been adequately treated and when no distant metastases are apparent.

Generalised lymphadenopathy If the inguinal lymphadenopathy is part of a more generalised lymphadenopathy, then an explanation for a generalised illness is required. Investigations under these circumstances may need to include: ll full blood count; ll erythrocyte sedimentation rate or C-reactive protein levels; ll chest x-ray; ll CT scan to look at those ‘hidden’ mediastinal and aortic lymph nodes; ll HIV status; ll serological tests for infectious mononucleosis (e.g. mono spot test); and ll other serological investigations for infection, such as toxoplasmosis and cytomegalovirus infections. If the cause is not found by non-invasive investigations, then surgical biopsy may be required. Nodes other than inguinal lymph nodes are usually biopsied as non-specific inflammatory

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changes are commonly found in inguinal lymph nodes of normal patients.

ll

Management of a saphena varix

ll

The management of this lesion will be the management of incompetent veins in the leg. If the lesion is to be treated, then ligation of the saphenofemoral junction needs to be performed.

ll

Management of a psoas abscess A psoas abscess presenting as a groin lump is extremely uncommon. In the past, when tuberculosis of the spine was a condition commonly encountered in clinical practice, the ‘cold abscess’ (so described because of the lack of an associated acute inflammatory response and lack of pain and tenderness) could point to the groin usually lateral to the femoral artery. In current practice, the development of a psoas abscess is usually secondary to a posterior bowel perforation. The primary pathology may be retrocaecal appendicitis, an inflammatory condition of the bowel such as Crohn's disease, diverticulitis or local invasion from an overlying colon cancer. The symptoms, loin pain and fever, generated by bowel organisms focally invading the psoas muscle are usually sufficient to demand clinical attention at an earlier stage. The diagnosis is usually confirmed by imaging the retroperitoneum by CT. Drainage of the abdominal abscess is performed either posteriorly or anteriorly, together with surgery for the primary problem.

Key Points ll

ll

ll

Know your landmarks. The inguinal and femoral regions are separated by the inguinal ligament, which stretches between the anterior superior iliac spine laterally and the pubic tubercle medially. Ask the patient to cough. A cough impulse may be elicited; this is a pathognomonic sign of a hernia. Examine the patient complaining of a lump in the groin while the patient is standing because a hernia may be apparent only in this position.

ll

ll

ll

ll

Causes of a reducible groin lump include an inguinal hernia (most common), femoral hernia or saphena varix. An irreducible inguinal lump (positioned above the inguinal ligament) may be due to an irreducible inguinal hernia, lipoma, hydrocele or maldescended (ectopic) testis. An irreducible non-pulsatile lump in the femoral region (below the inguinal ligament) is probably a femoral hernia. Multiple lumps in the femoral region suggest multiple enlarged lymph nodes, not a hernia. A markedly tender lump in the groin usually indicates a strangulated hernia (inguinal or femoral) or an inflamed lymph node. Urgent surgical referral is indicated unless the doctor is convinced the cause is an inflamed lymph node, when the primary focus of infection is usually very apparent. Incarceration of the contents of a hernia within a hernial sac may be associated with colicky pain, vomiting, abdominal distension and constipation (intestinal obstruction). An ultrasound may help to further define the nature of a lump in the groin.

Further reading Avisse C, Delattre JF, Flament JB. The inguinal rings. Surg Clin North Am 2000; 80:49–69. Corder AP. The diagnosis of femoral hernia. Postgrad Med J 1992; 68:26–28. Kingsnorth A, LeBlanc K. Hernias: inguinal and incisional. Lancet 2003; 362:1561–571. McIntosh A, Hutchinson A, Roberts A, et al. Evidencebased management of groin hernia in primary care—a systematic review. Fam Pract 2000; 17:442–447. Oishi SN, Page CP, Schwesinger WH. Complicated presentations of groin hernias. Am J Surg 1991; 162:568–570. Talley NJ, O'Connor S. Clinical examination. 6th edn. Sydney: Churchill Livingstone; 2010.

Acknowledgement The original chapter was written by Professor C Martin.

22 Rectal/perianal mass and colorectal cancer

Colorectal cancer is the third most common cause of cancer mortality in most developed countries. Screening and early endoscopic intervention form the crux of management strategy.

Case A 60-year-old man presents with a 6-months’ history of intermittent rectal bleeding. In the last few weeks, he has experienced a change in bowel habit with faecal urgency and frequency. He attributes the bleeding to haemorrhoids as he feels a lump protruding out of his anus following defecation. He does not have a family history of bowel cancer. This may be the first presentation of an individual with colorectal cancer.

Rectal or Perianal Mass There are three ways a patient with a perianal or rectal mass may present: 1. the patient may have felt a lump; 2. the patient may present with some other anorectal symptom, such as pain, and a lump is found on physical examination; or 3. a mass may be an incidental finding on routine physical examination. The causes of a lump in the rectum are listed in Box 22.1.

History Establish when the lump was first recognised and whether it has changed over time. An intermittent nature suggests that the lump relates to prolapse of a lesion from the rectum (e.g. haemorrhoids or rectal prolapse). Determine if the lump could be manually reduced when the lump is external to the anus. Haemorrhoids are a classic example of a potentially reducible lump, but the differential diagnosis includes rectal prolapse and hypertrophied anal papilla. An acute time course favours conditions such as thrombosed internal

or external haemorrhoids. Tenderness suggests an infective process such as an ischiorectal abscess (Chapter 12). If a rectal lump is found, ask about painful straining or feeling of incomplete rectal evacuation. The sense of faecal urgency associated with these symptoms is referred to as tenesmus; these complaints may occur with any irritating lesion of the rectum. Another key symptom is rectal bleeding. Never ignore rectal bleeding and never assume it has a benign cause; bleeding should raise the suspicion of colorectal cancer. Ask about a family history

Box 22.1  Causes of a palpable mass in the rectum ll ll ll ll

ll

ll

ll

ll ll ll ll ll ll ll ll

Rectal carcinoma Rectal polyp Hypertrophied anal papilla Diverticular phlegmon (prolapsing into the pouch of Douglas) Sigmoid colon carcinoma (prolapsing into the pouch of Douglas) Metastatic deposits at the pelvic reflection (Blumer's shelf) Primary pelvic malignancy (uterine, ovarian, prostatic or cervical) Mesorectal lymph nodes Endometriosis Solitary rectal ulcer syndrome Foreign body Faeces (indent) Presacral cyst Amoebic granuloma A vaginal tampon and even the pubic bone may be mistaken for a rectal mass.

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of gastrointestinal disease and, in particular, colon cancer or polyps. Less commonly, a solitary rectal ulcer secondary to prolapse of the rectum can cause bleeding and tenesmus. The passage of mucus may occur with benign or malignant tumours as well as ulceration. Systemic symptoms such as weight loss (e.g. with malignancy) or fever (e.g. with an abscess) may also help point towards the correct diagnosis. A history of menstrual bleeding associated with a tender lump may suggest a perineal endometrial deposit that rarely occurs.

Physical examination Inspection Careful inspection is crucial (see Chapter 12) but, importantly, one must expect to find an abnormality. Place the patient in the left lateral position with the buttocks well over the edge of the couch. Part the buttocks, looking for perianal skin tags, which may be associated with pruritus due to suboptimal hygiene. These are usually haemorrhoidal remnants, but they can occasionally be an indicator of a systemic process such as Crohn's disease (Chapter 15). A perianal haematoma may be visible, which is usually small (under 1 cm). Rectal prolapse can occur at any age; suspect this if the anus is patulous or gaping. Ask the patient to strain; perineal descent may be seen and sometimes rectal prolapse (circumferential folds of red mucosa) may be demonstrated. Palpation To begin digital rectal examination, warn the patient, then apply gentle but firm pressure to the anal verge with the flat of the well lubricated right index fingertip. The initial contraction of the sphincter will relax after several moments and allow the finger in. The examination will be uncomfortable for the patient; if it is painful, desist. Note the resting muscle tone of the sphincter, and ask the patient to squeeze down on the examining finger to evaluate active tone. Note the anorectal ring where the external anal sphincter spreads out to become pelvic floor and the narrow anal canal (3 cm long) gives way to the spacious rectum. Palpate the coccyx between finger and thumb. This will lead you onto the pelvic floor; feel one side, then the other. Pronation and supination of the forearm may not give sufficient ‘degrees of freedom’ to the pulp of the index finger; change your angle of approach by squatting or sitting beside the examination couch to better feel the

smooth mobility of normal mucosa over the midline groove of the prostate (in males). Expect to feel a mass. If you feel a mass, determine its size, shape (e.g. polypoid, plaque or ulcer), consistency (soft, firm or hard; it may indent like faeces), surface texture (smooth or granular) and mobility. Tenderness of the lesion suggests an inflammatory process. Decide whether the lesion is mobile or fixed to surrounding structures, such as the prostate, pelvic floor or sacrum. Tethering implies that the pathological process has extended beyond the limits of the muscularis propria to involve the adjacent structure or organ. Fixation may occur as a result of fibrosis, but usually indicates malignant infiltration. Ask yourself: ‘Will I be able to describe this mass in my notes or referral letter?’ An example is: ‘On the left lateral wall of the rectum about 2 cm from the anorectal ring is a hard, fixed mass, 3 cm in diameter that does not indent’. Occasionally you may feel a mass through the rectal wall; these arise most commonly in the sigmoid colon (e.g. a diverticular mass). Alternatively, there may be a hard, relatively immobile mass anterior to the rectum near the tip of the finger on deep palpation associated with a tumour that has spread from a primary elsewhere (such as in the stomach); this is termed a Blumer's shelf. Other masses that might be felt include a tampon or a pessary lying in the vagina, or lateral lumps from enlarged lymph nodes infiltrated with tumour from a primary rectal carcinoma. As a general rule, benign processes are soft, whereas malignant processes are hard. Fixed, irregular lesions with friable mucosa are more often malignant. Blood on the examining finger is an important sign of friable mucosa.

Sigmoidoscopy and proctoscopy A sigmoidoscope or proctoscope may allow you to see the lesion that you have felt, exclude other impalpable lesions (e.g. multiple rectal polyps, or areas of ulceration that might be suggestive of inflammatory bowel disease) and take a biopsy of the lesion for histological examination. The examination is most commonly performed with the patient in the left lateral decubitus position. In some centres, particularly those equipped with specialised tables, the examination is performed with the patient in the jack-knife position resting on the knees. Usually, adequate clinical information can be achieved without rectal preparation. When the rectum is totally loaded, it can be cleared by inserting an enema;

22 Rectal/perianal mass and colorectal cancer

281

Figure 22.2  Plastic disposable and metallic reusable proctoscopes. Note the oblique working end to visualise, inject or band haemorrhoids. Figure 22.1  Disposable rigid sigmoidoscope with bellows.

full mechanical bowel preparation is not needed for this examination. Most patients will be anxious about proctoscopy or sigmoidoscopy. They need not see the instrument (Figs 22.1 and 22.2). The examiner needs to reassure the patient, pointing out that the diameter of the instrument is less than the diameter of a large stool and that the examination will be discontinued if there is excessive discomfort. With the patient in position, lift the uppermost buttock upwards and gently insert the lubricated instrument with the obturator in place in the line of the anal canal. Note that the line of the anal canal is toward the patient's umbilicus for the first 3–4 cm, then angles posteriorly. Once the instrument has been inserted into the lower rectum, remove the obturator. The sigmoidoscope can usually be passed with deft insufflation (reassure the patient that you are putting air in and tell them not to be embarrassed) and minor deviations to the level of the rectosigmoid junction at about 15 cm from the anal verge. At the rectosigmoid junction there is usually acute angulation, which can make progression into the sigmoid colon more difficult. In older patients who are likely to have diverticulosis, it is always best to stop at this point if there is any degree of difficulty. It is important to realise that the rectum is covered with peritoneum to a greater extent anteriorly than laterally or posteriorly. The limit of peritonealisation anteriorly is usually about 7–10 cm from the anal verge so you need to be more careful with the depth of biopsy above the level of the peritoneal reflection to minimise the risk of rectal perforation. Biopsy may be best left to the specialist.

If further examination is required (e.g. colon cancer is confirmed), full colonoscopy should be performed at a later stage (see below).

Tumours of the Colon and Rectum History A colorectal tumour can present with any symptom referable to the gastrointestinal tract; such symptoms include a recent change in bowel habit (constipation or diarrhoea), abdominal pain, bleeding (occult or major) or, rarely, an abdominal catastrophe (perforation or bowel obstruction). Other symptoms include weight loss, lethargy and those of disseminated metastatic disease (e.g. bone pain, jaundice, pathological fracture and, uncommonly, thrombophlebitis migrans, skin nodules or acanthosis nigricans). The classic right-sided colon cancer is soft, protuberant and located where the lumen is large and the contents semisolid; anaemia is therefore more likely than obstruction. The classic leftsided colon cancer is annular, stenosing and located where the lumen is narrow and contents are firm; consequently, obstruction is more likely (Fig 22.3). Cancers may form a fistula into the bladder or elsewhere. Advanced cancers may be asymptomatic, while a very early caecal cancer may occasionally present with appendicitis, having obstructed the appendiceal opening. History taking should include any family history of colon polyps, and colorectal or breast cancer, and past history of screening or surgery for bowel cancer. Weight loss, recent change of bowel habit, rectal bleeding, abdominal pain and tenesmus are all indications for further investigation. Rarely, infective endocarditis caused by Streptococcus bovis or Clostridium septicus is the first manifestation of colon cancer.

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Physical examination Physical examination is directed towards making a diagnosis, assessing for metastases and detection of other medical or surgical conditions likely to influence treatment. General examination should include evidence of muscle wasting, malnutrition or anaemia. Jaundice suggests hepatic metastases. Subcutaneous metastatic nodules may rarely be present. A left supraclavicular lymph node should be sought, but it is rare. Lung consolidation or pleural effusion will suggest lung metastases.

Abdominal examination may reveal distension due to ascites or bowel obstruction; there may be hepatomegaly due to secondary spread. A tumour mass may be palpable. On digital rectal examination, a middle or lower-third rectal tumour or polyp will usually be palpable, but a higher cancer will not be unless it has prolapsed into the pouch of Douglas. The cervix, uterus, pubic bone and even a tampon may cause diagnostic confusion for the beginner. The rectum may be evaluated with a rigid ‘sigmoidoscope’—a misnomer in that the sigmoid is not adequately seen with this 30-cm instrument. Full evaluation of the colon is necessary with a colonoscopy to identify any tumours (Fig 22.3) and to rule out synchronous cancers. The bowel must be prepared (emptied of all stool) to see the wall clearly. Colonoscopy has the advantage of allowing biopsies and/or therapeutic intervention, and the disadvantage that it can cause rare bowel perforation.

Investigation

Figure 22.3  Colonic adenocarcinoma.

Diagnosis is made on the basis of history, physical examination and special investigation (Table 22.1). Preoperative investigations should include a full blood count, electrolyte tests and liver function tests. Baseline carcinoembryonic antigen can be sought to aid follow-up, although the benefit of this is controversial (Ch 17). A chest x‑ray examination may detect metastatic disease. If advanced disease is suspected, computed tomography (CT) scanning of the abdomen may be useful; surgery may still be needed for palliation.

Table 22.1  Preoperative assessment of patients with colorectal carcinoma Investigation

Comment

Blood count, electrolytes, creatinine and liver function tests

Results probably will be normal; useful base-line assessment if major surgery planned

Carcinoembryonic antigen (CEA)

Useful—optional CEA is of no value in the preoperative diagnosis of colonic cancer or as a prognostic indicator CEA is of value in the follow-up of resected colonic cancer; a consistently rising titre suggests metastatic disease and further diagnostic evaluation is indicated

Chest x-ray

Useful—not necessary if patient is healthy or if CT chest is contemplated together with the CT abdomen/pelvis

Colonoscopy with biopsy of tumour

Essential unless patient presents acutely with bowel obstruction/perforation

Abdominopelvic CT

Essential especially if a laparoscopic colectomy is being considered

Transrectal ultrasonography (TRUS)

Essential for staging of rectal cancer which determines the course of management

Note: Intravenous pyelogram, abdominal ultrasound and MRI may be indicated in special circumstances.

22 Rectal/perianal mass and colorectal cancer

Colorectal cancer Incidence Colorectal cancer is common. In Australia, the lifetime risk for colorectal cancer before the age of 75 years is 1 in 18 for males and 1 in 23 for females. It is more common than breast cancer. The risk of developing colorectal cancer increases exponentially after 50 years of age; those that occur before 50 account for 8% of all colorectal cancer. An average person's risk at the age of 50 for developing colorectal cancer is about 1 in 300 in the next 5 years, 1 in 100 in the next 10 years, and 1 in 30 over the next 20 years. The majority of colorectal cancers are sporadic. Hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP) and MUTYH-associated polyposis (called MAP, an autosomal-recessive polyposis syndrome similar to FAP caused by MYH gene mutations) constitute the group with a well-defined genetic basis that account for fewer than 5% of all colorectal cancers. Other susceptibility categories, potentially more common, have become apparent on population studies, including high-risk familial, non-syndromic colorectal cancers and common familial-risk colorectal cancers. Aetiology Colorectal tumours can arise from any of the tissue elements found in the large bowel. The most common neoplasms develop from the mucosa (the columnar glandular lining of the large bowel) as premalignant adenomatous polyps, which can develop into adenocarcinoma. Endocrine, lymphatic, smooth muscle and fatty tissue neoplasms are rare. Inherited factors are indicated in 30% of colorectal cancers. Many of the inherited factors are still unidentified; they are either genetic (information is transmitted on the basis of gene sequence) or epigenetic (information is transmitted through gene expression without alteration in the DNA sequence). Both processes are not mutually exclusive. Epigenetic processes important in normal development and differentiation may be misdirected to cancer, via altered methylation (e.g. DNA hypermethylation), post-translational modification of histones, or chromatin remodelling, which leads to inactivation of tumour suppressor genes, activation of oncogenes or altered imprinting patterns. Recent evidence indicates that such events may be modified by diet and drugs.

283

There are many identified genes involved in colorectal cancer, including the adenomatous polyposis coli gene (APC) on chromosome 5, the ras oncogenes (K-ras) on chromosome 12, the tumour suppressor gene (p53) on chromosome 17 and the deleted colorectal cancer gene (DCC) on chromo­ some 18. Downstream mechanisms of colorectal carcinogenesis include defects in Wnt signalling, DNA mismatch repair (MMR) and apoptosis. Most sporadic colorectal cancers (70%) are caused by mutational inactivation of APC. These tumours are characterised by chromosomal instability with changes to large segments of chromosomes. On the other hand, defective DNA MMR characterised by microsatellite instability (MSI) is responsible for a smaller subset (15–25%) of colorectal cancers. In HNPCC, the majority are due to germline mutaions in the MMR genes on chromosome 2 or 3, MLH1, MSH2, MSH6, PMS1 and PMS2 among others, whereas sporadic MSI tumours are associated with epigenetic silencing of the MLH1 promotor through hypermethylation. Patients with tumours caused by defective DNA MMR might not benefit from 5-fluorouracil (5-FU)based chemotherapy. Genetic tests for mutations in the APC and other genes have been developed. Genetic understanding will have implications for screening, surveillance and therapy in the near future. Sporadic colon cancer in a first-degree relative above the age of 55 years is associated with twice the risk of developing colorectal cancer compared with the rest of the population. If there is one firstdegree relative diagnosed before the age of 55 or two first/second degree relatives on the same side of the family diagnosed at any age involved, the risk is increased up to sixfold. Inflammatory bowel disease (particularly longstanding ulcerative colitis of more than 8 years) leads to an increased incidence of colon cancer (Ch 14). Familial adenomatous polyposis: classic and attenuated FAP is caused by an inherited autosomaldominant gene located on chromosome 5q. Polyps usually appear in the second decade of life. Patients usually have no symptoms until colon cancer develops. More than 95% of patients will have polyps on sigmoidoscopy by the age of 30 years, so the condition can usually be diagnosed by sigmoidoscopy in adults. The number of polyps in a colectomy specimen of a patient with FAP averages approximately 1000. Colorectal cancer inevitably occurs in patients with FAP by the age

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of 50 years, approximately 10–15 years after the first onset of polyps. Where a mutation in APC is identified in the proband, predictive testing can be done on other family members to identify individuals at risk. Those found negative for the family-specific APC mutation do not require screening beyond that offered to individuals with average risk. The presence on sigmoidoscopy of more than 100 polyps that are adenomas histologically establishes the diagnosis (Fig 22.4). Such patients should be referred to a centre of expertise because it can be difficult to detect cancer early in these cases. Attenuated FAP is a less severe form of the condition, manifest with 10 or more but 100 or less colonic polyps (on average 30) and a later onset of colorectal cancer. Surgical management is the only acceptable approach unless there are other contraindications. Medical management may be a useful adjunct in some cases. Non-steroidal anti-inflammatory drugs have been shown to lead to partial regression of polyps but complete regression does not occur. A variant of FAP known as Gardener's syndrome consists of all the features of FAP plus a number of extracolonic manifestations that may include desmoid tumours (non-metastasising fibrous tumours, commonly found in the abdominal wall in surgical wounds), osteomas (which can affect the long bones, skull and mandible), lipomas, fibromas, dental abnormalities (e.g. extra teeth) and, rarely, neoplasms of the biliary tree, liver, adrenal or thyroid. Both the classical and variant types of FAP can cause upper gastrointestinal tract polyposis. Proximal small bowel adenomas are observed in over 50% of cases, classically involving the duodenal papillae, which have malignant potential. For this reason, 1–3-yearly screening with upper endoscopy (including side-viewing endoscopy) is recommended from the age of 25–30; subsequent management is determined by staging for duodenal adenomatosis (based on number, size, histology and degree of dysplasia of polyps). Hereditary non-polyposis colorectal cancer HNPCC is an autosomal-dominant disease characterised by multiple cancers (of the colon as well as other sites, particularly endometrium and ovary) and early age of onset. The HNPCC contributes 1–4% of all colorectal cancer. HNPCC can be identified by evidence of a mismatch repair

Figure 22.4  Familial adenomatous polyposis. Note the numerous polyps.

gene mutation in the tumour on DNA testing or historically by the Amsterdam criteria: ll three or more relatives having colorectal cancer with one case being a first-degree relative to the other two; ll colorectal cancer involving at least two generations; ll at least one case occurring before the age of 50 years; and ll exclusion of familial adenomatous polyposis. Polyps and the polyp-cancer sequence Dysplastic proliferation of the mucosa leads to a heaping-up of the regular parallel ‘tubular’ glands and their cells, causing a polyp (adenoma). As long as the dysplastic cells are confined to their normal position above the muscularis mucosa, the adenomatous polyp is not malignant; this is because lymphatics rarely cross the muscularis mucosa. Adenomatous colorectal polyps may be found in up to 40% of the population in Western countries by the age of 60 years, but only a minority develop into cancer. The pathologist recognises malignant change in a polyp when dysplastic cells cross the muscularis mucosa. Malignant spread then occurs both by direct extension along the bowel as well as through the muscle layers of the bowel wall to serosa and adjacent organs. Lymph nodes can be involved and distant spread may be lymph or blood-borne. The neoplastic lesion is ‘superficial’ if it is an adenomatous polyp with absence of invasion in the lamina propria, or if it is an early carcinoma with invasion of the lamina propria but the depth of penetration was limited to the submucosa in the colon. Superficiality relates to the potential for complete cure after endoscopic mucosal resection.

22 Rectal/perianal mass and colorectal cancer Adenomas grow in different microscopic architectural patterns reflecting the extent of their de-differentiation from the parent glandular structure: ll tubular adenomas—where the glandular structure is still discernible, although it may be branching and irregular (Fig 22.5); ll villous adenomas—consist of fingers of lamina propria lined by dysplastic cells. Laterally spreading tumours refer to flat lesions over 10 mm in diameter. Malignant risk in a polyp depends on the size, microscopic architecture and site of the polyp (Table 22.2). The risks are greater with increase in size, villous architecture, and rectal site. The malignant risk of a polyp may be identified by its endoscopic appearance. Advances in endoscopic technology with zoom, narrow band imaging and high-definition white-light imaging have allowed further morphological assessment of the polyp using the Kudo pit pattern (Fig 22.6) and the Paris classification (Fig 22.7) in defining those polyps likely to have submucosal invasion. Together with differentiation into granular (polyps with nodules on the surface) and non-granular (polyps with a smooth surface) subtypes, the endoscopist is able to determine whether or not a polyp would be suitable for endoscopic mucosal resection (Table 22.3). Other epithelial polyps of the colon include hyperplastic and serrated polyps. Serrated polyps are classified into sessile serrated adenoma and traditional serrated adenoma. Serrated adenomas are characterised by the cytological features of an adenoma and the architectural features of a hyperplastic polyp. As opposed to the adenomacarcinoma sequence involving the adenomatous polyposis coli gene, the serrated pathway to colorectal cancer involves the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and K-ras mutations, which account for up to 20% of sporadic colorectal cancers. The surveillance protocol for serrated polyps has not been fully established, but it has been proposed to follow that used for patients with conventional adenomas. Hyperplastic polyps are usually considered an incidental finding with no potential for progression to colorectal cancer. However, there is a rare type of hyperplastic polyp syndrome known as hyperplastic polyposis, which has been shown to be associated with hypermethylation of numerous genes. Polyps in this syndrome are large and flat, and hence there is an increased

285

Figure 22.5  Tubular adenoma on a stalk. Table 22.2  Risk of invasive carcinoma in colorectal adenomas Proportion of polyps with carcinoma (%)

Parameter Size (mm)

≤5

0

6–15

2

16–25

20

26–36

40

≥ 37 Architecture

Tubular Tubulovillous/ villous

Site

> 60 4 30

Right colon

6

Left colon

8

Rectum

23

Modified from Nusko G, Mansmann U, Altendorf HA, et al. Risk of invasive carcinoma in colorectal adenomas assessed by size and site. Int J Colorectal Dis 1997; 12:267–271

risk of colon cancer. The following definition for hyperplastic polyposis has been proposed: ll at least five histologically diagnosed hyperplastic polyps proximal to the sigmoid colon of which two are more than 10 mm in diameter; or ll any number of hyperplastic polyps occurring proximal to the sigmoid colon and in

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Pit pattern I Roundish pits

Pit pattern II Stellar pits

Pit pattern IIIS Small tubular pits

Pit pattern IIIL Large tubular pits

Pit pattern IV Gyrus-like pits

Pit pattern V Non-structured

Figure 22.6  Kudo pit pattern. From Kudo S, Hirota S, Nakajima T, et al. Colorectal tumours and pit pattern. J Clin Pathol 1994; 47:880–885, with permission.

0-Ip

0-Is

Protruded, pedunculated

0-IIa

Protruded, sessile

0-IIb

0-IIc

Superficial, elevated

Flat

Superficial shallow depressed

0-III Excavated

Figure 22.7  Paris grading. From Paris Workshop Participants. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointest Endosc 2003; 58(suppl 6):S3–S43, with permission.

individuals who have a first-degree relative with hyperplastic polyposis; or ll more than 30 hyperplastic polyps of any size distributed throughout the colon. There is no consensus on these criteria, but these patients are quite distinct because of the

frequency, distribution and often large size of the hyperplastic polyps. These polyps may arise in patients with a family history of colorectal cancer, are often large and are found in the right colon. Due to the risk of developing right-sided colorectal cancer, these patients should have a follow-up

22 Rectal/perianal mass and colorectal cancer Table 22.3  Risk of malignancy in polyps Classification Granular Non-granular

SMI (%)

M (%)

Stage grouping Stage 0

Tis N0 M

14

Stage 1

Tis 1–2 N0 M0

Stage IIA Stage IIB

T3 N0 M0 T4 N0 M0

Stage IIIA Stage IIIB Stage IIIC

T1–T2 N1 M0 T3–T4 N1 M0 Any T N2 M0

Stage IV

Any T, any N M1

0–Is

7

0–IIa

3

0–IIc or IIa+c

Table 22.4  TNM staging of colorectal cancer

7

Paris grade

46

Pit pattern

287

I–II

0

0

T: primary tumour

IIIL

0

4

Tis

IIIS

4

9

IV

4

18

Carcinoma in situ; intraepithelial (within glandular basement membrane) or invasion of lamina propria (intramucosal)

V

34

35

T1

Tumour invades submucosa

T2

Tumour invades muscularis propria

T3

Tumour invades through the lamina propria into the subserosa or into non-peritonealised pericolic or perirectal tissues

T4

Tumour directly invades other organs or structures and/or perforates visceral peritoneum

SMI = submucosal invasion; M = intramucosal cancer. Adapted from Uraoka T, Saito Y, Matsuda T, et al. Endoscopic indications for endoscopic mucosal resection of laterally spreading tumours in the colorectum. Gut 2006; 55(11):1592–1597; Kudo et al. Pit pattern in colorectal neoplasia: endoscopy magnifying view. Endoscopy 2001; 33(4):367–373.

colonoscopy at a relatively short interval (1–2 years) and have the polyps removed endoscopically. Staging of colorectal cancer More advanced disease carries a worse prognosis. Our understanding of the natural history of tumour behaviour is reflected in staging systems, several of which have been developed. Staging systems are used for selecting appropriate treatment and estimating prognosis. Historically, the Dukes’ classification is best known and still widely used for colorectal cancer: ll stage A: cancer limited to mucosa or submucosa (5-year survival: over 90%); ll stage B: cancer extends into muscularis or serosa (5-year survival: 70–80%); ll stage C: cancer involves regional lymph nodes (5-year survival: 30–60%); ll stage D: distant metastases (5-year survival: 5%). However, this classification is based solely on the pathologist's examination of the resected surgical specimen. The presence of residual tumour at the completion of operation after resection of the primary is a powerful prognostic factor that influences long-term survival, but it is not recognised in the traditional Dukes’ classification. Another approach to staging is the TNM classification (Table 22.4).

N: regional lymph node NX

Regional lymph nodes cannot be assessed

N0

No regional nodal metastases

N1

Metastasis in 1–3 regional lymph nodes

N2

Metastasis in 4 or more regional lymph nodes

M: metastasis MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Based on Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. 6th edn. New York: Springer Verlag; 2002, with permission.

Treatment Polyps are usually excised endoscopically and examined histologically. If cancer is found in the polyp, further surgical resection of that segment of bowel may be indicated. However, a resection may not be necessary if there are:

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Adenocarcinoma 0

1

Adenomatous epithelium

2

Normal colonic epithelium

3

Level

4

Adenocarcinoma

SUBMUCOSA

Muscularis mucosae

MUSCULARIS PROPRIA

SUBMUCOSA MUSCULARIS PROPRIA

SEROSA PEDUNCULATED ADENOMA

SEROSA SESSILE ADENOMA

Figure 22.8  Haggitt’s levels of carcinoma invasion. From Haggitt RC, Glotzbach RE, Soffer EE, et al. Prognostic factors in colorectal carcinomas arising in adenomas. Gastroenterology 1985; 89:328–336, with permission.

a clean margin of excision (at least 1 mm); well or moderately differentiated cancer; and ll absence of lymphatic or venous invasion. To ensure adequate margin of excision and accurate staging, lateral spreading tumours should be excised en block via endoscopic mucosal resection or dissection; the specimen should be pinned on a piece of foam for proper orientation during processing. The Haggitt's level of invasion (Fig 22.8, Table 22.5) is a useful guide in considering further management for a malignant polyp after endoscopic resection, as it has been validated to determine prognosis in surgical series. Stages 0, 1, 2 and 3 do not require surgery. On the other hand, surgery would be recommended for stage 4. By definition, submucosal invasion in a sessile polyp would require surgery. However, it has been suggested that superficial submucosal invasion (under 300 mm) in such sessile polyps might also be considered low in risk. Obviously, comorbidity of the patient should be taken into account in the management algorithm. Most colorectal cancer will be amenable to surgical excision. Chemotherapy, radiotherapy and palliative endoscopic stenting have a role in advanced disease. Surgical treatment aims to remove the tumour with a margin of normal bowel in continuity with draining lymph nodes and blood vessels. ll ll

Table 22.5  Haggitt's levels of carcinoma invasion Haggitt level

Description

0

Intramucosal high grade dysplasia

1

Carcinoma invading the head of the polyp above the junction of the adenoma and the stalk

2

Carcinoma invading the neck of the polyp at the junction between the adenoma and the stalk

3

Carcinoma invading any other part of the polyp

4

Invasion into the submucosa of the bowel wall below the stalk in the pedunculated polyp and in the submucosa of the sessile polyp

Restoration of intestinal continuity is usually possible. In the case of low rectal cancer requiring an abdominoperineal resection, an end colostomy would result. Patients who had laparoscopically assisted colectomy have a similar survival rate to those who had open colectomy at 4 years follow-up. Laparoscopically assisted colectomy also produced better clinical outcomes, such as early recovery, less pain and reduced length of stay. It is believed that there will be reduced incidence of small bowel obstruction and incisional hernia in the long term.

22 Rectal/perianal mass and colorectal cancer In the case of FAP or dysplastic change in ulcerative colitis, the entire colon is ‘at risk’ and should be resected; the rectum can be preserved in some circumstances, although this is a calculated risk and it must be watched closely. Traditionally, surgery takes place electively with a fully prepared (clean) bowel. More recently, it was shown that a fully prepared bowel is not needed. In fact, it is beneficial not to prepare the bowel in most colectomies as it avoids dehydration and improves patients’ clinical outcomes. If the operation was performed as an emergency (e.g. for obstruction, bleeding or perforation), the surgeon may elect to form a temporary colostomy. Small cancers and polyps readily accessible through the anus can sometimes be removed locally. However, local excision of T2 rectal tumour has been shown to have a poor outcome. At surgery, the surgeon will make a thorough search for spread of the cancer (especially to the liver). It is possible to resect that part of the liver containing metastatic disease, although this is best done at a second operation up to 6 months later. Resection of metastatic disease will be undertaken only if further investigations (angiographic, CT or PET scanning) directed at detecting small metastatic deposits confirm that all metastases can be safely removed. Rarely, a cancer will be too advanced to remove surgically and palliative stenting, colostomy or medical palliation alone will be the only options. Chemotherapy Adjuvant chemotherapy after resection for stage III colon cancer is now the standard of care as it has been shown to improve progress and overall survival. The usual combination is 5-FU infusion (with or without leucovorin) and oxaliplatin (FOLFOX). In the elderly, capecitabine may be used instead of 5-FU to minimise the inconvenience related to infusions. The benefit of adjuvant chemotherapy in stage II colon cancer remains controversial due to insufficient evidence of benefit. However, it may be considered on an individual basis for patients with adverse features (e.g. T4 tumours, poorly differentiated histology, lymphatic or venous invasion, bowel obstruction or perforation on presentation, and fewer than 10 lymph nodes examined). In advanced colon cancer, including those with four or fewer resectable metastases, FOLFOX or 5FU, leucovorin and irinotecan (FOLFIRI) in combination with bevacizumab, a recombinant humanised monoclonal antibody to the vascular

289

endothelial growth factor VEGF-A, have been shown to improve survival. The alternate combination with cetuximab, an epidermal growth factor receptor targeted antibody therapy, have also been shown to improve survival in a subset of patients with wild type k-ras. In rectal cancer (located at 10 cm or less from the anal verge) with advanced stage (T3/T4, N1/N2 as determined from preoperative investigation), survival benefit from chemoradiotherapy of 20–40% has been shown, and preoperative chemoradiotherapy is associated with half the recurrence rate and severe late side effects compared to postoperative treatment. Chemoradiotherapy may also be indicated preoperatively to ‘downgrade’ the tumour. Follow-up Follow-up after the colon is cleared of polyps is directed at detection of postsurgical complications, new colon cancers (metachronous disease) or tumour recurrence. Three-monthly visits for the first year, 6-monthly visits for the second year and annual visits thereafter is a typical regimen, although its benefit has not been proven. Colonoscopy should be done at 1 year and, if the colon is still free of polyps and cancer, colonoscopy should be repeated every 3–5 years. Colorectal cancer screening Colorectal cancer screening using faecal occult blood testing has been shown by level I evidence to provide a 15–33% reduction in mortality. At surveillance colonoscopy, up to 25% of men and 15% of females over the age of 50 years are expected to demonstrate evidence of adenomatous polyps. Such adenoma detection rates have become the benchmark for quality indicators in surveillance programs. Guidelines frequently change and depend on the risk category, as follows: ll category 1—those at average risk: – Faecal occult blood testing annually from the age of 50 years. – Consider flexible sigmoidoscopy every 5 years from the age of 50 years. – I n some countries (e.g. USA), colonoscopy every 10 years is recommended from age 50 years. ll category 2—moderately increased risk (family history of sporadic colon cancer): – Colonoscopy every 5 years starting at age 50 years, or at an age 10 years

290

ll





Clinical gastroenterology: a practical problem-based approach

younger than the age of first diagnosis of colorectal cancer in the family, whichever comes first (the ‘10-year rule’). Sigmoidoscopy plus doublecontrast barium enema 5-yearly is an acceptable alternative to colonoscopy if the latter is unavailable, but colonoscopy is considered the ‘gold standard’. CT colonography 5-yearly is an alternative. – Consider faecal occult blood testing in intervening years. category 3—those at potentially high risk: – Members of a family with a known genetic predisposition (FAP or HNPCC). – FAP family members should have a flexible sigmoidoscopy annually from the age of 10–15 years to 30–35 years and flexible sigmoidoscopy every 3 years after the age of 35 years. – HNPCC family members should have a colonoscopy every 1–2 years beginning at the age of 25 years or 5 years earlier than the youngest affected member of the family (whichever is the earlier). Faecal occult blood test may be offered in the intervening years. Genetic testing is available for some of the genes responsible for the microsatellite instability. This will imply more frequent colonoscopy for the confirmed individuals.

Adenomatous polyp surveillance The interval between surveillance colonoscopy (and polypectomies) depends on the number of polyps, size of polyps, any dysplastic change, completeness of the examination and completeness of the polypectomy. Therefore, the interval can vary from 3- to 10-yearly. In general, the finding of multiple adenomas (three or more) or one large adenoma (1 cm or more) should lead to a follow-up colonoscopy within 3 years; a 5-year interval is reasonable if there were one or two small adenomas. If over 10 adenomas, repeat colonoscopy in under 3 years is recommended. A sessile adenoma removed piecemeal requires a follow-up colonoscopy in 2–6 months to confirm complete resection. Hyperplastic polyps do not require follow-up (unless there is hyperplastic polyposis).

Anal Canal Cancer Anal canal cancer is more commonly seen in women, although carcinoma of the anal margin is more common in men (Fig 22.9). Together,

Figure 22.9  Cancer of the anus.

these are rare tumours constituting only 3–4% of anorectal malignancies. There is a strong association between anal canal cancer and sexually transmitted diseases, including HIV infection and condyloma acuminata caused by the human papilloma virus. Anal canal cancer arises at or above the dentate line from transitional zone epithelium, the remnant of the cloacal membrane of early embryonic growth. However, this zone is not fixed in its relationship to other common landmarks. It may extend in the adult for a variable distance over the anal columns into the lower rectum, and it is composed of a variety of epithelia, including stratified squamous non-keratinised, stratified columnar or cuboidal and simple columnar epithelium. This partly explains the confusion that exists in the histological classification of this tumour. Most tumours of the upper anal canal are poorly differentiated squamous cell carcinomas (SCC), usually showing little keratin production. Other tumours include basaloid carcinoma and malignant melanoma. Carcinoma of the lower anal canal, below the dentate line is commonly a well differentiated squamous cell carcinoma situated at the anal

22 Rectal/perianal mass and colorectal cancer margin where the modified skin of the pecten becomes continuous with normal hair-bearing skin. The treatment of anal canal cancer is primarily chemoradiotherapy. Radical surgery is reserved for persistent or recurrent tumour.

Key Points ll

ll

ll

ll

ll

ll

ll

ll

ll

ll



ll

Perianal or rectal mass may present as a lump or may be incidental. A colorectal tumour can present with a recent change in bowel habit (constipation or diarrhoea) or weight loss. A sense of faecal urgency with painful straining or a feeling of incomplete rectal evacuation is referred to as tenesmus, and occurs with irritating rectal pathology. As a general rule, benign processes feel soft, while malignant processes feel hard on rectal examination. Adenomatous colorectal polyps may be found in up to 40% of the population. Different microscopic architectural patterns have different prognoses: tubular adenomas and villous adenomas. The risk of a polyp being malignant increases with size, villous architecture and rectal site. Hyperplastic polyps have no potential for progression to colorectal cancer. Inherited colon cancer-predisposing syndromes such as hereditary non-polyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP) account for under 5% of all colorectal cancers. Colorectal cancer inevitably occurs in patients with FAP, approximately 10–15 years after the first onset of polyps. The presence on sigmoidoscopy of more than 100 polyps that are adenomas establishes the diagnosis histologically. The Dukes’ classification for colorectal cancer is: – stage A: cancer limited to mucosa or submucosa (5-year survival: 90% or more); – stage B: cancer extends into muscularis or serosa (5-year survival: 70–80%); – stage C: cancer involves regional lymph nodes (5-year survival: 30–60%); – stage D: distant metastases (5-year survival: 5%). If cancer is found in a polyp histologically, further surgical resection of that segment of bowel may be indicated. A resection may not be necessary

ll

ll

ll

ll

ll

ll

ll

291

if there is a clean margin of excision (at least 1 mm); well or moderately differentiated cancer; and an absence of lymphatic or venous invasion. The surgical treatment of colon cancer aims to remove the tumour with a margin of normal bowel in continuity with draining lymph nodes and blood vessels. In the case of low rectal cancer requiring an abdominoperineal resection, an end colostomy would result. Adjuvant chemotherapy after resection for advanced (stage III) colon cancer is now the standard of care. In rectal cancer with advanced stage, chemoradiotherapy is recommended. FAP family members should have a flexible sigmoidoscopy annually from the age of 10–15 years. HNPCC family members should have a colonoscopy every 1–2 years beginning at the age of 25 years or 5 years earlier than the youngest affected member of the family. The finding of multiple adenomas (three or more) at routine colonoscopy should lead to a follow-up colonoscopy within 3 years; a 5-year interval is reasonable if there were just one or two small adenomas.

Further reading Fuchs CS, Giovannucci EL, Colditz GA, et al. A prospective study of family history and the risk of colorectal cancer. N Engl J Med 1994; 331:1669– 1674. Gastroenterological Society of Australia [GESA]. Early detection, screening and surveillance for bowel cancer: an update for clinicians. 3rd edn. Sydney: Digestive Health Foundation;2006. Goldberg RM, Meropol NJ, Tabernero J. Accomplishments in 2008 in the treatment of advanced metastatic colorectal cancer. Gastroint Cancer Re 2009; 3(suppl 2): S23–S27. Hyman NH, Anderson P, Blasyk H. Hyperplastic polyposis and the risk of colorectal cancer. Dis Colon Rectum 2004; 47:2101–2104. Jass JR, Burt R. Hyperplastic polyposis. In: Hamilton, SR, Aaltonen LA (eds), WHO international classification of tumors. 3rd edn. Berlin: Springer-Verlag, 1989; 135–136. Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology 2010; 138:2044–2058. Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345:638–646. Kudo S, Hirota S, Nakajima T, et al. Colorectal tumours and pit pattern. J Clin Pathol 1994; 47:880–885.

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Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003; 348:919–932. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993; 328:1365–1371. Mitchell PJ, Haboubi NY. The malignant adenoma: when to operate and when to watch. Surg Endosc 2008; 22:1563–1569. Moser L, Ritz J, Hinkelbein W et al. Adjuvant and neoadjuvant chemoradiation or radiotherapy in rectal cancer—a review focusing on open questions. Int J Colorectal Dis 2008; 23:227–236. Nelson H, Sargent DJ, Wieand HS, et al. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 2004; 350:2050–2059.

Paris Workshop Participants. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointest Endosc 2003; 58 Suppl:S3–S43. Schippinger W, Samonigg H, Schaberi-Moser R, et al. A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer. Brit J Can 2009; 97:1021–1027. Tanaka T. Colorectal carcinogenesis: review of human and experimental animal studies. J Carcinogenesis 2009; 8:1–19.

23 Jaundice and pruritus

Case

Physiology

A 50-year-old female presented with a 2-week history of episodic right upper quadrant pain that radiated around the costal margin to the back. Similar pains had occurred over 5 years. The current episode had persisted, although fluctuating over several days with the development of jaundice, pale stools and dark urine. Serum alkaline phosphatise was 400 IU/L and alanine aminotransferase (ALT) 300 IU/L. Physical examination revealed a jaundiced patient in obvious discomfort with right upper abdominal quadrant tenderness. An abdominal ultrasound examination was performed. This revealed no cholelithiasis but a dilated common bile duct of 1.2 cm diameter; no stones were seen. Subsequently, an endoscopic ultrasound study demonstrated a gallstone within the distal common bile duct. At endoscopic retrograde cholangiopancreatography with sphincterotomy, the stone was removed. The patient's symptoms and biochemical abnormalities resolved. She subsequently underwent laparoscopic cholecystectomy and remained well.

Jaundice results from either increased production and/or decreased excretion of bilirubin. The metabolism of bilirubin is summarised in Figure 23.1. Under normal conditions, 80% of serum bilirubin is generated by senescent red blood cells, which are broken down by the reticuloendothelial system in the spleen, liver and bone marrow. The released haeme (ferroprotoporphyrin IX) is oxidatively cleaved to biliverdin and then bilirubin, which is tightly bound to albumin and transported in the serum. The other 20% of serum bilirubin arises from the breakdown of other haeme-containing proteins (e.g. cytochrome, myoglobin and haeme-containing enzymes) and ineffective erythropoiesis (the premature breakdown of red cells in the bone marrow before release). Bilirubin, which is lipid soluble, is made water soluble by conjugation in the liver. Unconjugated bilirubin is delivered to the liver via the portal vein and hepatic artery. Bilirubin is conjugated in the liver by UDP-glucuronyltransferase (in the endoplasmic reticulum); glucuronic acid is joined to propionic acid groups on bilirubin. Hepatocytes take up and conjugate 30% of available bilirubin on each pass. Conjugated bilirubin is then secreted into bile canaliculi by an active transport mechanism. It flows through the intrahepatic biliary system to the common bile duct and then into the small intestine where it is either deconjugated or metabolised to urobilinogen by gut bacteria. Conjugated bilirubin is not absorbed by the bowel but some urobilinogen is resorbed. Faecal urobilinogen gives stools their colour. Following absorption in the terminal ileum or colon, urobilinogen undergoes enterohepatic circulation. Jaundice may be caused by obstruction or overloading at various points in the bilirubin metabolism pathway (Fig 23.1). The proportions

Introduction Jaundice is yellow pigmentation of the sclera, skin, and mucous membranes caused by deposition of bilirubin in tissue. Jaundice becomes apparent when the serum bilirubin level rises above 50–75 μmol/L (normal: 3–15 μmol/L). It is most often associated with hepatocellular dysfunction or cholestatic syndromes including biliary obstruction, and is often associated with pruritus. The history and physical examination of the patient with suspected liver disease and an approach to abnormal liver function tests are discussed in Chapter 24. Here, bilirubin physiology and diagnostic methods are outlined, focusing on the clinical approach to patients with obstructive jaundice.

293

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Clinical gastroenterology: a practical problem-based approach

Haemolysis (1)

Senescent red blood cells

Unconjugated bilirubin + albumin

Uptake (3)

Haeme ( + haptoglobin)

Unconjugated bilirubin Biliverdin reductase

Conjugation (3)

Unconjugated bilirubin Glucuronyl transferase (2) Conjugated bilirubin HEPATOCYTE

Excretion (3)

(4) Bile canaliculus (4) Bile ducts (4) Duodenum

Figure 23.1  Increased haemolysis (1) overwhelms the hepatocytes’ ability to conjugate bilirubin and excrete the conjugated form, leading to increased serum levels of unconjugated bilirubin. Low levels of glucuronyl transferase (2) (e.g. Gilbert's disease) cause decreased conjugation. Hepatocellular dysfunction (3) causes decreased uptake, conjugation and excretion with increases of unconjugated bilirubin and conjugated bilirubin. Posthepatic obstruction (4) from stones or tumours prevents passage of bilirubin through the bile ducts into the bowel, leading to increased serum levels of conjugated bilirubin.

of conjugated and unconjugated bilirubin detected in the serum depend on the site of the obstruction or overloading. Haemolysis or reabsorption of a haematoma leads to an unconjugated hyperbilirubinaemia because the hepatocytes become overloaded. Reduced uptake and rates of conjugation will likewise lead to increases in serum unconjugated bilirubin. Hepatic diseases lead to increases in both serum conjugated and unconjugated bilirubin. Uptake, conjugation and excretion will all be affected. However, transport across the canalicular membrane into the bile ductules is reduced more than uptake and conjugation—this is the ratelimiting step for excretion of bilirubin. Therefore, conjugated bilirubin is produced but is not excreted into the biliary system. It accumulates and diffuses back into the serum with consequent increase in conjugated serum bilirubin. There may be parallel increases in the

levels of unconjugated bilirubin due to decreased rates of conjugation, portal systemic shunting of blood around the liver, and low-grade haemolysis associated with hepatocellular diseases. Bile duct obstruction results in elevations of conjugated bilirubin in the serum because uptake and conjugation are unaffected, whereas secretion into the biliary system is compromised. Unconjugated bilirubin is tightly bound to albumin and cannot be filtered by the kidneys, but conjugated bilirubin is only 60% bound and some is filtered. The urine then becomes dark. Finding bilirubin in the urine by dipstick indicates the presence of conjugated bilirubin.

Measurement of serum bilirubin The normal range for serum bilirubin is 3–15 μmol/L in adults. Bilirubin is classified as direct (conjugated) and indirect (unconjugated). This terminology is derived from the commonly

23 Jaundice and pruritus

295

Table 23.1  Clinical features and liver function test profiles in hepatic (hepatocellular) and cholestatic (or obstructive) jaundice Suggests hepatocellular jaundice

Suggests obstructive jaundice

Clinical features

Nausea, anorexia, fatigue, myalgia, known infectious exposure, IV drug use, blood transfusions, alcohol, medication abuse, positive family history of liver disease or jaundice

Pain, pruritus, dark urine, pale stools, fever, past biliary surgery, weight loss, older age

Transaminases (AST, ALT)

++ (> 3 × normal)

+ (< 3 × normal)

Alkaline phosphatase

Normal to increased (< 3 × normal)

++ (> 3 × normal)

INR or prothrombin time after vitamin K

Does not correct

Corrects if extrahepatic obstruction

ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalised ratio.

used assay that makes use of a diazo reaction. Diazotised aromatic amines cleave the bilirubin molecule into two identical molecules, which are bound to the azo compound. These are measured spectrophotometrically. In an acidic aqueous media, conjugated bilirubin reacts ‘directly’ with the azo compound; whereas unconjugated bilirubin requires the addition of an accelerator molecule such as alcohol, thus reacting ‘indirectly’. In adults, the measurement of direct and indirect fractions of bilirubin is not routine but may sometimes be clinically useful when the total serum bilirubin concentration is less than 70–90 μmol/L. Levels greater than this will most often be due to conjugated hyperbilirubinaemia. Chronic overproduction from haemolysis and ineffective erythropoiesis can increase bilirubin loads by up to eight times the normal level, but the hepatocytes are easily capable of increased conjugation rates to meet the demand. However, if there is acute, severe haemolysis, as in sickle cell crisis or paroxysmal nocturnal hemoglobinuria, short-term production can overwhelm hepatocytes and lead to temporary levels of unconjugated serum bilirubin greater than 90 μmol/L. Impaired hepatocellular function in the setting of chronic overproduction can also cause indirect serum bilirubin levels greater than 90 μmol/L due to impaired rates of conjugation and transport. The causes of jaundice are typically classified into three groups corresponding to the site of impaired bilirubin metabolism: prehepatic, hepatic and posthepatic (cholestasis, obstruction). This classification is clinically useful when evaluating patients with jaundice or hyperbilirubinaemia. There are distinctive clinical features and liver function test profiles and clinical presentations for each group (Table 23.1). These help the physician

to identify the likely site of impaired bilirubin metabolism, narrow the differential diagnosis, and then order the most appropriate investigations.

Prehepatic jaundice Isolated unconjugated hyperbilirubinaemia is a common clinical problem. Patients typically present with mildly elevated serum bilirubin but normal levels of serum transaminases and alkaline phosphatase (refer to Ch 24 for a detailed discussion of liver function tests). The serum bilirubin is almost entirely unconjugated. Hepatocellular function and biliary excretion are normal. Intermittent jaundice is often a feature. Patients have no hepatobiliary symptoms and abdominal examination is normal. The first investigation should be to fractionate the serum bilirubin to determine if it is primarily unconjugated or conjugated. If it is unconjugated, then the two most likely causes are (1) Gilbert's disease (often detected on routine blood screens performed on fasting individuals who show no other signs of liver disease); and (2) haemolysis.

Hepatic jaundice Hepatic jaundice may be acute or chronic in origin. These two groups have different clinical presentations and liver function test profiles, but there may be considerable overlap. The level of hyperbilirubinaemia can vary greatly and it is seldom a clue to the diagnosis (Ch 24).

Obstruction or cholestasis Obstructive jaundice occurs when bile flow through the extrahepatic biliary tree is impaired, usually by a stone or tumour. Intrahepatic cholestasis occurs

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when excretion of conjugated bilirubin from the liver cell into the bile canaliculus is disrupted. The most common cause is a drug reaction, but some cases of viral hepatitis and some chronic liver diseases (e.g. primary biliary cirrhosis) can also cause cholestasis. The clinical features and liver function test abnormalities produced by cholestasis and obstruction are similar. Both present with prominent jaundice, dark urine and pale stools. Pruritus may be present if the cholestasis or obstruction is longstanding. The serum alkaline phosphatase level is usually greater than three times the normal level, transaminases are usually less than three times normal, and serum bilirubin concentration is elevated. It should be noted that in acute biliary obstruction, as may occur in choledocholithiasis, serum transaminase levels rise earlier than the alkaline phosphatase. The prothrombin time may be prolonged due to poor absorption of vitamin K but is rapidly corrected by administering parenteral vitamin K in obstruction. Constant pain in the right upper quadrant may be present. Severe episodic pain lasting a few hours suggests stones in the bile duct. Painless jaundice is the hallmark of malignant biliary obstruction commonly seen in patients with pancreatic cancer (Ch 17) (Fig 23.2). Abdominal ultrasound scans showing dilated extrahepatic and/or intrahepatic ducts indicate the presence of obstruction, while normal duct calibre suggests intrahepatic cholestasis. The process of duct dilatation usually appears 3–5 days after the onset of extrahepatic obstruction.

Clinical Syndromes Prehepatic jaundice Gilbert’s disease While not strictly prehepatic, Gilbert’s disease is included here because it is the most common cause of an unconjugated hyperbilirubinaemia. Conjugation is decreased due to a mild, hereditary deficiency of glucuronyl transferase, which occurs in 5–7% of the population. There may also be decreased uptake and transport. The disease is exacerbated by fasting and febrile illnesses. It is typically diagnosed on routine fasting blood screen in young adults or incidentally in hospitalised patients. Blood tests reveal a mild hyperbilirubinaemia (15– 90 µmol/L). It is completely benign and requires no further investigation if serum transaminases and alkaline phosphatase are normal, haemolysis is excluded (see below) and hyperbilirubinaemia is unconjugated. Patients should be reassured but counselled that episodic jaundice could occur. The serum bilirubin will fluctuate over time. Other causes of unconjugated hyperbiliru­ binaemia are bilirubin overproduction, impaired uptake by hepatocytes, or impaired delivery to the liver (Table 23.2). Bilirubin overproduction Overproduction arises from accelerated red blood cell destruction and is a common cause of prehepatic jaundice. Examples include chronic haemolysis seen in patients with prosthetic heart

Bilirubin > 3 x normal Alkaline phosphatase > 3 x normal Ultrasound = dilated ducts

Biliary pain Fever Fluctuating liver function test profiles Bilirubin < 100 µmol/L

SUSPECT STONE

Painless Progressive rise of serum bilirubin Bilirubin > 200 µmol/L

SUSPECT TUMOUR

Figure 23.2  Typical symptoms and biochemical profiles that help to distinguish biliary obstruction due to stones from malignant biliary obstruction.

23 Jaundice and pruritus Table 23.2 Mechanisms for the development of unconjugated hyperbilirubinaemia with typical examples Mechanism

Example

Impaired conjugation

Gilbert's syndrome

Impaired uptake

Drug, e.g. rifampicin

Overproduction: red cell destruction; ll ineffective erythropoiesis; ll red blood cell extravasation.

Haemolysis Severe iron deficiency anaemia Postoperative haematoma

Impaired delivery

Portal systemic shunt

ll

valves, hereditary spherocytosis and glucose6-phosphate dehydrogenase deficiency, or acute intravascular haemolysis seen in patients with sickle cell crisis or transfusion reactions. Haemolysis can be diagnosed on the basis of a characteristic blood film, low haptoglobin and high lactate dehydrogenase levels. Ineffective erythropoiesis results in the premature destruction of red blood cells in the bone marrow and is caused by pernicious anaemia, severe iron deficiency anaemia, sideroblastic anaemia, folate deficiency and lead poisoning. Following trauma or operations, extravasation of blood into body cavities with reabsorption of the haematoma may cause a transient rise in unconjugated serum bilirubin as the red blood cells are destroyed. Impaired delivery to the liver Impaired delivery is usually the result of portal systemic shunting, which occurs in patients with cirrhosis and severe congestive heart failure. Decreased flow through the liver leads to decreased delivery of unconjugated bilirubin to hepatocytes with a resultant rise in serum unconjugated bilirubin. Crigler-Najjar syndrome This is a very rare hereditary deficiency of uridine 5’-diphospho-glucuronosyltransferase, and two forms exist. In type 1 there is complete absence of the enzyme leading to kernicterus in infancy and early death; children rarely reach adolescence. In type 2 there is a moderate deficiency and the prognosis is better.

Hepatic jaundice This is discussed in Chapter 24.

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Cholestatic and obstructive jaundice Intrahepatic cholestasis One of the commonest causes of cholestasis is an idiosyncratic drug reaction. Common offending agents are amoxicillin with clavulinic acid, flucloxacillin, erythromycin, non-steroidal anti-inflammatory drugs, oral contraceptives, oral hypoglycaemics, chlorpromazine, and captopril. Jaundice is more frequent after longer courses of treatment and in elderly patients. Symptoms typically appear 2–3 weeks after the onset of treatment, and usually resolve when the medication is withdrawn. Recovery may take up to several months. The diagnosis of drug-induced cholestasis is presumed if jaundice occurs shortly after a course of medication and resolves on withdrawal of the drug. Other causes need to be excluded. If the clinical features are atypical, a liver biopsy is sometimes helpful but rarely definitive. Rechallenge carries risk and is rarely done. Viral hepatitis, particularly hepatitis A, can occasionally cause intrahepatic cholestasis. Acute hepatitis A can cause a cholestatic hepatitis with an elevated alkaline phosphatase level, fever, arthralgia and jaundice lasting 2–8 months. When chronic alcohol consumption leads to significant fatty infiltration of the liver, cholestasis can also occur. These diseases are discussed in Chapter 24. HIV and postsurgical or critically ill patients can develop cholestatic jaundice; these issues are discussed later in this chapter. Extrahepatic obstructive jaundice Extrahepatic biliary obstruction is usually caused by either stones or tumours. About 80% of patients with stones in the bile duct have biliary pain (Ch 4). This is severe abdominal pain that is constant in nature rather than colicky, localises to the epigastrium (or right upper quadrant if cholecystitis intervenes), and may radiate around or through to the back. The pain lasts 30 minutes to several hours and occurs episodically. Obstruction due to stones is often intermittent, so the level of jaundice may fluctuate. The obstruction is less complete than that seen with malignancy and the serum bilirubin level usually does not rise above 100 μmol/L. There is often an abrupt rise and fall of transaminase activity over 48 hours coinciding with the pain. On the other hand, tumours usually cause painless jaundice. There may be associated weight loss. Fever is unusual and suggests the development of cholangitis. As the obstruction becomes more

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complete, the level of serum bilirubin increases steadily and is often greater than 150 μmol/L at presentation. An ultrasound scan performed to differentiate between the two causes of obstructive jaundice may identify stones within the ducts or a tumour mass. However, equivocal results are not uncommon. Stones (choledocholithiasis) found in the bile duct are usually passed down from the gallbladder through the cystic duct into the common bile duct. However, stones may also form de novo in the common bile duct. These primary duct stones are uncommon in Western societies. They are more common in Japan and Hong Kong where chronic parasitic infections predispose to their formation. In Western societies, primary duct stones are commonly associated with biliary strictures. Stones may also be found in the common bile duct after a cholecystectomy has been performed. These may be retained stones or primary duct stones. Retained stones left behind at the time of surgery usually present within 3 months to 2 years of the original operation with similar symptoms to those noted before surgery. Primary duct stones may present up to 30 years following the original operation. Tumours causing obstruction of the bile duct include carcinoma of the pancreas or gallbladder, cholangiocarcinoma and metastases to hilar lymph nodes. Carcinoma of the pancreas is most common and causes obstruction of the lower bile duct where it passes in a groove behind the head of the pancreas before entering the duodenum. It is an aggressive tumour that locally invades or obstructs the major vessels which transverse the pancreas, and metastasises early to the lymph nodes and liver (Ch 17). Carcinoma of the ampulla of Vater is an uncommon tumour that may present with progressive obstructive jaundice but can also mimic choledocholithiasis and present with cholangitis or pancreatitis. It is important to distinguish ampullary carcinoma from carcinoma of the pancreas as it is a relatively slow-growing tumour and surgical resection produces a cure in more than 40% of patients. Benign strictures of the bile duct may present with progressive jaundice mimicking a malignant stricture, with cholangitis and pain mimicking choledocholithiasis, or occasionally with the insidious onset of secondary biliary cirrhosis. The most common causes are an ischaemic or traumatic injury following cholecystectomy. These may be due to a suture or clip occluding the duct, in which case they present shortly after the operation with cholangitis, a bile leak or increasing jaundice.

Interruption of the blood supply to the bile duct leads to slow development of fibrotic strictures, which present at least 3 months after the original operation and may not become clinically apparent for up to 10 years. Chronic pancreatitis may also cause stricturing with obstruction of the low bile duct where it passes behind the head of the pancreas. The duct is compressed by fibrosis and oedema within the pancreas (Ch 6). There is usually a long history of chronic alcoholic pancreatitis and care needs to be taken to distinguish the change in the liver function test profile due to alcoholic liver disease from that of biliary obstruction. Chronic parasitic infestation can lead to episodes of recurrent cholangitis, stricture formation and biliary cirrhosis. These are most common in developing countries in Southeast Asia, China, India and South America. The main parasites are Ascaris lumbricoides and the liver fluke Clonorchis sinensis. Diagnosis is made by noting fluctuating alkaline phosphatase and bilirubin levels, recurrent episodes of cholangitis (see ‘Cholangitis’ below), and demonstrating the parasite on cholangiogram. Biliary infection in patients with AIDS may cause jaundice. Three immune-mediated diseases cause cholestasis and jaundice. Primary biliary cirrhosis may present as cholestatic jaundice or chronic liver disease or as a combination of both. Patients are usually middle-aged females with lethargy, an elevated alkaline phosphatase level and antimitochondrial antibodies. Primary sclerosing cholangitis is a chronic cholestatic disease characterised by fibrosis of both the intra- and extrahepatic bile ducts. IgG4-associated sclerosing cholangitis (autoimmune pancreatitis) is a steroidresponsive cholangiopathy that can present with primarily pancreatic or cholangitis features. There can be a relapsing and remitting clinical course with chronic pancreatitis and secondary biliary cirrhosis. IgG4 levels are elevated in most cases.

Diagnostic Tests Laboratory evaluation A detailed history, thorough physical examination and routine laboratory evaluation yield the diagnosis in most instances. Clues to the diagnosis of various diseases have been mentioned in previous sections. Routine biochemical tests of liver function are simple, cheap and yield much useful information (Ch 24). Once this has been done, appropriate serological and radiographical

23 Jaundice and pruritus studies can be performed to establish the definitive diagnosis.

Organ imaging The results of imaging must be interpreted together with the clinical history and laboratory investigations. If a radiological test is not consistent with the clinical impression, consideration should be given to further imaging. A comparison of the various imaging modalities is shown in Table 23.3. Ultrasonography An ultrasound scan is simple, widely available, and is the initial test of choice in suspected obstructive jaundice. It accurately identifies the bile duct diameter (Ch 26), although it should be noted that the bile duct diameter may be normal shortly after the onset of obstruction. This problem is avoided by repeating the ultrasound scan 5–7 days after the onset of jaundice. It should be remembered that the common bile duct dilates after cholecystectomy. Stones in the gallbladder are readily identified, with a false-negative rate of only 5%. Stones in the bile duct are more difficult to identify because the duct passes behind the air-filled duodenum. The false-negative rate in this instance approaches 70%. Ultrasound examination can identify primary tumours in the pancreas, gallbladder and bile duct, and liver metastases. Real-time ultrasound with Doppler

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flow studies has an advantage over computerised tomography in that it can assess the patency of the portal vein, hepatic artery, inferior vena cava and splenic vein. This is useful in staging tumours, identifying portal hypertension, and identifying vascular thrombosis. Obesity, distortion of the normal anatomy from previous surgery and the presence of intestinal gas obscuring the area of interest can detract from the accuracy of this examination. Computerised tomography (CT) and CT cholangiography CT complements ultrasound scanning. Where ultrasound scanning has not provided satisfactory images for technical reasons, CT can provide good images of the pancreas, bile ducts and liver. It is useful in staging malignancy. The presence of obesity or overlying bowel gas does not interfere with this examination. This examination can involve an amount of radiation that can become significant in those undergoing multiple studies, however. Helical CT scanning provides more accurate imaging of the bilary tract and surrounding structures. Endoscopic ultrasound Ultrasonography from the duodenum allows good views of the bilary tract. Endoscopic ultrasound (EUS) can be useful in the evaluation of jaundiced

Table 23.3 Imaging in jaundice Test

Advantage

Disadvantage

Ultrasound

Detects dilated ducts Best test for stones in gallbladder Detects small liver masses

Misses ~70% of common bile duct stones Pancreas visualisation may be inadequate

Computerised tomography (CT)

Visualisation of pancreas Detects nodes or metastases Differentiates types of liver masses

Expensive Radiation exposure

Magnetic resonance imaging (MRI)

Similar to CT

Expensive Not as widely available

Endoscopic retrograde cholangiopancreatography (ERCP)

Identifies cause of biliary obstruction in 95% of cases Diagnostic and therapeutic

Invasive

Magnetic resonance cholangiopancreatography (MRCP)

Diagnostic alternative to ERCP, the preferred diagnostic test

Non-therapeutic

Percutaneous transhepatic cholangiography (PTC)

Alternative to ERCP Diagnostic and therapeutic

Invasive Uncomfortable for the patient

Liver biopsy

Helpful in obscure causes of hepatitis/cholestasis

Invasive May miss diseased tissue

Endoscopic ultrasound

Good for common duct stones and pancreatic masses

Invasive Not widely available

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patients where ultrasound and CT scanning have not revealed the cause of obstruction. It can be particularly useful in evaluating pancreatic masses, common bile duct stones and masses in the hilum of the liver. Small pancreatic lesions not well seen by other imaging methods can be identified. Furthermore, fine needle aspiration biopsy can be obtained from mass lesions identified at EUS. When choledocholithiasis is suspected, EUS can be used as the preliminary investigation, avoiding endoscopic retrograde cholangiopancreatography (ERCP) in two-thirds of patients. This approach significantly reduces the risk of procedural complications such as pancreatitis. This technique has similar accuracy to ERCP in detecting stones in the common bile duct. Magnetic resonance imaging Magnetic resonance imaging (MRI) yields good images, but this test is more costly and less available than CT. Without MRCP (see below) it offers no definite advantage over CT in the evaluation of jaundice. Magnetic resonance cholangiopancreatography Magnetic resonance cholangiopancreatography (MRCP) is non-invasive and in many centres has replaced diagnostic ERCP generating images similar to those achieved by the latter. When the patient's bilary system is dilated MRCP has a specificity and sensitivity of 90–100% for choledocholithiasis, identifying the level of obstruction in up to 100%, an accuracy similar to that of ERCP. Indications currently also include suspected pancreas divisum and incomplete imaging of the pancreatic duct (e.g. obstructed by tumour) following other imaging modalities. Endoscopic retrograde cholangiopancreatography Endoscopic retrograde cholangiopancreatography (ERCP) is performed by placing a side-viewing endoscope into the second part of the duodenum and then inserting a small catheter into the bile duct through which a contrast agent can be injected. The advantages of this process include visualisation of the stomach, duodenum and ampulla, visualisation of the pancreatic duct, and direct viewing of the papilla, which can sometimes be involved with cancer. In addition, biopsies and brushings of any lesion can be taken, stones can be removed and stents can be placed to relieve obstruction. Bile ducts can be successfully cannulated in 90–95% of cases performed by experienced proceduralists. The overall complications

rate is 5%. The most common and important complications are pancreatitis, cholangitis, bleeding and duodenal perforation, most of which settle with conservative management. Mortality for diagnostic procedures is 0.1%, and 0.5–1.0% if a sphincterotomy is performed. Percutaneous transhepatic cholangiography Percutaneous transhepatic cholangiography (PTC) is usually performed only if a cholangiogram is required and other imaging techniques have failed or when the insertion of a stent is required and ERCP has been unsuccessful. PTC is performed by passing a needle into the liver under radiographic guidance and injecting a radiocontrast agent into the biliary system. The success rate is about 70% in patients whose biliary system is not dilated and approaches 100% in patients with dilated ducts. The rate of complications with PTC is approximately 5%, with the most serious and frequent complications being bile peritonitis, haemorrhage and sepsis. Its overall mortality is 0.2–1%. Liver biopsy Biopsies are not typically required for the evaluation of jaundice unless intrahepatic disease is suspected (Ch 24). They are usually reserved for the evaluation of suspected hepatocellular or infiltrative liver disease. Scintigraphy (HIDA scanning) Hepatobiliary scintigraphy plays little part in the evaluation of jaundice. The examination is performed by injecting a radiolabelled organic anion (hepatobiliary imino-diacetic acid, HIDA), which is taken up by the hepatocytes and excreted into the biliary system. The liver and biliary system are then scanned by a gamma camera. The main role for scintigraphy is in evaluating the patency of the cystic duct when cholecystitis is suspected. It is quite sensitive in detecting the presence of complete bile duct obstruction but it yields false-positive results in up to 30% of cases. It is also used to evaluate drainage of the biliary tree non-invasively after biliary surgery. Intravenous cholangiogram X-ray tomography of the bile duct is performed after an intravenously introduced contrast agent is excreted by the liver into the bile ducts. A raised serum bilirubin level precludes uptake of the contrast agent by the liver so the test is useful only for identifying stones in non-obstructed ducts. In the past, intravenous cholangiography has not

23 Jaundice and pruritus often been used because of allergic reactions to the contrast agent and poor accuracy. The recent development of new contrast agents with fewer adverse reactions and the use of CT scanning to improve accuracy may see this test used more often in the future.

Management of Suspected Obstructive Jaundice Bile duct obstruction Patients with suspected obstructive jaundice should be initially investigated by ultrasonography. If the bile ducts are not dilated, the causes of intrahepatic cholestasis need to be considered (Ch 24); for example, the patient's drug history should be re-examined, and checks made of viral serology (e.g. hepatitis A), autoantibodies (for autoimmune hepatitis) and antimitochondrial antibody (for primary biliary cirrhosis). Liver biopsy may sometimes be needed for a definitive diagnosis. Treatment must be directed at the underlying cause and, where necessary, managing the complications of irreversible liver disease. Patients with dilated ducts usually have stones or a tumour.

Tumours Carcinoma of the pancreas is the most common tumour that causes biliary obstruction (50–60% of tertiary referrals) (Ch 17). The principles of management are similar for other tumours such as cholangiocarcinoma and gallbladder carcinoma (Fig 23.3). A good quality ultrasound examination will usually identify the tumour mass and the site of obstruction in addition to any liver metastases. If the ultrasound results are equivocal and clinical suspicion is high, then a CT scan may give more information. An EUS can provide further detailed assessment. Occasionally cholangiography by MRI or ERCP is required to define a small pancreatic or bile duct lesion. Once the diagnosis has been established, the patient should be assessed to determine his or her risks for a surgical resection. For a pancreaticoduodenectomy (Whipple's procedure) or hepatobiliary resection, the morbidity and mortality increase for patients over the age of 70 years. Patients with cardiovascular and pulmonary diseases or diabetes have higher complication rates. If the patient is fit for surgery, and does not have evidence of tumour spread to lymph nodes or liver,

Tumour diagnosed by ultrasound/computerised tomography

Assess medical condition

Fit for surgery Assessment for tumour spread Resectable? Yes

Resect

Bilirubin > 100 µmol/L Cholangitis Pruritis No

Endoscopic stent

Resectable? Yes

Not fit for surgery

No

Laparotomy

No

Surgical bypass

Figure 23.3  Jaundice due to tumours.

301

Conservative management

Yes

Endoscopic stent

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Clinical gastroenterology: a practical problem-based approach

then further assessment for surgical resection may be worth undertaking, although none is routine. Useful investigations may include: 1. angio CT of liver and pancreas looking for previously undetected liver metastases, and invasion or encasement or involvement of vascular structures such as the portal vein, the superior mesenteric vein and the hepatic artery and its branches, which may preclude the possibility of resection for cure if the finding is confirmed; 2. duplex scanning of the superior mesenteric and portal veins looking at possible local involvement; 3. laparoscopy looking for small peritoneal seedings or small liver metastases not detected by previous imaging. Large tumours of the pancreas (over 4 cm) tend to be unsuitable for resection because of either local involvement or distant metastases. Cholangiocarcinoma of the biliary tree below the confluence and ampullary carcinoma tend to present earlier and are more likely to be resectable. Jaundice caused by carcinoma of the gallbladder, like carcinoma of the pancreas, tends to present late, making resection for cure uncommon. The optimum management of jaundice in patients with non-resectable disease remains controversial. Prior to the development of endoscopically placed biliary stents, most patients underwent surgical biliary bypass. Surgical bypass usually with a choledochojejunostomy is presently

restricted to younger and fitter patients who are thought likely to survive for more than 6 months. In older, frailer patients with a worse prognosis, the morbidity and mortality of endoscopic stenting is less than with surgical bypass. The other consideration is pancreatic carcinoma causing duodenal obstruction. This occurs in 10% of these patients. Patients with evidence of gastric outlet obstruction should have a biliary bypass and gastroenterostomy. Stones Patients with choledocholithiasis can usually be identified by their history of biliary pain and fluctuating jaundice, and their obstructive liver function test profiles. Abdominal ultrasound scans usually demonstrate a dilated bile duct. It should be noted that ultrasound scans are very accurate in identifying stones in the gallbladder; however, the bile duct is more difficult to image as it passes behind the airfilled duodenum and ultrasonography may miss bile duct stones in up to 70% of patients. A high index of suspicion in a patient with a negative or equivocal abdominal ultrasound result should prompt further investigation initially with an EUS or MRCP. For the purpose of planning management, patients with stones in the common bile duct can be divided into those with and those without a gallbladder (Fig 23.4). In patients who have had a cholecystectomy, ERCP with sphincterotomy and stone extraction is the treatment of choice. Patients with their

Previous cholecystectomy Yes

No

ERCP

Severe cholangitis Gallstone pancreatitis High risk for surgery

Remove stones

Yes

ERCP

No

ERCP with elective laparoscopic cholecystectomy or Laparoscopic cholecystectomy with laparoscopic common bile duct exploration

Figure 23.4  Jaundice due to stones—management. ERCP = endoscopic retrograde cholangiopancreatography.

23 Jaundice and pruritus gallbladder in place have several treatment options. Those who are at high risk for surgery, have severe cholangitis, or have severe gallstone pancreatitis should be treated with ERCP, sphincterotomy and stone extraction. Cholecystectomy can be considered after their other medical conditions have stabilised. In young, fit patients with choledocholithiasis and the gallbladder in situ, laparoscopic cholecystectomy has largely replaced open cholecystectomy. Some surgeons currently favour endoscopic removal of the bile duct stones followed by an elective laparoscopic cholecystectomy. Others reserve endoscopic removal for patients in whom laparoscopic clearance of the common bile duct has been unsuccessful. Successful drainage of an obstructed biliary tree is signalled by a gradual fall in serum bilirubin, relief of pruritus over 3–5 days, return of appetite, and an improved sense of wellbeing. These patients have a conjugated hyperbilirubinaemia; 60% of conjugated bilirubin is irreversibly bound to albumin and this limits the rate of fall in serum bilirubin. Albumin is not filtered by the kidneys, and its half-life in serum ranges from 17 to greater than 20 days. Therefore, serum bilirubin will demonstrate an initial fall of 20–40% as unbound bilirubin is quickly cleared, followed by a gradual fall to normal as the albumin is metabolised.

Cholangitis Obstruction of the bile duct due to stones and occasionally malignancy allows bacterial overgrowth in the bile. An increase in biliary pressure may disrupt liver defence mechanisms and allow bacteria to invade the liver parenchyma and blood stream (cholangitis). Fever, abdominal pain, and jaundice follow (Charcot's triad). There may also be altered mental status and shock. The mortality is 80% if pus is left undrained in the bile ducts. The treatment has two objectives: (1) relief of biliary obstruction; and (2) appropriate antibiotic coverage with fluid resuscitation. Most cholangitis is mild and responds to appropriate antibiotics so that drainage can be performed electively. However, in about 15% of patients cholangitis is severe and life-threatening. Old age, concomitant medical conditions, a low platelet count, a markedly elevated bilirubin level, and renal failure are markers of severity. If three or more of these factors are present, the cholangitis is severe and requires urgent drainage. Recent trials have shown that ERCP with sphincterotomy is preferable to open surgical drainage in acute, severe cholangitis.

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The main bacterial pathogens are Escherichia coli, Klebsiella spp. and Streptococcus faecalis. Pseudomonas ssp. should also be considered if there has been a previous endoscopic or surgical manipulation of the bile duct. Ampicillin and gentamicin have been recommended for treatment of cholangitis in the past. However, gentamicin does not achieve therapeutic concentrations in the bile and its toxicity is increased in the presence of jaundice, renal impairment and increased age. More recently, a combination of ceftriaxone plus ampicillin, or a ureidopenicillin combined with a beta-lactam inhibitor such as pipercillin plus tazobactam, has been used.

Pruritus Pruritus is a common, unpleasant feature of cholestatic syndromes. The exact cause of the pruritus is unknown. This is often worse at bedtime and resolves or improves by morning. Pruritus will occur in 75% of patients with malignant biliary obstruction. The pruritus caused by biliary obstruction improves over 3–5 days following relief of the obstruction. In patients with intrahepatic cholestasis, a variety of medical regimens have been used. Treatment is largely empirical and responses are variable. Bile acid binding resins such as cholestyramine, one 4-g packet, four times a day, is a reasonable initial therapy; however, some patients find its taste unpalatable. Ursodeoxycholic acid, 600 mg daily, has recently gained favour. It is a choleretic agent that replaces the more toxic bile salts in the biliary tree. Rifampicin is effective, although its mode of action is unknown. Antihistamines and topical agents are usually ineffective but may help with mild itching at bedtime. Other drugs that have demonstrated benefit are phenobarbitone, H2- receptor antagonists, methyl testosterone, corticosteroids and opioid antagonists. In extreme cases charcoal haemofiltration and plasmapheresis have been used with success.

The Postsurgical and Critically Ill Jaundiced Patient The evaluation of a postsurgical patient with jaundice can be challenging. The cause is often multifactorial and may include increased bilirubin production from reabsorption of a haematoma, impaired hepatocellular function from decreased blood flow, total parental nutrition (TPN), sepsis and occasionally extrahepatic biliary obstruction (Table 23.4). Therefore, information on the pattern of development, review of the operative and anaesthesia reports, pre- and postoperative

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Table 23.4  Distinguishing features that help to determine the cause of postoperative jaundice Aetiology

Feature

Hypotension

ALT > 1000 U/L, LDH elevated

Drugs, e.g. halothane

None

Infection

Increased white cell count, fever

TPN

Liver function test profiles rise 1–4 weeks after TPN commencement.

Haematoma resorption

↑ unconjugated bilirubin

Cardiac failure

Elevated jugular venous pressure, enlarged pulsatile liver

Haemolysis

↑ unconjugated bilirubin, ↑ LDH, ↓ haptoglobin, abnormal blood smear

Renal failure

↑ creatinine

ALT = alanine aminotransferase; LDH = lactate dehydrogenase; TPN = total parenteral nutrition.

drug use, haemodynamic changes and fluid management, and any history of hypovolaemia or hypotension are required. Increased bilirubin production can occur from rapid destruction of transfused red cells (20% of administered blood stored for 21 days is destroyed within 24 hours). Other causes of red blood cell destruction include breakdown of red blood cells damaged by cell-savers, reabsorption from haematomas, or haemolysis from heart valves or genetic diseases (e.g. sickle cell anaemia). In these cases, an unconjugated hyperbilirubinaemia develops. The level may be greater than 90 μmol/L if concurrent liver dysfunction is present. Hypotension causing liver dysfunction can occur intraoperatively, in recovery or postoperatively. This may not be obvious until nursing records and anaesthesia charts are reviewed. Typical findings suggesting liver ischaemia include a rapid rise of transaminase levels to 1000–10,000 U/L with hyperbilirubinaemia and a rapid fall within 24–48 hours if normal perfusion is maintained. Systemic infections can cause cholestasis. Up to a third of septic patients have been found to have elevated serum bilirubin levels. Jaundice is usually associated with gram-negative infections, although gram-positive organisms have also been implicated. The pathogenesis is unclear but circulating endotoxins probably cause a reduction

in excretion of conjugated bilirubin into the biliary system but do not affect conjugation. One of the most difficult aetiologies to identify is that due to drug toxicity. Antibiotics are most often the culprit, although occasionally an anaesthetic agent (e.g. halothane) is the cause. TPN causes many liver abnormalities including fatty liver, cholestasis, portal inflammation, gallstone formation and occasionally steatohepatitis and cirrhosis (Ch 17). Liver function abnormalities usually occur 1–4 weeks after the initiation of TPN and resolve on discontinuing therapy. Transaminase levels can become elevated within 1 week, and alkaline phosphatase and gamma glutamyl transpeptidase levels often begin to rise after 3–4 weeks. Increases in serum bilirubin levels can occur but are unusual. The causes are commonly multifactorial. The transaminase rise is most likely due to glucose intolerance, while cholestasis is considered to be the result of abnormal lipid metabolism. Often small adjustments in TPN composition can correct the liver dysfunction and discontinuing the TPN usually leads to regression of dysfunction. Renal failure will lead to decreased excretion of bilirubin and may cause mild hyperbilirubinaemia to manifest itself as jaundice following surgery.

The Immunocompromised Patient who is Jaundiced Patients who are immunocompromised by infection with HIV or who are receiving immunosuppressive therapy may develop hepatobiliary infections not usually found in the immunocompetent patient. Biliary tract infections can produce marked jaundice and right upper quadrant pain. Other causes of jaundice include neoplasms and drug reactions (see Table 23.5).

Human immunodeficiency virus (HIV) Hepatomegaly is quite common in AIDS, occurring in 60–80% of patients. Elevated liver enzyme levels may occur in two-thirds of patients, and abnormal histological findings in 85% of patients, but the liver disease is usually mild and jaundice is uncommon. The most common causes of hepatocellular disease, in decreasing order, are Mycobacterium avium-intracellulare, drugs, cytomegalovirus, bacillary peliosis hepatis, lymphoma and Mycobacterium tuberculosis. Kaposi's sarcoma, hepatitis C and B and cryptococcal infection are other causes of jaundice. Drugs such as sulfonamides, isoniazid, phenytoin and azidothymidine (AZT) may cause cholestatic jaundice.

23 Jaundice and pruritus

Table 23.5  Common causes of jaundice in immunosuppressed patients Aetiology

Examples

Hepatitis: infectious

Mycobacterium aviumintracellulare, tuberculosis, cytomegalovirus

Hepatitis: drugs

lsoniazid, AZT, sulfonamides

AIDS cholangiopathy

Cytomegalovirus, Cryptosporidium spp.

Veno-occlusive disease

Antineoplastic drugs (e.g. busulfan)

Neoplasm

Lymphoma, Kaposi’s sarcoma

A syndrome of biliary pain and fever is termed ‘AIDS cholangiopathy’. Clinical jaundice is unusual. There are different types: sclerosing cholangitis (focal strictures and dilatations of intrahepatic and extrahepatic bile ducts), papillary stenosis (causing a dilated bile duct) and extrahepatic biliary strictures. The syndrome can be caused by biliary infection with cytomegalovirus, Cryptosporidium or microsporidia. ERCP with sphincterotomy leads to rapid relief of pain in 80% of patients with sclerosing cholangitis or papillary stenosis. Acalculous cholecystitis is more common in this group of patients and can be caused by cytomegalovirus, Cryptosporidium and Campylobacter. Bile duct obstruction can also occur as a result of primary duct lymphoma, nodal metastases or Kaposi’s sarcoma.

recover spontaneously; 25% develop multi-organ failure and die. Viral hepatitis may develop following transplantation of any organ. Hepatic cytomegalovirus infection presents as an acute hepatitis often with extrahepatic disease, and responds to treatment with gancyclovir. Immune suppression may cause an exacerbation of chronic hepatitis B infection leading to acute hepatitis with jaundice. Hepatic abscesses can develop following the use of immunosuppression or transplantation; these are usually diffuse fungal microabscesses. Drug-induced liver disease is common but jaundice is not. Cyclosporin does cause a conjugated hyperbilirubinaemia and jaundice, but other signs of cyclosporin toxicity such as hypertension, renal dysfunction and oedema are also usually present.

Key Points ll

ll

ll

ll

ll

ll

Organ transplantation Patients receiving transplanted organs may develop complications from their immunosuppressive therapy or the transplanted organ (Ch 25). Bone marrow transplantation recipients seem particularly susceptible to developing hepatobiliary dysfunction. Hepatic graft versus host disease following bone marrow transplant causes cholestasis and jaundice, typically with an erythrodermatous skin rash and diarrhoea. It usually responds to immunosuppression, and progression to cirrhosis occurs rarely. Veno-occlusive disease is the most common cause of jaundice in the first few weeks after bone marrow transplant. Diffuse venous occlusion within the liver leads to rapid onset of ascites, hepatomegaly and jaundice. Up to 75% of patients

305

ll

ll

ll

ll

An understanding of bilirubin metabolism is essential in the assessment of the jaundiced patient. Hyperbilirubinaemia may be considered as prehepatic, hepatic and obstructive (posthepatic). The proportion of the elevated bilirubin that is conjugated as opposed to unconjugated can help differentiate the underlying pathology when one form is markedly greater. Prehepatic jaundice may reflect increased bilirubin production or reduced hepatic uptake. Obstructive jaundice can be intrahepatic or extrahepatic. Extrahepatic biliary obstruction is usually caused by gall stones or tumours. Typically, gallstones causing obstruction are painful whereas obstructive tumours are often not. Organ imaging initially with non-invasive modalities will usually provide an accurate diagnosis of obstructive jaundice. The abdominal ultrasound and selective use of endoscopic ultrasound, CT scan and MR cholangiography provide high yields, allowing planning of therapeutic ERCP, surgery or other appropriate therapy. Pruritus may accompany cholestasis, whether intrahepatic or related to the major bile ducts. Major illness, as in patients in the intensive care unit, may be associated with jaundice without significant primary liver or biliary disease.

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Further reading Clayton ES, Connor S, Alexakis N, et al. Meta-analysis of endoscopy and surgery versus surgery alone for common bile duct stones with the gallbladder in situ. Br J Surg 2006; 93:1185–1191. Hiramanek N. Itch: a symptom of occult disease. Aust Fam Physician 2004; 33(7):495–499. Kocher M, Cerna M, Havlik R, et al. Percutaneous treatment of benign bile duct strictures. Eur J Radiol 2007; 62:170–174. Petrov MS, Savides TJ. Systematic review of endoscopic ultrasonography versus endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis. Br J Surg 2009; 96:967–974.

Radhakrishnan J, Uppot RN, Colvin RB. Case records of the Massachusetts General Hospital. Case 5-2010. A 51-year-old man with HIV infection, proteinuria, and edema. N Engl J Med 2010; 362(7):636–646. Vassilou MC, Laycock WS. Bilary dyskinesia. Surg Clin N Am 2008; 88:1253. Wamsteker EJ. Updates in biliary endoscopy 2006. Curr Opin Gastroenterol 2007; 23(3):324–328.

24 Abnormal liver function test results

Case A 45-year-old male was found to have abnormal liver function tests on routine investigations performed for an insurance examination. Serum alanine aminotransferase level was elevated at 105 IU/L. International Normalized Ratio (INR), albumin and bilirubin were normal. The patient also had a history of hypertension controlled on antihypertensive therapy and an elevated fasting serum triglyceride concentration. His father had type 2 diabetes, but there was no family history of liver disease. An abdominal ultrasound examination demonstrated changes consistent with fatty liver, but no other abnormality. Further investigations showed no evidence of autoimmune, viral or inherited liver disease. His ferritin was mildly elevated, but with normal transferrin saturation and no mutation of the haemochromatosis (HFE) gene. Physical examination revealed him to be overweight, but otherwise was unremarkable. The patient was advised to reduce his weight and exercise regularly. Under the guidance of a dietician a 5% weight loss was achieved with an improvement in alanine aminotransferase levels. Following that he failed to maintain the intervention, gained weight and discontinued medical review. Ten years later he again was found to have abnormal liver tests but also INR 1.6, albumin 28 gm/L and bilirubin 25 μg/L. He had become diabetic with symptomatic ischaemic heart disease. Abdominal ultrasound on this occasion showed a small irregular liver with splenomegaly, consistent with cirrhosis and an apparent mass in the liver. On a triple phase computed tomography (CT) scan of the liver, the 2-cm mass lesion was typical of a hepatocellular carcinoma and was managed surgically.

An Approach to the Patient with Liver Disease The liver is a remarkable organ with substantial functional reserve and impressive regenerative capacity. The presence of abnormal liver function profiles, therefore, may not be apparent at the bedside. However, when abnormal liver function test results are found, their significance needs to be assessed in the light of clinical (bedside) findings. The pattern of liver function test abnormalities can be subdivided into either a hepatocellular or cholestatic disease category as discussed below. Organ imaging is an important complementary tool in the assessment of abnormal liver function profiles. The presence of normal liver function profiles makes hepatic disease unlikely, although there are many exceptions, including wellcompensated cirrhosis, some cases of chronic hepatitis C, and those with certain space-occupying lesions of the liver. Liver disease will present as one of a limited number of clinical syndromes. Each syndrome may be caused by a number of specific disease processes. A diagnosis is achieved by paying attention to historical features and physical findings (Box 24.1) and the results of laboratory and other investigations. Only then can specific treatment for the cause of the liver abnormality be planned. Therapy, in many instances, is directed to the management of the clinical problem in addition to treatment directed to the underlying condition. In this chapter, liver function tests and their clinical relevance are discussed first because abnormalities are commonly detected in asymptomatic individuals. Next, the common clinical presentations of liver disease are covered. Finally, important liver diseases are described.

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Box 24.1  Symptoms and signs of liver disease Symptoms Fatigue, pruritus, bleeding, abdominal pain, nausea, anorexia, myalgia, jaundice, dark urine, pale stools, fever, weight loss; may be no symptoms Peripheral signs of chronic liver disease, hepatocellular dysfunction Spider naevi, palmar erythema, white nails, gynaecomastia, body hair loss, testicular atrophy, hepatomegaly Signs of portal hypertension Splenomegaly, ascites, peripheral oedema Signs of poor hepatocellular synthetic function Bruising, peripheral oedema (reflecting depleted coagulation factors and albumin levels) Signs of end-stage liver disease Wasting, progressive severe fatigue, encephalopathy (asterixis, fetor, coma) Other signs Hepatic rub—peritoneal inflammation from underlying infarction or malignancy Right upper quadrant bruit—intrahepatic shunting, alcoholic hepatitis, malignancy, large haemangioma

Liver Function Test Interpretation In the initial assessment of a patient with abnormal liver function test results, a number of questions need to be considered: ll Is the illness a primary liver disorder, or is it secondary to some other condition (which could be more clinically important)? ll Is the source of the abnormal test levels extrahepatic? An abnormality in a single ‘liver function test’ may be due to a non-hepatic cause. Evidence of disease processes involving other organs should be sought. ll Do the liver function test abnormalities signify a serious illness? What is the severity of the illness—is the cause of the abnormality a threat to the patient’s wellbeing now or in the future? What is the diagnosis and, more importantly, what is the prognosis? ll Is this an acute illness or a chronic one? If chronic, is it compensated or decompensated? Routine liver function tests usually include serum bilirubin, albumin, International Normalised Ratio (or prothrombin time),

transaminases, alkaline phosphatase, gamma glutamyl transpeptidase and, in some laboratories, lactate dehydrogenase. Other tests should be ordered only for specific indications.

Bilirubin Elevated serum bilirubin levels may occur in all forms of liver disease. However, it must be remembered that a jaundiced patient does not necessarily have significant hepatic disease. Serum levels of bilirubin reflect production, hepatic uptake, processing (conjugation) and secretion. The physiology of bilirubin and an approach to diagnosis and management of jaundice is described in Chapter 23. The value of the ratio between conjugated and non-conjugated bilirubin in distinguishing the nature of a liver disorder is limited. Conjugated bilirubin levels are highest in cholestatic disease and in fulminant hepatic failure. Unconjugated hyperbilirubinaemia may reflect haemolysis, neonatal physiological jaundice or genetic defects in bilirubin transport and conjugation (Gilbert’s and Crigler-Najjar syndromes). Haemolysis rarely produces total bilirubin levels greater than 50–90 μmol/L. In acute liver disease, the bilirubin level is of little prognostic significance. On the other hand, rising serum bilirubin levels reflect the approach of end-stage disease in many chronic liver diseases. For example, in primary biliary cirrhosis this signals the need to consider liver transplantation. In secondary malignancy it is often a signal of a preterminal event. In the presence of chronic liver disease, when hepatic reserve is limited, relatively small increases in bilirubin production (as with haemolysis) can produce a disproportionate increase in serum bilirubin. When there is cholestasis, renal failure will reduce the clearance of conjugated bilirubin sufficiently to increase serum levels. Furthermore, conjugated bilirubin binds irreversibly to albumin such that bound bilirubin will not be cleared until the albumin it is bound to is catabolised.

Tests reflecting hepatic function Serum albumin This protein is a key synthetic product of the liver. Its concentration in the serum is dependent on nutrition, hepatic synthesis and losses (e.g. nephrotic syndrome and protein-losing enteropathy). In chronic liver disease, low serum albumin concentrations represent a major prognostic

24 Abnormal liver function test results indicator (see ‘Child-Pugh score’ later in this chapter). This can reflect the absence of sufficient functioning hepatocytes to maintain albumin production. Furthermore, malnutrition can be a significant contributor to hypoalbuminaemia in patients with chronic liver disease. Alcohol consumption can reduce albumin synthesis. Serum albumin concentrations may also fall without a reduction in hepatic synthesis when the volume of distribution of albumin is expanded by ascites and oedema. As albumin has a half-life of 17–26 days, low levels usually reflect chronic rather than acute hepatitic dysfunction. Prothrombin time or INR As with albumin, the vitamin K-dependent clotting factors are synthesised by the liver. The plasma concentrations of prothrombin and factors VII, IX and X often fall in the presence of significant liver disease. The prothrombin time assesses the activity of these coagulation factors. The INR is the ratio between the clotting time (in seconds) using the patient’s plasma divided by that for a control sample using standardised reagents (normal range: 0.8–1.2). Because of the relatively short half-life of some of these proteins, abnormalities can develop quickly following the onset of hepatic decompensation. In certain circumstances, this may occur within hours (e.g. fatty liver of pregnancy). Cholestasis can result in vitamin K malabsorption and, in so doing, lead to a raised INR. In that situation, parenteral vitamin K promptly reverses the abnormality. On the other hand, a raised INR that is unresponsive to vitamin K often suggests significant hepatocellular dysfunction. In a patient with liver disease who is bleeding, the abnormal clotting may represent direct losses and consumption of clotting factors. Stored blood has no effective clotting factors, and contains anticoagulant. After a large transfusion, the clotting factors must therefore also be replaced by giving fresh frozen plasma. It should be noted that the INR does not necessarily reflect the severity of chronic liver disease. It may be normal or near normal in the presence of advanced cirrhosis. In fulminant hepatic failure, serial INR measurements are of prognostic value with recovery being more likely if the INR decreases. Prognosis is poor when the INR is greater than 3. In vitro tests of clotting factors, such as the INR, will not necessarily reflect the coagulation status of the patient with liver disease.

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Tests of Liver Injury Transaminases The serum transaminases are best considered as tests of hepatocyte damage or injury. They do not reflect the functional capacity of the liver. Transaminases enter the circulation following hepatocellular lysis. However, sublethal hepatocyte injury can also release these enzymes. Budding of cytoplasm or leakage from breaches in the plasma membrane may occur. Marked elevations in serum transaminase levels (over 1000 U/L) often reflect acute viral hepatitis. Drug reactions and acute exacerbations of chronic autoimmune hepatitis can produce similar levels. Non-hepatocellular disease including acute cholestasis, shock and cardiac failure can also produce substantial rises. Lesser rises in serum transaminases do not, however, exclude the diagnosis of these conditions. Persistent elevation of serum transaminase levels may indicate significant chronic liver disease such as chronic viral or autoimmune hepatitis, and require investigation. Thus, treatable diseases can be identified and managed prior to the onset of symptomatic (often endstage) liver disease. In Western countries such as Australia, non-alcoholic fatty liver disease is the most common cause for abnormal transaminase levels. That condition is present in 15–20% of these populations. In the presence of malignant disease, increases in transaminases often indicate hepatic metastases.

Alanine aminotransferase Alanine aminotransferase (ALT) is a liver-specific enzyme; thus, an isolated elevation of ALT is highly suggestive of liver disease. Persisting abnormalities should precipitate a search for the cause.

Aspartate aminotransferase Aspartate aminotransferase (AST) is an enzyme found in liver, skeletal muscle, myocardium, kidney, pancreas and erythrocytes. Damage to any of these cell types will result in an elevation of serum AST. ALT levels are usually higher than AST levels in viral liver injury. When liver disease is present, and the AST level is more than twice that of ALT, alcoholic liver disease must be considered (see later). In the presence of cirrhosis, the diagnostic value of the AST:ALT ratio is lost. The mitochondrial isoenzyme of AST is especially elevated in the presence of alcoholic liver injury.

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Alkaline phosphatase Alkaline phosphatase (ALP) is an enzyme localised to the biliary membrane of hepatocytes. An elevation of the serum ALP level is a marker of biliary disease or a hepatic infiltrative disorder. Although cholestasis may be present with a normal ALP level, in three-quarters of patients with cholestasis, serum ALP levels will be three or more times greater than the upper limit of normal. Mild elevations of hepatic ALP levels are often seen in hepatocellular injury. Serum ALP levels may also be elevated, at times in isolation, in other disorders affecting the liver, including congestive cardiac failure and lymphoma. A mild elevation is often seen in patients with a non-hepatic illness; this returns to normal over a period of weeks to months, after the underlying condition is treated. ALP is also found in bone, intestine, kidney and placenta. Consequently, damage to these organs will elevate the serum ALP level. Furthermore, during pregnancy and periods of rapid growth (neonatal and adolescent periods), serum levels of this enzyme are higher. When the serum ALP level is elevated in the absence of other abnormalities in the liver function tests, a non-hepatic cause, such as Paget’s disease, tumours involving bone, acromegaly and fractures, should be considered. Milder rises in ALP may occur following infarction involving the heart, lung, gastrointestinal tract or kidneys. 5′-nucleotidase, a membrane-associated enzyme, is elevated in the plasma primarily in cholestatic liver disease. Although present in pancreas, brain, intestine and heart, this enzyme is more specific for liver disorders than is alkaline phosphatase.

Gamma glutamyl transpeptidase Gamma glutamyl transpeptidase (GGT) is a membrane-bound enzyme present in the liver, pancreas, kidney, intestine and prostate. GGT levels increase with any liver disease. Its greatest value is its association with alkaline phosphatase in cholestatic disorders. An elevated serum GGT level supports a hepatic origin of an elevated alkaline phosphatase, as serum GGT is not raised in pregnancy or bone disease. Although a marker of prognostic significance in alcoholic liver disease, not all heavy drinkers will display elevated serum GGT levels. Elevations of the serum levels of this enzyme are associated with biliary disease, pancreatitis, obesity, hyperlipidaemia, anorexia nervosa, diabetes mellitus, hyperthyroidism, porphyria, myocardial infarction and liver disease in general. Enzymeinducing drugs, such as barbiturates, tricyclic

antidepressants and anticonvulsants, are also associated with elevated serum GGT activity. The serum levels of this enzyme can be raised in the absence of other liver function test abnormalities in obese individuals, with excessive alcohol consumption, and following the use of enzyme-inducing medications.

Lactate dehydrogenase Lactate dehydrogenase (LDH) is a glycolytic enzyme present in all cells. Different isoenzymes occur with limited tissue specificity, and their measurement is of limited clinical value. However, when the LDH level is elevated out of proportion to the transaminases, ischaemic liver injury and secondary malignancy need to be considered.

Cholestasis versus hepatocellular disease Liver function patterns may be used to guide the discrimination between cholestasis (e.g. due to stones or tumour obstructing the large bile ducts) and hepatocellular disease (e.g. cirrhosis or chronic hepatitis). These patterns can be used only as a broad guide and should not be relied on alone. However, if cholestasis is suspected, then looking for evidence of duct obstruction (e.g. by ultrasound) is the next step, while if hepatocellular disease is suspected, then a search for liver disease markers (e.g. virology, immunological tests) is the next step (see Table 23.1 in Ch 23).

Other tests useful in hepatic assessment A marked elevation (over 1000 U/L) of alphafetoprotein is most often due to hepatocellular carcinoma. This test has been used for screening an individual with chronic hepatitis B for the development of hepatocellular carcinoma, having a sensitivity of 70%. It is of limited value, however, because the sensitivity falls to 30% in non-hepatitis B hepatocellular carcinoma. Milder elevations occur in both acute and chronic liver disease of many causes (Ch 25). Autoantibodies are helpful in diagnosing certain forms of liver disease (Table 24.1). Serum concentration of caeruloplasmin and iron studies are important tools in the diagnosis of Wilson’s disease and haemochromatosis, respectively (Table 24.2), but are also altered by liver injury unrelated to either of these conditions. Tests for viral hepatitis are also important (Table 24.3). Liver biopsy Histological and, on occasion, chemical analysis and microbiological examination of the liver are essential in the diagnosis of many hepatic disorders. The usual technique for obtaining a

24 Abnormal liver function test results

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Table 24.1 Tests for autoimmune liver disease Test

Condition

Comment

Antinuclear antibody (ANA)

Autoimmune chronic hepatitis

Diagnosis requires liver biopsy

Smooth muscle antibody (SMA) (anti-actin)

Autoimmune chronic hepatitis

Diagnosis requires liver biopsy

Anti-liver kidney microsomal antibody (anti-LKM1)

Autoimmune chronic hepatitis

Diagnosis requires liver biopsy

Antimitochondrial antibody (AMA)

Primary biliary cirrhosis(95%)

Diagnosis requires liver biopsy

Antineutrophil cytoplasmic antibody (pANCA)

Primary sclerosing cholangitis

Diagnosis requires magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography

Table 24.2 Tests for metabolic disorders affecting the liver Test

Condition

Comment

Iron studies

Haemochromatosis

See text

Copper and caeruloplasmin

Wilson's disease

See text

Alpha-1 antitrypsin level and phenotype

Alpha-1 antitrypsin deficiency

Heterozygotes may have abnormal liver function tests without significant liver disease

Thyroid function tests

Hypothyroidism

Fatty liver

Blood glucose level

Diabetes mellitus

Fatty liver, haemochromatosis

Insulin/C-peptide

Insulin resistance

Fatty liver, metabolic syndrome

Cholesterol and triglycerides

Primary and secondary hyperlipidaemia

Fatty liver, alcoholic liver disease

liver biopsy involves a percutaneous approach through a lower intercostal space in the right midaxillary line. Ultrasound scanning or CT can be used to optimise the needle entry point or target specific abnormalities. Haemorrhage from the biopsy wound to the liver or injury to adjacent organs are the major risks. These may be significant in approximately 1% of biopsies. The risk of haemorrhage is minimised by ensuring a platelet count greater than 80 × 109/L (80,000/ mm3) and an INR less than 1.2. When coagulopathy or gross ascites prevents a percutaneous biopsy, a transjugular approach can be used. The decision to proceed to liver biopsy is reached when the potential information gained outweighs the risks of the procedure. In particular, obtaining information about the patient’s prognosis or diagnostic information that might alter therapy is the important consideration. Although it is not always appropriate to perform a liver biopsy to only achieve a diagnosis, it is not unusual for the clinical diagnosis to be altered by the information gained at biopsy. The clinical course of the illness

should also be considered. The patient with improving liver function test profiles and resolving symptoms is probably best observed rather than biopsied early. It should be noted, however, that, in certain conditions such as chronic hepatitis C and haemochromatosis and in some alcoholic patients, hepatic fibrosis can progress to cirrhosis with little clinical or laboratory evidence of aggressive liver disease. The significance of liver biopsy features is considered in relation to specific disorders later in this chapter. The extent, nature and activity of inflammatory and fibrotic processes are of particular concern. The presence of fibroinflammatory changes is more likely to be related to a progression to cirrhosis. The absence of such changes carries a better prognosis. Sampling error can be a problem as the tissue sample represents only a tiny proportion of the liver mass and the disease process may not be uniform across the organ. Cirrhosis can be missed in 10–20% of cases, depending on the size and number of samples taken.

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Table 24.3 Tests for viral hepatitis Test

Meaning of a positive result

Comment

Anti-HAV IgM

Recent acquisition of HAV

Acute hepatic illness likely to be HAV

Anti-HAV IgG

Past infection/vaccination

Immunity

HBsAg (surface ag)

Present/chronic infection

Structural component of virus

Anti-HBsAg (surface ab)

Past infection/vaccination

Immunity

Anti-HBc IgM (core ab)

Recent acquisition of HBV

The test for acute HBV infection

HBeAg (e ag)

Marker of viral replication

High risk of infectivity

Anti-HBeAg (e ab)

Suggests no viral replication

Unlikely to be infectious

HBV DNA

Presence of complete virus

High risk of infectivity

Anti-HCV

Exposure to HCV

Interpret in conjunction with other clinical and laboratory data

HCV RNA by PCR

Presence of virus



HCV genotyping



Treatment planning and response

Anti-HDV IgG/IgM

Exposure to HDV

Acute or chronic HDV

Delta antigen

HDV present

Acute or chronic HDV

Recent acquisition of HEV

Acute hepatitic illness likely to be HEV

Cytomegalovirus (CMV) IgM

Recent acquisition of CMV

Acute hepatitic illness likely to be CMV

Epstein-Barr virus (EBV) IgM

Recent acquisition of EBV

Acute hepatitic illness likely to be EBV

Anti-HIV

HIV-AIDS

Opportunistic hepatobiliary infections

Toxoplasmosis serology



Consider toxoplasmosis

Q fever serology



Consider Q fever

1. Tests for hepatitis A virus (HAV)

2. Tests for hepatitis B virus (HBV)

3. Tests for hepatitis C virus (HCV)

4. Tests for hepatitis D virus (HDV)

5. Tests for hepatitis E virus (HEV) Anti-HEV IgM 6. Tests for other organisms

ag = antigen; ab = antibody; PCR = polymerase chain reaction.

The Well Patient with Abnormal Liver Function Profile Many patients now present to their practitioner apparently in good health but with an abnormal set of liver function test results, often found at routine insurance medical examination. These patients raise a whole range of diagnostic possibilities and, in evaluating them, a full history and examination is required. The most common causes of abnormal liver function test results in otherwise well individuals are non-alcoholic fatty disease (which may or may not be associated with significant inflammation) and alcohol-related liver damage. Another common cause will be the ingestion

of medications. However, the presence of other serious, progressive and eventually potentially life-threatening conditions needs to be considered.

History All patients with abnormal liver function test results need to be questioned about their family history of liver disease, and their ingestion currently or in the past of alcohol and medications. A history of diabetes mellitus, thyroid disease and high lipid levels should be sought; these together with obesity are associated with hepatic steatosis. The features of the metabolic syndrome with rising body weight and reduced physical

24 Abnormal liver function test results activity are common in those with non-alcoholic fatty liver disease, especially when there is a family history of type 2 diabetes. A history of overseas travel and exposure to blood products from transfusions or injection of drugs, legally or illegally, needs to be sought (e.g. hepatitis B or C). A history of known exposure to patients with infectious liver diseases should be asked about. A sexual history must be obtained because exposure to some viruses is much more common in individuals with multiple sexual partners (e.g. hepatitis B and HIV). When there is a family history of liver disease, social background requires close review. ‘Learned’ excessive alcohol consumption can lead to liver disease without the patient being aware that their intake is potentially dangerous. The amount of alcohol the ‘social drinker’ consumes varies according to his or her background. There is a possibility of genetic predisposition to alcoholic liver disease. Migration from areas of high prevalence of hepatitis B or C (e.g. Southeast Asia) should be noted. These viruses, acquired at birth or in early childhood, may not generate symptoms for many years. Haemochromatosis is preferably diagnosed prior to the onset of symptoms; abnormalities of liver function tests and abnormal iron study findings are clues. However, a history of joint pains, diabetes mellitus, cardiac disease or impotence in the patient or the existence of an affected relative suggests the possibility of haemochromatosis. Wilson’s disease is likely to be asymptomatic only in younger children. At older ages, features of cirrhosis or neurological abnormalities are likely. Alpha-1 antitrypsin deficiency, homozygote or heterozygote, may present with the incidental finding of abnormal liver function profiles in an otherwise well patient. In the otherwise well patient, a history of abdominal pain (e.g. biliary pain: Ch 4), loss of appetite or weight (Ch 17), or a change in the colour of stools or urine (Ch 23) needs to be sought but is almost invariably absent.

Examination Patients with abnormal liver test results must be regarded as having a liver disorder and thus signs of chronic liver disease should be sought because cirrhosis may be completely asymptomatic (Fig 24.1). The patient’s weight and height should be measured during the examination to allow evaluation of the body mass index (weight in kilograms divided by the square of the height in

313

metres: kg/m2). Truncal obesity is common and waist measurement should be taken. There should be an examination for signs of acute liver disease because the patient may be in the prodromal phase of a viral hepatitis (e.g. jaundice and encephalopathy). In the usual patient presenting with no history of symptoms and no awareness of liver problems, it is likely that there will be no signs of liver disease. A minor degree of hepatomegaly should be expected in patients with alcohol-related fatty liver or non-alcoholic fatty liver disease (Ch 17). Mild splenomegaly may also be found.

Investigation The approach to investigations is guided by the history, examination and liver function test pattern. Further testing is based on the provisional diagnosis and likely prognosis. When no hints as to the diagnosis have been found, a systematic investigation for potentially dangerous causes of liver disease needs to be considered. This would normally be done after a period of observation with serial liver function tests to determine whether there is a spontaneous recovery, a stable abnormality or deterioration. Liver imaging is of value (Ch 23). Abdominal ultrasound scans can provide information about the size and shape of the liver and spleen. Often any mass lesions present can also be identified. Ultrasonography will often detect fatty liver. Abdominal CT will provide information on the presence or absence of space-occupying lesions while, in addition, providing insight into liver density, which may be increased in haemochromatosis. Magnetic resonance imaging will usually add little to the information provided by a CT scan but can be of value in certain circumstances, such as in the assessment of mass lesions and of the biliary tract. Tests for evidence of viral hepatitis (Table 24.3), autoimmune liver disease (Table 24.1) and other causes of chronic liver disease (iron or copper overload, and other inherited liver diseases) (Table 24.2) should be done if hepatocellular disease is possible. If the diagnosis remains unclear and the prognosis of concern, a liver biopsy is required. Chronic hepatitis is an ongoing inflammatory process. The causes are listed in Table 24.4. If fibrosis follows as part of the healing process consequent to this inflammation, progression to cirrhosis and eventual liver failure is possible. For this reason, potentially controllable chronic hepatitis needs to be identified and treated before irreversible injury has occurred.

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Mental state Nutrition Anaemia

Jaundice Xanthelasma Kayser-Fleischer rings Pigmentation Fetor hepaticus

Body hair loss

Vascular spider

Gynaecomastia

Purpura

Spleen

Scratch marks

Ascites Liver Erythema Xanthomas

Dupuytren’s contractures (alcohol)

“Flapping” tremor Nails white, clubbed

Testicular atrophy

Bruising Wasting Tattoos Oedema

Figure 24.1  Signs of chronic liver disease. From Sherlock S, Dooley J. Diseases of the liver and biliary system. 11th edn. Oxford: Blackwell; 2002, with permission.

In each of the conditions generating chronic hepatitis there is an ongoing inflammatory attack directed toward the hepatocyte. This can be the result of direct hepatocyte injury, as is the case in hepatitis C infection (the most common cause of chronic hepatitis in Australia) and Wilson’s disease, which is rare. On the other hand, liver cell injury may be immune-mediated, as occurs with hepatitis B infection, autoimmune chronic hepatitis and certain drug reactions. Evidence of continuing hepatic inflammation based on a persistent elevation of serum transaminases (6 months or more) is usually required to entertain the diagnosis of a chronic hepatitis. However, it can take many months for serum transaminases to return to normal levels following some acute hepatic illnesses. Once the presence of chronic hepatitis is considered likely,

Table 24.4  Important causes of chronic hepatitis and cirrhosis Chronic hepatitis Cirrhosis ll ll ll ll ll ll

Hepatitis C virus Hepatitis B virus Autoimmune Drug-induced Wilson's disease Alpha-1 antitrypsin deficiency

ll ll ll ll ll ll ll ll ll ll ll

Alcohol Hepatitis C and B Drugs (as for chronic hepatitis) Non-alcoholic steatohepatitis (fatty liver disease) Primary sclerosing cholangitis Primary biliary cirrhosis Haemochromatosis Wilson's disease Chronic constrictive pericarditis Alpha-1 antitrypsin deficiency Idiopathic (cryptogenic)

24 Abnormal liver function test results establish the aetiology of the illness, the extent of liver damage and the activity of the inflammatory process. These latter two features can be assessed only by the histological examination of a liver biopsy.

The Sick Patient with Jaundice: Acute Liver Disease Acute hepatitis History Acute hepatitis of any cause can present with similar clinical features. Typically there is nausea with or without vomiting, right upper quadrant pain, weakness, fever, fatigue, itching and jaundice. An acute icteric illness may follow infection with one of the hepatitis viruses (see below). A similar clinical picture may be seen in Epstein-Barr virus and cytomegalovirus infections, in toxoplasmosis and occasionally in other viral infections. Viral exposure is suggested by parenteral risk factors such as intravenous drug use, tattooing, intimate contacts with hepatitisinfected patients, blood transfusion, travel to endemic areas and during local epidemics. Acute autoimmune disease is suggested by the presence of other autoimmune disorders (e.g. thyroid disease). A careful and complete drug history is vital. Both recently commenced drugs and those taken for prolonged periods should be considered. In patients showing evidence of depressive behaviour, drug overdose must be considered. If paracetamol (acetaminophen) has been used, then a careful ethanol consumption history is vital (see the next page). Normally safe, therapeutic doses of paracetamol may produce significant liver injury in those chronically consuming excessive amounts of ethanol. It should also be noted that inadvertent paracetamol overdose may occur due the patient’s lack of knowledge of safe dosage or the use of multiple different preparations containing the drug. Excessive ethanol consumption, especially recent bingeing, could indicate acute alcoholic hepatitis. Gallstone disease can occasionally present as an acute hepatitic illness that can be difficult to differentiate clinically. A family history of liver disease should be noted. Wilson’s disease may present as an acute illness, usually in childhood. Acute hepatitis may occur in a previously well person or in the presence of underlying chronic liver disease. In the latter case, the result can be devastating when preexisting liver disease results in little functional hepatic reserve. In pregnancy, acute viral hepatitis is the most common cause

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of this syndrome, but consideration should be given to pregnancy-related liver disease (see ‘Liver disease in pregnancy’ later in this chapter). Examination The patient can appear relatively well or profoundly ill. Jaundice may or may not be present. The liver size is noted. It will often be enlarged and tender. There may be splenomegaly. Look for evidence of an underlying condition (e.g. signs of alcohol excess). Complications (e.g. hepatic encephalopathy) may supervene. Look for signs of chronic liver disease (Fig 24.1). Investigation Serum transaminase levels are elevated, usually more than five times the upper limit of normal. In viral hepatitis, transaminase levels of 1000 U/L and over are not unusual. Moderate elevations of alkaline phosphatase also occur. Serum albumin and INR usually remain normal. Specific blood tests are required to diagnose viral illnesses, including viral hepatitis (A, B, C, D and E), cytomegalovirus and Epstein-Barr virus, toxoplasmosis, Q fever and autoimmune disease (Table 24.3). Paracetamol levels should be determined and laboratory evidence of alcohol excess sought. These may be relatively low in patients with chronic, but toxic paracetamol consumption. Abdominal ultrasound scans are useful to document the size of the liver and spleen and to exclude biliary disease. Management Treatment of viral hepatitis is supportive. Patients should be observed to ensure that fulminant hepatic failure (see below) or, with hepatitis C or B, chronic disease does not develop. It may take months for liver function profiles to normalise and liver biopsy should be considered if this does not occur. Absolute exclusion of ethanol is not necessary in the recovery phase. Offending drugs must be withdrawn. In the case of paracetamol, N-acetylcysteine is administered and close observation maintained over several days, with the patient’s clinical status, INR and transaminase levels monitored regularly. Alcoholic hepatitis is managed supportively; in certain circumstances specific interventions may be of value. Ethanol is withdrawn, and vitamin (especially thiamine) and nutritional supplementation should be given (enteral feeding may provide a survival benefit). Corticosteroids (prednisone, 40 mg daily for 28 days) may provide a survival benefit when there is encephalopathy (see below) and no gastrointestinal haemorrhage.

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Propylthiouracil may be of benefit in less severe cases of alcoholic hepatitis, but is rarely used. Abstinence remains the mainstay of therapy. When gallstone disease is found to be the cause of an acute hepatitic illness, cholecystectomy may be indicated. Choledocholithiasis may require endoscopic clearance of the bile duct (Ch 23). Acute autoimmune hepatitis is managed with corticosteroids (e.g. prednisone, 30–60 mg daily, then taper).

Acute Liver Failure Definition Liver failure occurring in a previously well patient is termed ‘acute’ or ‘fulminant’ hepatic failure; hepatic encephalopathy (an organic neurological syndrome) with elevated INR (impaired hepatocellular synthetic function) evolves within 8 weeks of the onset of the illness. Subfulminant or subacute hepatic failure is used to describe the onset of hepatic decompensation up to 26 weeks after the initial illness. These need to be differentiated from acute hepatic failure evolving in the presence of established chronic liver disease.

History The historical features of acute hepatitis should be enquired about. However, details will need to be obtained from others when the patient has established encephalopathy. Acute infection with the hepatotropic viruses A, B, D or E (and very rarely C) can cause fulminant hepatic failure. In late pregnancy, acute fatty liver should be considered. Ask about drugs, which may cause direct toxic effects (e.g. following overdose of paracetamol) or cause idiosyncratic reactions (e.g. halothane and sulfonamides). Following an acute overdose of 140 mg/kg or more of paracetamol, the glucuronide and sulfate pathways in the liver become saturated and hepatic glutathione becomes depleted, leading to reactive metabolites covalently binding to liver cells causing lysis. Hepatotoxicity manifests 24– 48 hours after ingestion. The early identification of paracetamol overdose is crucial. Serum levels should be measured 4 and 24 hours after suspected ingestion; the administration of N-acetylcysteine will prevent progression to hepatic failure. It gives maximal benefit if instituted within 8–10 hours of ingestion (but is indicated after that time as well). ALT levels are typically very high while the bilirubin is relatively low. An intake of a normally subtoxic dose of paracetamol in the presence of chronic alcohol abuse may lead to

acute hepatic failure. In the USA approximately 50% of paracetamol overdose is non-intentional with the drug taken over days. In these cases the serum drug levels are lower. Toxicity normograms are of no value in this circumstance. Fluorinated hydrocarbon solvents (in glue sniffing) and mushroom poisoning have also been linked to acute hepatic failure. Wilson’s disease may rarely present in acute liver failure, and death usually follows without liver transplantation. In fulminant hepatic failure there is a sudden loss of functional hepatocyte mass, often associated with portal hypertension. The associated complications of encephalopathy, coagulopathy, renal failure and sepsis evolve. Multi-organ failure often occurs, with the patient’s death from cerebral oedema or infection.

Assessment and management Examination is directed towards assessing the possible aetiology and evolving complications of hepatic failure (outlined below). Serial liver function tests can be useful, but a falling ALT level may reflect either recovery or progression to massive hepatic necrosis. A temperature above 38°C or below 36°C, a pulse rate above 90 beats per minute and/or a white cell count above 12,000 or below 4,000 are associated with a greater mortality. The prognosis, and therefore need for liver transplantation, of a patient in acute liver failure can be assessed using the Kings College Criteria (Table 24.5). The patient with fulminant hepatic failure needs to be admitted directly to a unit capable of offering Table 24.5  Kings College Criteria for listing of a patient in acute liver failure (ALF) for liver transplantation Type

Criteria

Paracetamolinduced ALF

Arterial pH < 7.30 after fluid resuscitation or all of: ll INR > 6.5; ll creatinine > 259 μmol/L; ll grade 3 or 4 encephalopathy.

Nonparacetamolinduced ALF

INR > 6.5 or any three of: non-A, non-B viral hepatitis, druginduced or indeterminate aetiology Time from jaundice to encephalopathy > 7 days Age < 10 years or > 40 years INR > 3.5 Serum bilirubin > 297 μmol/L

INR = International Normalized Ratio.

From O'Grady JG, Alexander GJM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445.

24 Abnormal liver function test results liver transplantation. Admission to intensive care is required with careful management of cerebral oedema, gastrointestinal bleeding, infection and renal failure. Hepatic encephalopathy and cerebral oedema This may develop rapidly and may even precede the onset of jaundice. Raised ammonia levels associated with liver failure cause brain swelling, inflammation, increased cerebral blood flow and a breakdown of the blood–brain barrier. Deeper grades (described later in this chapter) of encephalopathy are associated with a worse prognosis. Unlike the encephalopathy of chronic liver disease, there is often early agitation and delusional ideation. Cerebral oedema is more likely to occur when encephalopathy develops rapidly after the onset of jaundice. However, survival is worse in those in whom encephalopathy evolves slowly. Cerebral oedema, present in up to 80% of those in grade IV encephalopathy, is a significant cause of death. Clinically, this is reflected by systemic hypertension, bradycardia with progressive rigidity and decerebrate posturing. Direct pressure monitoring with a subdural or epidural transducer is the only reliable means of assessing cerebral pressure. Prognosis is particularly poor and liver transplantation inappropriate when the cerebral perfusion pressure is less than 50 mmHg, and is refractory to mannitol therapy. Grade III and IV encephalopathies (see below) are associated with a worse prognosis. Management aims to reduce systemic vasodilatation and cerebral perfusion pressure, maintaining a low mean arterial pressure and central venous pressure. Mannitol, sodium, hypothermia (when there is hyperacute high grade encephalopathy and requiring vasopressors) and dialysis (in those developing renal impairment) have been used in the treatment of cerebral oedema. Coagulopathy Coagulopathy of acute hepatic failure occurs as the result of loss of hepatic synthetic function, sepsis, bleeding and intravascular coagulation. Platelet levels decrease and their function is impaired. Spontaneous bleeding is rare and postprocedural bleeding is uncommon. Platelet transfusion and fresh frozen plasma can be of value when there is active haemorrhage. There is no evidence that correcting an abnormal INR or platelet count is of value in the absence of bleeding. On the other hand the INR can be used to assess recovery in liver function. Patients with acute liver failure may be hypercoagulable despite a low INR.

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Hypotension, renal failure and hypoglycaemia Hypotension is common and renal failure is not unusual. The latter is usually associated with the hepatorenal syndrome. This syndrome represents a functional renal impairment and carries a poor prognosis. Normal renal function returns with recovery or liver transplantation. Acute tubular necrosis secondary to hypotension may also occur in acute hepatic failure. When renal failure does occur, therapy is supportive; dialysis is problematic because of the associated coagulopathy, hypotension and cerebral oedema. N-acetylcysteine may improve oxygen delivery. In acute liver failure, peripheral circulatory changes lead to impaired oxygen delivery, tissue hypoxia and lactic acidosis (a poor prognostic sign). As the functional hepatocyte mass decreases, the liver is unable to sustain gluconeogenesis, and life-threatening hypoglycaemia follows. Blood sugar levels require close monitoring and are a measure of remaining hepatic function. Ten per cent glucose infusions are usually required. Hypokalaemia (with respiratory alkalosis) and dilutional hyponatraemia may also occur. Infection Evidence of infection must be actively sought in any episode of hepatic failure. The chest and urinary tract are common sites of infection. Multifactorial mechanisms leave these patients prone to severe bacterial and fungal infections. Death will rapidly follow unless aggressive antibiotic therapy, or drainage of pus if possible, is instituted once the possibility of infection is considered. Prophylactic antibiotics may be of value when there is renal failure or while awaiting transplantation. Empiric antibiotics therapy may increase encephalopathy. Prognosis The prognosis of acute hepatic failure related to paracetamol overdose, hepatitis A viral infection and fatty liver of pregnancy (if there has been prompt delivery) tends to be better than that of other causes. The outcomes appear worst in those in whom the cause is unclear. Liver transplantation is a therapeutic option. The decision to transplant and the timing of transplantation are difficult. However, 1-year survival rates of approximately 70% can be achieved. This compares favourably with mortality rates from fulminant hepatic failure without transplantation of up to 90% although with optimal intensive care unit management 30–40% survival can be achieved. N-acetylcysteine may

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also improve overall survival and transplant-free survival in patients with non-paracetamol-related acute liver failure, especially if encephalopathy is limited to grade I or II. Hepatitis B-associated fulminant hepatic failure should be managed with the antiviral agent entecovir. In herpes simplex hepatitis only about 50% of cases will have a rash, blood HSV DNA levels will be high and treatment with acyclovir should be initiated if the diagnosis is suspected. In autoimmune acute liver failure the ALT will often be around 600 and there will be appropriate autoantibodies, raised IgG level and, if performed, liver biopsy will show pericellular venulitis, interface necrosis and plentiful plasma cells. Corticosteroids do not alter the transplant-free survival, which approximates 20%.

Patients Presenting with Cirrhosis and its Complications Cirrhosis represents the non-specific end-stage of hepatic disease that has disrupted the structural organisation of the liver. The presence of cirrhosis is established on a liver biopsy. Fibrosis or scarring surrounding regenerative nodules of hepatocytes is its hallmark. Although cirrhosis is a histological diagnosis, its presence is clinically suspected by finding signs of chronic liver disease and portal hypertension (Box 24.1) or on high quality imaging. Symptomatic liver disease and eventually liver failure occur as the result of impaired hepatocellular function within the distorted architecture of the regenerative nodules and, with progression, eventual loss of an effective liver cell mass. Distortion of the hepatic circulation contributes to portal hypertension and inefficient/ ineffective perfusion of parenchymal cells. Portal systemic shunts may develop, allowing blood from the gastrointestinal tract to flow directly to the systemic circulation. Cirrhosis should be considered as either compensated, with no signs of complications and a relatively good prognosis, or decompensated (Ch 25). Those with compensated cirrhosis are likely to be asymptomatic and the diagnosis may

be made incidentally during the investigation of an unrelated condition. In this situation, counselling regarding diet, ethanol consumption and the identification and management of any underlying treatable condition are warranted (see ‘The well patient with abnormal liver function profile’ above). Recent data have indicated that the removal or cure of the underlying disease process can be followed by a reduction in hepatic fibrosis (e.g. after the cure of hepatitis C). The serum levels of liver enzymes (ALT, AST and ALP) can be mildly abnormal or even normal in compensated cirrhosis. However, because of reduced hepatic synthetic function or poor nutrition, the serum albumin concentration is often reduced, and the INR may be increased. There may be thrombocytopenia related to splenomegaly from portal hypertension. Anaemia can be multifactorial but is often related to gastrointestinal blood loss, poor nutrition (e.g. in alcoholics), chronic disease and hypersplenism. The Child-Pugh score (Table 24.6) provides a useful means of assessing the severity of cirrhosis and the prognosis. A Child-Pugh ‘A’ classification applies to a score of less than 7; ‘B’, a score between 7 and 9; and ‘C’, greater than 9. The 1-year survival of these classification groups is 100%, 80% and 45%, respectively. A higher score also indicates those more likely to succumb to complications during hepatic and no hepatic surgical procedures. The MELD (Model for End Stage Liver Disease) score is a validated means of assessing the prognosis and survival of a patient with chronic liver disease that incorporates bilirubin, INR and creatinine values. This score can be used to prioritise the allocation of organs within a liver transplantation program (see Ch 25). Maintaining adequate nutrition is vital to the management of patients with cirrhosis and chronic liver disease in general. These patients are often catabolic, requiring greater than usual energy intake. Nausea and dyspepsia are common and may reduce food intake and thus their nutritional status further. Dietary measures should be put

Table 24.6 Child-Pugh score Score

Serum albumin (g/L)

Serum bilirubin (μmol/L)

Prothrombin time (seconds prolonged)

Ascites

Encephalopathy

1

> 35

< 35

1–3

Nil

Nil

2

28–35

35–51

4–6

Slight

Grades 1–2

3

< 28

> 51

>6

Moderate

Grades 3–4

24 Abnormal liver function test results in place to ensure a diet of adequate energy and protein intake with attention to micronutrient supplementation as needed (e.g. fat-soluble vitamins). The advice of an experienced dietician should be sought.

The Well Patient with Cirrhosis History Patients with cirrhosis may be asymptomatic, coming to medical attention following an incidental finding of abnormal laboratory tests or physical findings suggestive of chronic liver disease. Such patients should be assessed to determine the likely aetiology as outlined in ‘The well patient with abnormal liver function profile’ above. Attention should be directed to identifying evidence of ongoing hepatic injury that may be modified by therapeutic intervention. A careful history of exposure to alcohol, drugs and potential hepatotropic agents (e.g. solvents) is required. Removal of exposure may help slow progression. Risk factors for exposure to hepatitis B and C viruses and family history of liver disease should be assessed.

Examination Physical examination includes a search for signs of chronic liver disease (Box 24.1) and evidence of extrahepatic features of possible aetiological factors.

Investigation Investigations are directed to (1) determining the aetiology of the cirrhosis (Table 24.4); and (2) assessing the severity of hepatic injury. When physical findings and investigations suggest cirrhosis, liver biopsy should be considered to establish its presence, to assess the activity of the fibroinflammatory process and to seek evidence of the aetiology. A past history of excessive ethanol consumption is often identified. In other cases, a specific aetiology can often be established by using special tests for autoantibodies, viral serology and metabolic disorders (Tables 24.1–24.3). Elevations in serum transaminase levels imply ongoing hepatocellular injury. Raised INR (prolonged prothrombin time) and hypoalbuminaemia suggest reduced hepatocellular synthetic function. Abdominal ultrasound scans with Doppler studies will provide evidence of portal hypertension (splenomegaly, portal flow and wave pattern), ascites and liver size (reflecting the remaining liver cell mass). Varices are excluded by upper endoscopy.

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Management The management of the well cirrhotic patient depends on the underlying cause. The cirrhotic should cease drinking alcohol completely. Failure to do so is likely to cause progression and early death. Abstinence, on the other hand, can allow a long and productive life despite the cirrhosis. Cirrhotic patients with autoimmune chronic hepatitis and significant inflammation on biopsy could benefit from corticosteroid therapy. Interferon is of limited benefit, and potentially dangerous in those with cirrhosis due to chronic hepatitis B. Oral antivirals, on the other hand, may be of value. Counselling of the patient and, if necessary, family members is required when infectious or genetic conditions are identified. Regular ultrasound screening for hepatocellular carcinoma should be performed at 6-monthly intervals. Upper gastrointestinal endoscopy should be performed to seek and, if present, treat significant oesophageal varices. Apart from any treatment associated with the underlying cause, the asymptomatic patient with cirrhosis needs to maintain an adequate diet. Sufficient kilojoules, protein and micronutrients should be ingested. A complex carbohydrate snack before retiring in the evenings could help prevent the patient from becoming catabolic overnight as the hepatic glycogen stores become depleted. Regular follow-up is necessary, specifically seeking evidence of evolving complications of cirrhosis (namely, portal hypertension and ascites, portal vein thrombosis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome and hepatocellular carcinoma). See Chapter 25 for more details.

Complications of Portal Hypertension in the Patient with Chronic Liver Disease Portal hypertension In cirrhosis, the disturbed architecture of the liver and perivascular fibrosis increase the resistance of portal blood flow. Portal pressure is also increased consequent to sodium retention and expansion of the blood volume that follows the peripheral vasodilatation of cirrhosis. Cirrhotic patients suffer the combined effects of hepatocellular dysfunction and portal hypertension. Although cirrhosis is the commonest cause, primary liver disease is not the only basis for portal hypertension. Portal and hepatic vascular disorders can also cause portal hypertension while leaving

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Box 24.2  Classification of causes of portal hypertension ll ll

ll



Intrahepatic sinusoidal—cirrhosis Presinusoidal (the portal vein end: liver function is largely unimpaired): – extrahepatic, e.g. neonatal sepsis, hypercoagulable blood disease; – intrahepatic, e.g. lymphoma, schistosomiasis. Postsinusoidal (the hepatic vein end): – Budd-Chiari syndrome and inferior vena cava obstruction; – veno-occlusive disease (small hepatic veins injured by bush teas, drugs, e.g. azathioprine)

hepatocyte function relatively intact (Box 24.2). In these situations when liver cell function is maintained, portal systemic shunt surgery, rather than transplantation, may be appropriate for severe disease (Figs 24.2A and 24.2B). When vascular or thrombotic processes are found, an underlying cause for these should be sought and managed accordingly.

Acute upper gastrointestinal haemorrhage in patient with portal hypertension History In patients with chronic liver disease, acute gastrointestinal bleeding, especially upper gastrointestinal haemorrhage, should raise concern of a lesion consequent to portal hypertension. Oesophageal varices and portal hypertensive gastropathy are common causes. Variceal haemorrhages are usually of large volume, presenting with fresh haematemesis, melaena and shock (Ch 10). Small amounts of overt blood loss without haemodynamic changes are unlikely to be variceal in origin. Bleeding from portal hypertensive gastropathy may be slow, presenting with iron deficiency anaemia, or sufficient to produce overt haematemesis and melaena. Similarly portal hypertensive enteropathy can cause slower gastrointestinal bleeding. It must be noted that peptic ulceration and other causes of upper gastrointestinal haemorrhage are relatively common in cirrhotic patients and the history should be directed to consider these conditions as well (Ch 5).

Bleeding is a medical emergency and the history should be directed to the assessment of the amount of blood loss and the probable underlying cause. Examination Assessment of the physical signs of blood volume loss is vital (Ch 10). Signs of chronic liver disease (Box 24.1) support the possibility of cirrhosis and variceal bleeding. Splenomegaly suggests portal hypertension. In acute or chronic liver disease, the liver may be palpable and tender. The cirrhotic liver is likely to be small. Blood in the gastrointestinal tract can precipitate encephalopathy in cirrhotic patients. This should be sought and documented. There should be a search for signs of other complications of chronic liver disease including ascites and sepsis. The chest should be carefully examined for evidence of aspiration, especially in alcoholic patients. Investigations Basic haematological investigations are required as with any gastrointestinal haemorrhage (Ch 10). When chronic liver disease is present, particular attention is paid to the factors of the Child-Pugh score (above). Electrolyte disturbances are not uncommon. Renal function must be checked. The source of the upper gastrointestinal haemorrhage is demonstrated by upper gastrointestinal endoscopy as soon as is practical. Management Significant upper gastrointestinal haemorrhage requires urgent resuscitation. Once this is achieved, endoscopy can be used to confirm and often control the source of bleeding. Acute variceal bleeding is usually controlled endoscopically by band ligation. The long-acting somatostatin analogue, octreotide, or terlipressin (triglycyl lysine vasopressin) provides an effective pharmacological means of managing acute variceal haemorrhage. These agents are often used to complement endoscopic therapy or to achieve control of blood loss while endoscopy is being arranged. Octreotide is given as a bolus dose of 50 μg intravenously, followed by an infusion of 50 μg/hour for at least 72 hours. When endoscopic therapy is unavailable or not possible, balloon tamponade applied at the cardio-oesophageal junction can be used to control bleeding from oesophageal varices for up to 24 hours. Gastric varices do not respond to endoscopic therapy as well as oesophageal varices, although injection

24 Abnormal liver function test results

IVC

Normal

321

End-to-side porta-caval anastomosis

Portal v Renal v

Spleen

Kidney IVC = Inferior vena cava

Superior mesenteric v

Side-to-side porta-caval anastomosis

A

Coronary Portal vein Inferior vena cava

Superior mesenteric vein

PV

Spleen RGE

Renal vein Mesocaval shunt

B

Short gastric veins

Right gastric

Dacron graft RGE = right gastroepiploic PV = portal vein

Kidney

Distal splenorenal shunt

Figure 24.2  Portal systemic shunts. The operation aims to reduce portal pressure. Options include (A) portacaval (end-to-side or side-to-side); (B) meso-caval (using a Dacron graft between the superior mesenteric vein and inferior vena cava) and distal splenorenal shunts (where veins feeding varices are ligated and a splenorectal vein shunt is created, preserving portal blood flow to the liver). Complications include hepatic encephalopathy (20–40%), ankle oedema, deterioration in hepatic function and shunt closure. The choice usually depends on local surgical expertise: if there is no ascites, a distal splenorectal shunt may be referable; if ascites is present, a side-to-side porta-caval shunt may be most optimal. From Sherlock S, Dooley J. Diseases of the liver and biliary system. 11th edn. Oxford: Blackwell; 2002, with permission.

therapy using cyanoacrylate or fibrin glue can be a successful intervention in those with bleeding gastric varices. Transjugular intrahepatic portal systemic shunting (TIPS) or surgical portal systemic shunting may be considered to control variceal bleeding when endoscopic therapy fails. TIPS

involves the introduction of expandable metal stents between the portal and hepatic venous system, within the liver, placed under radiological control. Apart from portal systemic shunting, surgical alternatives acutely include transaction of the oesophagus. In cirrhotic patients, an acute surgical

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Clinical gastroenterology: a practical problem-based approach

shunt has a high mortality. The risk is directly related to the Child-Pugh score. The long-term value of the shunting procedures is questionable; a careful case selection is essential. Antibiotic prophylaxis is required during variceal bleeding, preferably prior to endoscopic therapy. Cefriaxone, 1 g daily, is appropriate and should be continued for at least 3 days. Liver transplantation should be considered in suitable cirrhotic patients in the long term. When liver cell function is well preserved (as in noncirrhotic portal hypertension), portal systemic shunting may be viable alternative (Fig 24.2A and B). Varices may occur anywhere in the gastrointestinal tract. Bleeding from these lesions may also be managed endoscopically if they are accessible, but surgical treatment could be required. Prognosis The prognosis of cirrhotic patients with an acute variceal haemorrhage is determined by their hepatic reserve. Three episodes of major variceal bleeding during a single admission are usually fatal. Once the acute haemorrhage is controlled, serial band ligation is performed until the oesophageal varices are obliterated. Recurrence of the varices is not unusual. A non-selective betaadrenergic blocker, such as propranolol, is used to reduce the chance of bleeding from oesophageal varices. Prophylaxis Not all varices bleed. Thus, smaller varices found incidentally do not necessarily require intervention. However, the larger the varices, the greater the chance of bleeding. The prophylactic use of non-selective beta-adrenergic blockers, such as propranolol, has also been shown to reduce the risk of an initial or subsequent haemorrhage, especially in those with medium to large varices or more severe portal hypertension.

Ascites in the Cirrhotic Patient with or without Renal Impairment The accumulation of fluid in the peritoneal cavity is a common feature of decompensating chronic liver disease. Ascites occurs in 50% of previously compensated cirrhotic patients over a 10-year period. This complication marks a poor prognosis with a 2-year survival of 50%. The survival in these patients is worse with increasing age, co-existent hepatocellular carcinoma, diabetes and ongoing alcohol consumption. The development of ascites

is also associated with a deterioration of quality of life and an increase in health care utilisation.

History A presentation of ascites in a patient known to have chronic liver disease often heralds endstage disease. Similarly people with unrecognised cirrhosis can come to medical attention with the development of ascites. The history is of progressive abdominal distension, often with peripheral oedema. This can progress rapidly and be associated with significant abdominal discomfort. History should note details of known liver disease or, in de novo cases, historical evidence of the cause of liver disease. Acute hepatic disease is possible when the history is short, so risk factors for viral hepatitis and vascular disease should be noted. The history should also seek evidence of cardiac, renal or malignant disease.

Examination Ascites is usually readily identified on physical examination. The demonstration of shifting dullness is not possible with volumes less than 2 L. Smaller amounts of fluid can be found by the finding of periumbilical percussion dullness with the patient on hands and knees. In obese patients, physical examination for ascites can be difficult and inconclusive. In such cases abdominal ultrasound examination is indicated. Signs of chronic liver disease (Box 24.1) are expected in patients presenting with ascites and cirrhosis. Peripheral oedema is often present. Other complications of chronic liver disease or of the underlying condition may be present. Their absence should raise the possibility of acute hepatic disease or non-cirrhotic portal hypertension. Alternately, there may be a non-hepatic cause for the ascites. Physical examination may identify other causes of ascites, including cardiac failure and malignant disease. A pleural effusion, particularly on the right, may be present. Umbilical hernias commonly occur in ascites patients and surgical repair in this circumstance carries a high mortality.

Investigation The diagnosis of the cause of ascites and exclusion of spontaneous bacterial peritonitis by paracentesis (tapping the peritoneal fluid) is mandatory. The gradient of albumin concentration between the serum and the ascitic fluid is particularly useful. A gradient greater than or equal to 11 g/L strongly suggests portal hypertension (as with cirrhosis). On the other hand, a gradient less than 11 g/L suggests malignancy or infection. If the patient is known

24 Abnormal liver function test results to have cirrhosis, a low serum–ascites albumin gradient raises the possibility of spontaneous bacterial peritonitis or the development of hepatocellular carcinoma (Ch 20). Abdominal ultrasound scans with Doppler studies will document the ascitic fluid and the state of the portal and hepatic vessels.

Management Symptomatic ascites is initially managed with fluid and sodium restriction (no added salt). If this fails to control the ascites, spironolactone, up to 400 mg/day, can be used. It must be noted that spironolactone will take several days to have an effect. A loop diuretic, such as frusemide, may then be added in resistant cases, initially at 20–160 mg/day. Careful monitoring of renal function and serum electrolytes is needed as renal impairment and electrolyte disturbances followed by hepatic decompensation with encephalopathy can be precipitated by this therapy. In profound ascites, paracentesis can also be used. Large volumes of ascitic fluid can be safely removed, especially if peripheral oedema is present; albumin should be infused during large volume paracentesis (greater than 5 L). There is evidence that intravenous albumin may be of value in the therapy of ascitic patients when used in combination with diuretics or paracentesis and during treatment for spontaneous bacterial peritonitis or the hepatorenal syndrome. Refractory ascites is an indicator of a poor prognosis. TIPS controls refractory ascites in more than 70% of cases. However, patients remain hyponatraemic and require ongoing diuretic therapy. The success of TIPS is tempered by portal systemic encephalopathy and shunt occlusion. The risk of encephalopathy increases with age, shunt size, liver function and prior portal systemic encephalopathy. In general, survival is similar with TIPS and large volume paracentesis, although TIPS may provide a survival advantage in those with higher MELD scores. The patient’s suitability for liver transplantation should be considered as transplant is the definitive therapy for refractory ascites. Peritoneovenous shunts can be used but are fraught with problems including infection, blockage and stimulation of the coagulation cascade (causing disseminated intravascular coagulation).

Mechanism The mechanism that generates ascites begins with the raised intrahepatic vascular resistance and consequent portal hypertension caused

323

by the disruption of the hepatic architecture. A hepatovenous portal gradient greater than 10  mmHg is generally required to develop ascites. There is nitric oxide (NO)-induced vasodilation with a reduction in effective arterial blood volume and a neuroendocrine response leading to sodium and water retention. There is an increase in aldosterone production, and a reduction in its removal, often accompanied by inappropriate levels of antidiuretic hormone. With progression there is renal artery vasoconstriction, which leads to the hepatorenal syndrome. When renal adaption occurs the patient remains compensated, but if it does not, refractory ascites is the result.

Ascites, Fever and Pain: Spontaneous Bacterial Peritonitis Spontaneous bacterial peritonitis is nearly always an indicator of severe liver disease. It carries a poor short- and long-term prognosis. There is a greater risk of this complication when the ascitic protein level is low. It may be asymptomatic initially.

History and examination The presenting features of spontaneous bacterial peritonitis are ascites with fever, abdominal pain, jaundice, confusion and abdominal tenderness, but there may be no symptoms. There may be a history of severe acute or chronic liver disease. Ascitic fluid is a prerequisite for this condition. There is likely to be large volume ascites, but it is possible even when peritoneal fluid is not clinically detectable. Signs of peritonitis may be absent, and death rapid. As few as 10% of patients will have rebound tenderness or shock at presentation.

Investigation and mechanisms Ascitic fluid must be sampled and examined in all patients with ascites and a recent decompensation (Ch 20); this should be done on admission regardless of clinical signs. Of all cirrhotic patients with ascites admitted to hospital, 12–15% will have spontaneous bacterial peritonitis. An ascitic polymorphonuclear leukocyte count greater than or equal to 250 cells/L is indicative of the condition. Ascitic fluid cultures should be collected and the samples inoculated into blood culture bottles, at the bedside. Cefotaxime is adequate antibiotic therapy in most cases. Outcomes may be improved by the addition of intravenous albumin: 1.5 g/kg of body weight at diagnosis, then 1 g/kg of body weight on the third day.

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Common organisms include Escherichia coli, Streptococcus pneumoniae and Klebsiella spp. Spread to the peritoneum appears to be via the blood. Bacteria may also breach a mucosal barrier as occurs during gastrointestinal haemorrhage or instrumentation. The lower the ascitic fluid protein concentration, the more likely spontaneous bacterial peritonitis becomes. Peritoneal macrophage dysfunction and reduced opsonic capacity of ascitic fluid may allow progression of colonisation of infection. Secondary peritonitis, following perforation of a viscus, needs to be excluded, as this would also require surgical intervention. Such surgery would carry a very high mortality. Cirrhotic patients with ascites and secondary peritonitis can also display a paucity of clinical signs.

Hepatic Encephalopathy in the Cirrhotic Patient

Table 24.7 Grades of severity of hepatic encephalopathy Grade

Clinical features

I

Personality and mood changes, disturbed sleep pattern, poor hand writing, fetor, asterixis

II

 ild disorientation, inappropriate behaviour, M slurred speech, ataxia, hyporeflexia

III

 isoriented, amnesia, somnolent but D rousable, incoherent speech, marked asterixis, hyper-reflexia, clonus, rigidity

IV

 . Responsive to painful stimuli, hypotonia, A hyporeflexia, hyperventilation B. Unresponsive, decorticate/decerebrate posture

The precise mechanisms responsible for this process are unclear. Under normal circumstances the liver detoxifies neuroactive nitrogenous metabolites that pass into the portal system from the gastrointestinal tract. With the loss of functional hepatocytes and/or portal systemic shunting of blood, these ‘toxins’ reach the systemic circulation where they may alter central nervous system function. The actions of the raised ammonia concentration in combination with other toxins could account for much of what occurs in those with hepatic encephalopathy, including changes to the blood–brain barrier and altered amino acid neurotransmitter metabolism. Blood ammonia concentrations correlate with the level of coma, but are not useful in the absence of a full clinical assessment or in the assessment of the patient’s progress.

Box 24.3  Proposed nomenclature of hepatic encephalopathy

History and examination

* Without recognised precipitating factors. HE = hepatic encephalopathy. From Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35:716–721.

The clinical features and grades of hepatic encephalopathy are shown in Table 24.7 and its classification in Box 24.3. Encephalopathy in cirrhotic patients may occur as an episodic, persistent or minimal form. Minimal encephalopathy may be objectively demonstrable only by psychometric testing. Although not easily identified, this chronic, low-grade deficit can adversely affect the patient’s functional capacity and quality of life. The identification of this group is important as they are subject to a greater rate of accidents (e.g. motor vehicle accidents) and altered work performance. The risk of minimal encephalopathy is higher in the presence of

A Encephalopathy associated with acute liver failure B Encephalopathy associated with portal systemic bypass and no intrinsic hepatocellular disease. C Encephalopathy associated with cirrhosis and portal hypertension/or portalsystemic shunts Episodic HE

Precipitated Spontaneous* Recurrent

Persistent

HE mild Severe Treatmentdependent

Minimal HE

Child-Pugh C cirrhosis, older age, alcoholic liver disease, TIPS and varices. These patients should not be permitted to drive a motor vehicle. Hepatic encephalopathy accompanying severe, acute liver disease carries a grave prognosis and is accompanied by the clinical features of acute

24 Abnormal liver function test results Box 24.4  Factors (and possible mechanisms) that may precipitate hepatic encephalopathy in chronic liver disease ll

ll

ll

ll ll

ll

Gastrointestinal bleeding (increases ammonia and other toxin load) High dietary protein intake or constipation (increases ammonia and other toxins) Electrolyte disturbances, e.g. after diuretics (hypokalaemia increases the renal production of ammonia, while alkalosis increases the amount of ammonia and other toxins that cross the blood-brain barrier) Infection Deteriorating liver function, e.g. alcoholic binge, development of hepatoma drugs, e.g. sedatives Metabolic, e.g. hypoglycaemia, hypoxia, hypercapnia, anaemia, myxoedema

disease. In chronic liver disease with appropriate clinical features (above), milder, overt long-term encephalopathy may be found. Insomnia can be an early feature. A reversal of normal sleep patterns (sleeping during daylight hours and waking at night) is suggestive of early encephalopathy. More profound encephalopathy accompanies acute episodes of decompensation (e.g. infection and gastrointestinal bleeding) or progression to endstage liver failure. Drug effects (especially sedatives), electrolyte abnormalities (diuretics), constipation, dietary protein load and renal failure should also be considered as precipitants (Box 24.4). Blood ammonia levels are elevated but vary widely. Infection may be present without fever, leucocytosis or localising signs. A systematic search for evidence of sepsis is required, with a chest x-ray examination and cultures of blood, urine, ascites and sputum. Portal systemic shunting, surgical or spontaneous, also often results in hepatic encephalopathy. Serum ammonia levels are useful in detecting unsuspected significant portal systemic shunts, as are Doppler ultrasound studies.

Management Management of hepatic encephalopathy attempts to improve the underlying condition, together with supportive measures and the reduction of the amount of ‘toxins’ entering the circulation from the intestine. Treatment is directed at any precipitating event, such as sepsis or gastrointestinal bleeding. The addition of lactulose, to acidify the colonic

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contents and act as a cathartic, is helpful. Alterations in colonic flora and the nitrogen, fatty acid and glutamine metabolism of colonic bacteria may also contribute to the activity of this agent. Treatment is aimed at producing one or two soft stools daily. Lactulose decreases the psychometric abnormalities associated with minimal encephalopathy as well as improving clinically overt encephalopathy. In these patients a positive trial of lactulose can assist in establishing the diagnosis. Neomycin suppresses the production of ‘toxins’ by bowel bacteria and is as effective as lactulose. The combination of these two agents is unlikely to provide added benefit. Another nonabsorbed antibiotic, rifaximin is equally effective but expensive. Rifaximin can be cost-effective if added to lactulose if the latter has been shown to be insufficient. L-ornithine L-aspartate (LOLA) is superior to placebo. Probiotics may prove effective therapy but require further study. Protein restriction is in general of no value and may negatively affect the patient’s nutritional status. Patients should not be permitted to become constipated and great care must be taken with the use of medications. Zinc, which may increase the capacity to metabolise ammonia, can be useful in malnourished patients. Hepatic transplantation will reverse the condition.

Liver Disease in Pregnancy In normal pregnancy, serum levels of AST and ALT are not altered, but the GGT level is reduced. ALP levels, on the other hand, may double after 3 months. The serum albumin concentration is reduced slightly by haemodilution. Hepatic diseases during pregnancy are generally managed as if the patient were not pregnant. Liver disease in pregnancy can conveniently be divided into disease that is incidental to the pregnancy, disease that is exacerbated by the pregnancy, and pregnancy-specific disorders (see Table 24.8). Severe chronic liver disease reduces fertility such that decompensated chronic liver disease is not common in pregnant women. Pregnancy does not preclude hepatic transplantation for acute hepatic failure. Furthermore, past hepatic transplantation does not prevent subsequent successful pregnancy.

History Patients presenting with liver disease in pregnancy require prompt assessment and close follow-up because severe life-threatening illness may rapidly follow a seemingly mild prodrome.

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Table 24.8 Liver disease in pregnancy Disease

Cause

Comment

Incidental to pregnancy

Viral hepatitis

Most common cause of liver disease in pregnancy

Alcohol-related Autoimmune chronic active hepatitis



Related to pregnancy (possibly influenced by hormones present in pregnancy)

Complicated gallstone disease

Bile ducts enlarge in pregnancy, tend to regress after delivery May enlarge and bleed, rare May enlarge Hepatic venous outflow obstruction

Specific to pregnancy

Severe hyperemesis gravidarum

Hepatic adenoma Focal nodular hyperplasia Budd-Chiari syndrome

Benign intrahepatic cholestasis Acute fatty liver of pregnancy Preeclampsia (HELLP)

Most prevalent in females of reproductive age

Intractable vomiting causing ketosis; elevated aminotransferases See text See text See text

HELLP = haemolysis, elevated liver function tests and low platelets.

Timing of the onset of illness should be noted. Hyperemesis gravidarum evolves early in the pregnancy. Cholestasis of pregnancy, acute fatty liver and preeclampsia usually occur in the third trimester. In cholestasis of pregnancy, itch is a predominant feature. There may be a history of a similar problem in previous pregnancies or after taking oral contraceptives. Nausea and vomiting with abdominal pain, especially in late pregnancy, indicate a need for complete and careful assessment for preeclampsia and acute fatty liver, especially if there is right upper quadrant pain. However, right upper quadrant pain at any stage in pregnancy could reflect a hepatitic process, biliary disease, a change in a hepatic mass lesion or vascular disease (Table 24.11). Drug and alcohol consumption must be considered, and history of potential exposure to infectious agents sought.

Examination Scratch marks with or without jaundice are the physical findings in cholestasis of pregnancy. Hypertension and proteinuria (on urinalysis) and hyperreflexia suggest preeclampsia. Jaundice, right upper quadrant tenderness and hepatomegaly are non-specific, but warrant intensive investigation. Signs of hepatic decompensation with fulminant hepatic failure, progressive jaundice, encephalopathy, haemorrhage or sepsis may mark preterminal disease. Conditions not specifically

associated with pregnancy present with the same clinical features as are seen in the non-pregnant patient.

Investigation Elevations in serum ALP levels may be predominant in cholestasis and biliary disease. Serum transaminase levels can also rise in these conditions. Evaluation of serum bile acid levels is helpful in the assessment of cholestasis of pregnancy. Marked elevations (over 1000 U/L) of transaminase levels are likely to indicate viral hepatitis. Levels greater than 500 U/L may accompany preeclampsia, whereas in acute fatty liver, transaminase levels generally are between 300 U/L and 500 U/L. Assessment of the full blood count, blood film and coagulation profile is vital in liver disease in late pregnancy. Abnormalities in these mark severe life-threatening disease (e.g. acute fatty liver of pregnancy or HELLP syndrome), requiring prompt intervention. When acute fatty liver or severe preeclampsia is considered likely, the need for urgent intervention (delivery) is determined on the basis of the clinical assessment and basic blood test results. In less urgent circumstances, organ imaging with ultrasound may be used to exclude gallstones or hepatic mass lesions or, with Doppler studies, vascular disease (e.g. Budd-Chiari syndrome). Viral and autoimmune serology where the clinical setting is suggestive should also be considered.

24 Abnormal liver function test results

Specific Hepatic Diseases Viral hepatitis Hepatitis A The hepatitis A virus is an RNA picornavirus transmitted by the faecal–oral route. It is not cytopathic to the hepatocyte; liver injury occurs as a consequence of T-lymphocyte activity. The incubation period is 15–45 days (mean: 30 days). In the pre-icteric phase there is viraemia, and the virus is also present in saliva and urine. Faecal viral shedding occurs late in the incubation period and extends for approximately 2 weeks. Viral shedding ceases about the time the patient becomes icteric. Vertical transmission is not a feature. Hepatitis A is a self-limiting acute illness. The diagnosis is established by finding IgM antibodies to the hepatitis A virus in the presence of an acute hepatitic illness. This virus does not cause chronic liver disease. There is a prodromal illness in 85% of icteric cases. Overall mortality is 0.1%, but this increases with age to approximately 1% in those over 40 years. Serum transaminase levels often reach several thousand units per litre and may remain elevated, at a much lesser extent, for months after the acute illness settles. Especially in adults, 10–20% of cases develop a relapsing course over several months. Occasionally protracted cholestasis may develop; these can benefit from cholestyramine or corticosteroid therapy. The proportion of symptomatic cases increases with age. In toddlers, approximately 10% of cases are symptomatic. On the other hand, between 50% and 70% of adults develop the symptomatic illness. The incidence of severe hepatitis and fulminant hepatic failure increases with increasing age. However, more than 60% of cases with hepatitis A fulminant hepatic failure survive without liver transplantation. In Australia there is a reduction in childhood exposure to hepatitis A, and so a reduction in immunity in the young adult population. There is little immunity in adults younger than 30 years. Overseas travel to areas of high prevalence carries a risk of acquiring hepatitis A (even if travel is restricted to five-star hotels). Vaccination is effective and should be considered for those at risk. Those at risk include travellers, plumbers and sewer workers, paediatric nurses and child-care staff, and people exposed during local epidemics. Vaccination could also be offered to food handlers, who if infected would represent a risk to others. People with compensated

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chronic liver disease or about to undergo immunosuppressive therapy should consider vaccination, as acute hepatitis A infection could precipitate a life-threatening decompensation. Passive immunity using pooled immunoglobulin is of limited temporary value. Hepatitis B Hepatitis B virus (HBV) is a hardy, highly infectious DNA virus. There is an incubation period of 30– 180 days (mean: 60–90 days) (Fig 24.3). Acute hepatitis occurs in approximately 25% of those who acquire the virus, with approximately 1% developing fulminant hepatic failure. The majority of cases are asymptomatic and recover completely, unaware of the infection. In hepatitis B infection, liver injury is mediated by T-lymphocytes; the virus itself does not seem to cause hepatocyte death. The treatment of acute hepatitis B is supportive. Five to 10% of adults who acquire hepatitis B progress to chronic infection (Figs 24.4 and 24.5). In these, the prognosis is dependent on the degree of liver injury and the duration of infection. Chronic infection is characterised by the persistence of hepatitis B surface antigen, and IgG antibodies to core protein with or without e-antigen. Chronic hepatitis B infection can progress through four phases: immune tolerance, immune clearance, immune control and immune escape. The management of patients depends on which phase they are in (Table 24.9). During active phases of infection, liver biopsy can be of great value in assessing the degree of inflammation and determining whether cirrhosis has developed. After a period of chronic infection, hepatitis B virus DNA may integrate into the hepatocyte genome, preventing its complete removal and predisposing to hepatocellular carcinoma. Worldwide, this virus is the most significant cause of hepatocellular carcinoma. Supercoiled hepatitis B DNA within hepatocytes is also resistant to removal by current therapies. Eventually, chronic hepatitis B results in cirrhosis and/or hepatocellular carcinoma. Wellcompensated, chronic hepatitis B liver disease has a 5-year survival of 84%. Five-year survival in decompensated chronic hepatitis B is only 14%. It is possible for a patient with chronic hepatitis B to spontaneously clear the virus as he or she mounts an immune response to the virus. This is usually associated with an episode of clinical hepatitis and is associated with loss of viral antigens and the development of antibodies. The tests used in

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Clinical gastroenterology: a practical problem-based approach

Acute hepatitis B with clearance of virus

Titre

Resolution

Acute hepatitis

Anti-HBclgM

HBsAg

Anti-HBs

HBeAg

Anti-HBe

6 months

Infection

Anti-HBclgG

12 months

10 years

Chronic hepatitis B and failure to clear virus Acute hepatitis Titre

Chronic hepatitis

Anti-HBclgm HBsAg

Infection

Cirrhosis

Hepatocellular carcinoma

Anti-HBclgG HBeAg

6 months 12 months

Anti-HBe

10 years 20 years integration

Figure 24.3  Hepatitis B serology in acute infection with viral clearance and chronic infection without viral clearance. From the Australian Gastroenterology Institute.

the assessment of hepatitis B infection are outlined in Table 24.3. The hepatitis B virus is physically resilient and extremely infectious. It is present in most body fluids of those infected and can readily be transmitted to close contacts. People living in the same house as the patient are at risk and should be vaccinated. Sharing needles amongst intravenous drug users, sexual exposure and inadequately sterilised skin-piecing equipment (e.g. that used for tattooing) carry a very high risk of transmitting the virus. Vertical transmission readily occurs. This is usually at the time of birth, and immunisation provides good protection to the infant. The presence of hepatitis B infection also needs to be considered in patients born in areas where there is a high

prevalence, such as southern and eastern Europe and Southeast Asia. Passive immunity against hepatitis B can be achieved with an injection of hyperimmune immunoglobulin directed against hepatitis B (HBIG) within 72 hours of exposure. Active immunity through a course of three injections of surface antigen is safe and effective. However, a small proportion of individuals are not capable of mounting a response to this vaccine. This is especially a problem with increasing age, in immunocompromised people, in those on dialysis and in obese individuals. The aim of treatment for chronic hepatitis B infection is to suppress viral replication (reduced hepatitis B DNA levels), thereby reducing liver injury as reflected by normalization of

24 Abnormal liver function test results

Figure 24.4  Viral hepatitis, acute, classic type. The inflammatory infiltrate has a perivenular accentuation, which is typically seen in the early phase of acute viral hepatitis. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

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Figure 24.5  Viral hepatitis, chronic, type B. The haematoxylin-eosin (H & E) stain shows discrete intracytoplasmic inclusions having a finely granular ‘ground-glass’ appearance, with peripheral cytoplasmic clearing. This staining characteristic represents proliferation of the endoplasmic reticulum synthesising the hepatitis B antigen (HBsAg) particles. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Table 24.9 Phases of chronic hepatitis B infection Phase

ALT

Hepatitis B DNA (IU)

e-antigen/antibody

Comment

Immune tolerance

Normal

> 1,000,000

Antigen

Observation < 35 years No inflammation/fibrosis

Immune clearance

Raised/variable

> 20,000

Antigen

Consider treatment Inflammation ± fibrosis

Immune control

Normal

< 20,000

Antibody

Observation No inflammation/variable fibrosis

Immune escape

Raised/variable

> 10,000

Antibody

Consider treatment Inflammation + fibrosis Precore or core promoter variant

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Clinical gastroenterology: a practical problem-based approach

ALT. In hepatitis B e-antigen positive patients seroconversion is associated with improved prognosis. Pegylated interferon is administered subcutaneously for 12 months with the advantages of the absence of viral resistance, durability of seroconversion and a defined duration. Side effects of interferon, on the other hand, include a flulike syndrome early, and later headaches, weight loss, alopecia and bone marrow suppression; depression may also occur. With interferon, higher ALT levels, recent acquisition of the virus and low HBV DNA titres are associated with good long-term responses. Thirty to 50% of selected cases lose circulating HBV DNA and HBeAg and become anti-HBeAg positive. Clearance of surface antigen is possible in a small proportion of patients. Improvement may continue for years after the completion of treatment. Five to 10% of patients relapse over 5 years after treatment. In HBe antigen-positive patients HBV genotype may help predict response to interferon therapy, the best candidates being those with genotype A, high ALT levels and low HBV DNA titres. Interferon therapy is generally not useful if there is combined infection with hepatitis C or D. Response in the presence of HIV infection is poor. Oral nucleosides and nucleotides effectively suppress viral replication and are well tolerated but require long-term therapy to prevent relapse. Entecavir and tenofovir are effective while adefovir can be used as second-line therapy. Lamivudine is effective but its use is often associated with the development of resistance (YMDD variant) and relapse. Other oral agents include telbivudine and emtricitabine. Combination therapy using these agents may prove more effective but requires further investigation. The optimal duration of oral therapy is not clear but in e-antigen positive patients who seroconvert with undetectable hepatitis B DNA, withdrawal may be considered after a further 6–12 months of treatment. In e-antigen negative patients therapy may need to be lifelong. Liver transplantation is a therapeutic option in those with end-stage chronic hepatitis B. If the patient is HBV DNA negative, a good response to transplantation is possible. On the other hand, liver transplantation into a HBV DNA-positive patient is often followed by severe recurrent disease, often rapidly progressing to graft destruction (fibrosing cholestatic hepatitis). Antiviral therapy and HBV immunoglobulins may improve outcomes. A number of mutant varieties of hepatitis B have been identified. A ‘precore’ mutant, which does not produce e-antigen, may be associated with

more severe acute hepatitis and fulminant hepatic failure. The serum of patients infected with this variant is negative for e-antigen but positive for surface antigen and HBV DNA. Another form of hepatitis B has evolved an alteration in the surface antigen that allows it to escape the immunity afforded by antibodies to this antigen (and thus vaccination). Patients with chronic hepatitis B who are to undergo chemotherapy or other immunosuppressive therapy should be treated to prevent a severe reactivation hepatitis. Hepatitis D virus Hepatitis D virus infection can occur only in the presence of hepatitis B. This RNA virus uses the hepatitis B surface antigen as part of its own structure, making it totally dependent on hepatitis B. Hepatitis D occurs as either a coinfection, when acquired together with hepatitis B, or as a superinfection, when acquired by a chronic carrier of hepatitis B. Transmission of the virus is similar to that of hepatitis B. The combined infection produces more severe liver injury and a worse prognosis. Therapy with interferon or liver transplantation is of limited value. Hepatitis C virus Hepatitis C virus (HCV) is an RNA virus, which is thought to be directly cytopathic to the hepatocyte (Figs 24.6 and 24.7). Prior to routine screening for this virus, it was responsible for at least 90% of cases of post-transfusion non-A non-B hepatitis. The carrier rate in the general population is unclear, but is probably between 0.2% and 1%. The incubation period for acute hepatitis C is 15– 160 days (mean: 50 days). In the majority of cases, the acquisition of hepatitis C virus is not associated with an acute symptomatic illness. Chronic infection is common, however, occurring in up to 80% of infected cases. Of those who acquire hepatitis C, approximately 10–15% develop severe liver disease, which can take decades to develop. Hepatic failure and hepatocellular carcinoma may then follow. Significant hepatitis or liver injury (on liver biopsy) can be associated with normal serum ALT levels. Conversely, some people with mild histological liver damage have serum ALT levels greater than two or three times the upper limit of normal. From this it is apparent that ALT measurements are of limited value in the assessment of the severity of hepatitis C virus infection. Hepatitis C virus appears to infect and replicate in both hepatocytes and mononuclear cells. Its

24 Abnormal liver function test results

Figure 24.6  Viral hepatitis, chronic, type C. Mild microvesicular fatty change is usually present. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Figure 24.7  Cirrhosis in a patient with chronic hepatitis C. Note the regenerative nodules of hepatocytes separated by thick bands.

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antigenic structure is variable and appears able to escape immune surveillance. Furthermore, there are multiple genotypes (varieties) of the virus. Prior or current infection with hepatitis C virus does not protect an individual from acquiring further hepatitis C infections. One patient may harbour a number of varieties of hepatitis C virus. The genotype will influence the severity of the infection, the response to therapy and the infection’s prognosis. Transmission of hepatitis C in Western society is primarily by sharing needles. In the past, blood transfusion was a major mode. Other modes of parenteral transmission, such as needlestick injuries, are possible. Under normal circumstances, the risk of sexual transmission is very low: approximately 0.1% per year in a monogamous sexual partnership. Sexual transmission is more likely when another sexually transmitted disease or HIV/AIDS is present. Vertical transmission is also unusual, occurring in approximately 5% of cases, particularly when the maternal viral load is high. Alcoholics are also at higher risk of acquiring hepatitis C. Risk factors for the progression of hepatitis C infection to more significant liver injury include excessive alcohol consumption, the presence of fatty liver, acquisition of the virus after the age of 40 years, male gender and coinfection with human immunodeficiency virus or hepatitis B. Pegylated alpha-interferon (given by onceweekly injection) in combination with oral ribaviron can be very effective in patients with chronic hepatitis C. Response to treatment is more likely with HCV genotypes 2 and 3, histologically less hepatic fibrosis, shorter duration of infection and lower viral titres. Moreover, the viral genotype may influence the severity of the disease and the viral titres. Patients with cirrhosis are less likely to respond to interferon and ribaviron therapy, but significant benefit can still be achieved. The addition of the investigational oral protease inhibitor telaprevir to standard therapy may improve treatment success in non- responders. In general, those without cirrhosis and genotypes 2 and 3 can expect a sustained virological response (the loss of HCV RNA from the blood and cure in most) in 80% or more who complete 24 weeks of treatment. Patients with genotype 1 will require treatment for 48 weeks and can reach response rates of over 50%. HCV therapy failure is associated with excessive alcohol consumption, insulin resistance, obesity, treatment non-compliance, adverse events requiring dose reduction and insufficient duration

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Clinical gastroenterology: a practical problem-based approach

of therapy. An individual’s genetic make-up may also influence his or her responsiveness to therapy. Liver transplantation is a therapeutic option in end-stage hepatitis C. Following transplantation, viraemia is common. Among transplanted patients, 75–90% will develop chronic hepatitis C within 2–3 years (usually within 1 year). Hepatitis C is responsibly for approximately 25% of hepatocellular carcinoma across the world. The incidence is increasing in Western countries and surveillance should be considered in cirrhotic patients. It is of note, however, that antiviral therapy reduces the risk of developing this malignancy. Six-monthly surveillance abdominal ultrasound examinations should be performed to screen cirrhotic patients for the development of hepatocellular carcinoma. Vaccinate hepatitis C patients to protect against hepatitis A and B. Hepatitic C can cause extrahepatic disease, including porphyria cutanea tarda (skin blisters—think C!), mixed cryoglobulinemia (palpable purpura) and lichen planus. Hepatitis E virus Hepatitis E virus (HEV) is an enterically transmitted RNA virus. This virus is endemic to India, Southeast Asia and Africa. It may also be endemic in the tropical Northern Territory of Australia. Hepatitis E infections occur sporadically or as epidemics. As with hepatitis A infection, the illness is self-limiting and recovery full; no chronic liver disease follows. There is a risk of fulminant hepatic failure especially if acquired during pregnancy, where the mortality approaches 20%. In Australia, most recorded cases have been acquired in overseas endemic areas. The travel history should therefore be noted. Personto-person transmission does not seem to occur. The diagnosis can be confirmed by the detection of IgM antibodies against the virus. The antigenic structure of this virus appears stable, and thus an effective vaccine is theoretically feasible. Hepatitis G Hepatitis G is transmitted by blood transfusion and causes persistent infection, but does not appear to cause disease.

Non-alcoholic fatty liver disease and steatohepatitis Non-alcoholic fatty liver disease is the most common cause for abnormal liver function tests in Australia, the USA and the UK. The prevalence of approximately 20% has been increasing dramatically over recent years as the average body

weights of these communities increase. It is often associated with mild (usually up to twice the upper limit of normal) rises in serum transaminase levels, often with elevated GGT levels. Typical patients are overweight with the features of the metabolic syndrome. Thus, strong associations exist with obesity, type 2 diabetes, hypertension and hyperlipidaemia. There is commonly a family history of type 2 diabetes and evidence of insulin resistance. When associated with hepatic inflammation (non-alcoholic steatohepatitis), non-alcoholic fatty liver disease can unusually progress to produce significant hepatic fibrosis and eventual cirrhosis. Insulin resistance is likely to be the main pathogenic mechanism by which fatty liver occurs in these patients. A subsequent insult or ‘second hit’ (e.g. endotoxaemia) is thought to precipitate the more aggressive inflammatory steatohepatitis. Usually there is fatty infiltration of the liver on ultrasonography, with no other apparent cause for abnormal liver function test results. CT scan of the abdomen can also identify hepatic fatty infiltration, often with associated marked visceral fat deposition. In the typical case, liver biopsy is not necessary. However, if a biopsy is performed, this condition may have histological findings indistinguishable from alcoholic liver injury. Careful history taking and viral serology are required to clarify the diagnosis in uncertain cases. A carbohydrate-deficient transferrin test will be negative (Table 24.10), but no other biochemical features are diagnostically helpful. High BMI, age greater than 50 years, ALT greater than twice the upper limit of normal and triglycerides greater than 1.7 μmol/L have been associated with a greater risk of hepatic fibrosis in non-alcoholic fatty liver disease. Management is directed towards weight loss and exercise, which can improve insulin sensitivity. When successful, this can result in biochemical and histological improvement. Sudden weight loss may be accompanied by further rises in serum transaminase levels. The rate of weight reduction should be less than 1 kg/week. When the patient’s weight fluctuates, the transaminase levels may vary in parallel. Clearly, optimal diabetic control is essential. When hyperlipidaemia is present, it should be managed as usual with diet and medications (e.g. statins) as normally indicated. The use of metformin, ursodeoxycholic acid and glitazones requires further investigation. Bariatric surgery has been found to improve non-alcoholic fatty liver disease as well as other complications of morbid obesity.

24 Abnormal liver function test results

333

Table 24.10 Tests useful in alcoholic liver disease Test

Comment

Erythrocyte mean cell volume

Round macrocytes, low specificity

Gamma-glutamyl transpeptidase

Enzyme-induced by ethanol, level related to long-term prognosis, sensitive but low specificity

Urate, high density lipoprotein and triclycerides

Elevated, low specificity

Carbohydrate-deficient transferrin

Sensitive and specific, reflects regular excessive ethanol consumption within previous 2 weeks

Other causes of hepatic steatosis include excessive alcohol consumption, recent profound weight loss, hyperalimentation, intestinal bypass surgery and thyroid dysfunction. In these cases the condition is asymptomatic and may be discovered when an abnormal liver function profile or hepatomegaly is detected incidentally. Certain drug toxicity reactions, fatty liver of pregnancy and Reye’s syndrome are also associated with hepatic steatosis, but cause no clinically apparent illnesses.

Alcoholic liver disease Although alcohol is a direct hepatotoxin, a patient’s nutritional state and genetic make-up will influence the degree of hepatic injury caused by excessive intake of this agent. Alcohol-induced liver injury is generally classified into fatty liver, alcoholic hepatitis and cirrhosis (Fig 24.8). The mainstay of therapy is abstinence from alcohol. Fatty liver is in general considered reversible if excessive alcohol consumption is ceased. Recovery and good hepatic function is expected. However if drinking continues, the degree of fatty change is a prognostic indicator of significant longterm liver injury. Clinically there is hepatomegaly. There are no peripheral signs of chronic liver disease. Serum transaminases and especially GGT levels are moderately raised. When serum AST levels are two or more times greater than the ALT level, alcoholic liver disease is more likely the cause. (This does not apply in the presence of cirrhosis.) Fatty infiltration may be apparent on ultrasonography. In alcoholic hepatitis there is active inflammatory injury to the liver. This may be mild, even subclinical, or severe and life-threatening.

Figure 24.8  Alcoholic fatty liver. The majority of hepatocytes show a microvesicular fatty change in an active alcoholic. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

The severe form is typified by a mild fever, jaundice, neutrophil leucocytosis, moderate elevations of serum transaminase levels (usually < 300 U/L) and tender hepatomegaly. There may be a hepatic bruit. Liver failure with encephalopathy, ascites, gastrointestinal bleeding (often from oesophageal varices) and sepsis may occur. Treatment is in general supportive. If the patient is malnourished, aggressive nutritional support may improve the short-term outcome; high kilojoule, high protein diets are appropriate. Corticosteroids may improve short-term survival in those with severe acute alcoholic hepatitis and jaundice, a high INR or prolonged encephalopathy but no gastrointestinal bleeding. However, the available data do not support the use of corticosteroids in alcoholic hepatitis. In these patients enteral nutritional supplementation may also improve survival. Furthermore, pentoxifylline (400 mg t.d.s.) has been shown to improve survival in severe acute alcoholic hepatitis, by reducing

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Clinical gastroenterology: a practical problem-based approach

the risk of developing the hepatorenal syndrome. Antioxidants have been shown not to be of benefit. Propylthiouracil may be of some value in alcoholic hepatitis, increasing survival, but it is not widely used. Colchicine may be of benefit in cirrhosis, but data are limited and conflicting. Cirrhosis caused by alcohol consumption is similar clinically to that of other causes. Liver injury can progress to cirrhosis after overt alcoholic hepatitis or in the absence of clinically apparent hepatitis. If alcohol consumption continues, there may be superimposed alcoholic hepatitis and rapid progression to decompensated, end-stage liver disease and death. It is important to note that severe alcoholrelated liver disease can be associated with a substantial reversible component if alcohol is stopped. Hepatocyte function will improve and, with the resolution of hepatocyte swelling, portal hypertension can also ameliorate. With abstinence a remarkable degree of recovery may occur, even though it is possible for liver injury to progress once drinking has ceased. Liver transplantation is a valid therapy, particularly in decompensated post-alcoholic cirrhosis where the long-term outcomes are similar to those of transplantation for other conditions. However, the patient’s condition can improve to such a degree with abstinence that transplantation is not required. Care must be taken to exclude alcoholrelated injury to other major organs, such as the brain and heart, prior to considering transplantation. The prevalence of hepatitis C virus is greater in alcoholics than in the general population. The reason for this is not clear. However, the consumption of excessive amounts of alcohol accelerates hepatitis C-associated liver disease. Interface hepatitis seen on liver biopsy in an alcoholic is likely to be due to hepatitis C infection. In assessing a patient’s alcohol consumption, an estimate of the number of grams of ethanol consumed per day is useful. The National Health and Medical Research Council of Australia recommends that consumption by males and females should not exceed an average of 20 g per day, with two alcohol-free days per week. Ethanol consumption above these levels is associated with increasing risk of injury. The clinician should aim to identify those individuals at risk. Once they are identified, brief counselling is often effective in reducing ethanol consumption towards safer levels. When applied by the general practitioner, this approach is effective in reducing a community’s overall alcohol consumption and reducing alcohol-related social and physical

trauma and pathology. ‘Skid row’ type alcoholics will not respond to this approach. These severe cases may require more intensive management, but are much less likely to respond favourably. Systematic questionnaires in relation to alcohol dependency are useful. A number of screening questions have been devised. One of the simplest is the CAGE screening test. In this, patients are asked if they ever felt: ll they needed to cut down their drinking; ll annoyed by others criticising their drinking; ll guilty about drinking; ll the need for an ‘eye opener’ in the morning. The greater the number of positive responses, the more likely the patient is to have an alcoholdependency problem. The GGT level could be used to monitor abstinence, but it is non-specific. GGT levels should normalise over 2–5 weeks of abstinence. Up to one-third of heavy drinkers do not have a raised GGT level. An isolated binge does not usually elevate the GGT level. The carbohydrate deficient transferrin (CDT) test is of more value but is not readily available. The CDT test detects a variant of transferrin in the serum that carries fewer sialic acid moieties than the usual form. The presence of CDT reflects the consumption of excessive amounts of ethanol. Levels rise after several weeks of excessive drinking and remain elevated for approximately 2 weeks after drinking has ceased.

Haemochromatosis This is the commonest genetic disorder in the Australian Anglo-Celtic population. Untreated, this condition, producing iron overload, significantly reduces life expectancy. Moreover, haemochromatosis treated before there is end organ damage is associated with a normal life expectancy. Patients often present because of the incidental finding of abnormal liver function test results or iron studies, or come to medical attention after a relative has been diagnosed. Adequate screening and an accurate diagnosis are essential in first and second order relatives of confirmed cases. One of the commonest presenting symptoms is unexplained fatigue. Haemochromatosis may be present in 1% of patients in diabetic and rheumatological outpatient clinics, where they may go unrecognised. Cardiac failure in the presence of a cardiomyopathy is another presenting feature, albeit unusual. Clinically apparent advanced haemochromatosis presents between 50 and 70 years of age (Fig 24.9). The male to female ratio is between 4:1 and 5:1,

24 Abnormal liver function test results

Skin pigmentation (bronze)

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Congestive cardiac failure (dilated cardiomyopathy)

Hepatomegaly Hepatoma

Arthropathy

Testicular atrophy Glycosuria (diabetes mellitus)

Figure 24.9  Clinical features of advanced haemochromatosis.

depending on the study that measures it. Presenting features may include unexplained hepatomegaly, fatigue, loss of libido and hypogonadism (from pituitary iron deposition), cardiac dysfunction from cardiomyopathy, skin pigmentation (from melatonin and iron) and arthralgias with arthropathy. The arthropathy may involve the second and third metacarpophalangeal joints as well as proximal interphalangeal joints, the knees, wrists and hips. The liver is usually the first organ damaged, and patients may present with cirrhosis or hepatocellular carcinoma. However, a diagnosis of haemochromatosis is not excluded by normal liver function test results. The defect responsible for iron loading in haemochromatosis appears to lie in malregulation of metabolism and intestinal iron absorption. Haemochromatosis is an autosomal-recessive condition. The responsible gene (HFE) lies

on chromosome 6 near the HLA site. There is an approximately 70% linkage with HLA-A3. Approximately 1 in 300 (0.3%) Australians of northern European (including UK) descents are homozygous for the C282Y mutation. People who are homozygous for the C282Y mutation and those with both C282Y and H63D mutations (compound heterozygotes) are at greatest risk of significant iron overload. However, only a limited number of those with these genotypes develop disease. A second defect in iron metabolism may be required to cause pathological iron accumulation. A defect in the hepatic iron-regulatory peptide hepcidin may determine the phenotypic expression of haemochromatosis. Juvenile haemochromatosis has been associated with mutation of the HFE2 (haemojuvelin) gene on chromosome 1. Iron studies (serum iron, transferrin and ferritin) are used to determine the likelihood of

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haemochromatosis. In this situation, the transferrin saturation and the serum ferritin concentration are of most value, especially the former. A normal transferring saturation makes haemochromatosis unlikely. In males, a transferrin saturation over 62% (in females, over 50%) identifies more than 90% of homozygotes. The serum ferritin concentration, a measure of tissue iron stores, predicts approximately 70% of homozygotes. It must be noted that ferritin is an acute phase reactant and can be non-specifically elevated in many conditions (e.g. alcoholic hepatitis, chronic hepatitis, hepatoma, hyperthyroidism, chronic inflammation and histiocytosis). Moreover, it will be elevated as a direct consequence of hepatocellular injury. As with the transaminases, cytoplasmic ferritin will be lost to the serum when hepatocytes are damaged. Similarly other components of the iron studies are influenced by many conditions. Gene testing (homozygous C282Y) confirms the diagnosis. The diagnosis of haemochromatosis when in doubt is established by the measurement of the tissue iron concentration on liver biopsy. The hepatic iron index (HII) is calculated by dividing the liver iron concentration (μmol/g dry weight) by the patient’s age in years. An HII >2 is indicative of haemochromatosis. This is complemented by hepatic histology with staining for iron (Fig 24.10). In haemochromatosis, excess iron occurs predominantly within hepatocytes (as opposed to Kuppfer cells in cases of secondary iron overload). A key role of liver biopsy is also to identify the presence of cirrhosis with its implications for long-term prognosis. Those individuals who are heterozygote for the C282Y mutation may also have abnormal iron test results, especially if they consume excessive amounts of alcohol. In these individuals, iron overload can become significant in the presence of other disorders such as hereditary spherocytosis, beta-thalassaemia minor, idiopathic sideroblastic anaemia and porphyria cutanea tarda. Screening of first- and second-degree relatives of patients with haemochromatosis using HFE analysis, fasting serum transferrin saturation and ferritin levels is necessary to identify cases prior to the onset of clinical disease. The treatment of haemochromatosis is phlebotomy. Venesections may be commenced at weekly intervals and adjusted according to the estimated iron load and the patient’s tolerance. Treatment is monitored with serial haemoglobin levels and iron studies. The aim is to achieve and maintain normal iron studies. The haemoglobin

Figure 24.10  Haemochromatosis. Abundant haemosiderin pigment is present diffusely throughout the liver. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

level will usually remain stable until the patient is ‘de-ironed’, then it can fall rapidly. If anaemia becomes problematic before the iron status has been normalised, lower volume or less frequent venesections can be used. Maintenance venesections are started, and continued indefinitely. If the patient is ‘de-ironed’ within 18 months and there is no end organ damage, life expectancy is normal. Haemochromatosis may be complicated by the development of hepatocellular carcinoma, with a relative risk of more than 200. This is more likely in males, in those over the age of 50 years, in the presence of cirrhosis, chronic alcoholism, smoking and past transfusion. It is not related to the amount of iron removed during treatment and only unusually occurs in a non-cirrhotic liver.

Wilson’s disease Wilson’s disease occurs in approximately 1 in 40,000 people and is the consequence of mutation of the ATP7B gene on chromosome

24 Abnormal liver function test results 13, leading to defective copper trafficking and thereby the progressive accumulation of copper with ongoing liver injury through childhood into adult life. More than 60 polymorphisms have been identified, making genetic testing unhelpful in clinical practice. ATP7B is a trans-Golgi membrane hepatocyte copper-transporting ATPase involved in biliary copper excretion. Catastrophic haemolysis and an acute hepatic illness are unusual complications. In those who do not succumb to liver disease in early life, neurological abnormalities can evolve in early adulthood (including psychiatric diseases, dysarthria, ataxia, incoordination and tremor). Patients with Wilson’s disease may also be at elevated risk of intraabdominal malignancy. Low serum caeruloplasmin levels suggest the diagnosis, although this may remain normal in some cases. The presence of Kayser-Fleischer rings (brown deposits around the periphery of the iris, best seen at slit-lamp examination) suggests this diagnosis. However, Kayser-Fleischer rings are also rarely found in chronic cholestatic liver diseases. Liver biopsy will often demonstrate excessive copper staining but this occurs in other diseases; chemical analysis of liver tissue copper concentration is usually a reliable indicator of the diagnosis. Urinary copper excretion and copper dynamic studies may also be needed to establish the diagnosis. Effective therapy is available for Wilson’s disease. D-penicillamine (250 to 500 mg daily increasing incrementally to 1000–1500 mg in two to four divided doses) chelates copper and allows its removal from the body. An alternative chelating agent for patients unable to take penicillamine is trimethylene tetramine dihydrochloride. Therapy is supplemented with oral zinc, which leads to the inhibition of gastrointestinal copper absorption. Effective chelation therapy early in the disease will stabilise, improve or prevent end organ injury. In early, presymptomatic Wilson’s disease, zinc (50 mg b.d.) therapy can prevent progression to clinical disease. Liver transplantation should be considered when there is liver failure or when chelation therapy fails in the presence of advanced liver disease. Medical therapy is the preferred therapy in those with neurological Wilson’s disease, as it is unclear whether transplantation provides any extra benefit in that circumstance.

Alpha-1 antitrypsin deficiency This autosomal-recessive genetic disorder may present in childhood or adult life with features suggestive of chronic hepatitis or with established

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cirrhosis. This often occurs in the absence of pulmonary disease. The diagnosis is obtained by measuring the level of alpha-1 antitrypsin in the blood and determining the phenotype. More than 75 variants of the gene have been identified. PiZ and PiS are the most common defective alleles, with the former most commonly associated with emphysema. Of homozygous deficient (PiZZ) children, approximately 10% will develop significant progressive liver disease. In adults, asymptomatic cirrhosis is a common presentation. Serum levels of alpha-1 antitrypsin in homozygotes are often 15% of normal. People who are heterozygous for PiZ may also be predisposed to developing significant liver disease. Heterozygotes may have serum levels of alpha-1 antitrypsin between 40% and 60% of normal, and can develop abnormal liver function test profiles without significant liver injury. Liver biopsy will show the extent of liver injury and the presence of cirrhosis. Histology is characterised by the presence of periodic acid-Schiff (PAS) positive globules within hepatocytes. These globules represent precipitated accumulations of the abnormal alpha-l antitrypsin protein, which is synthetised but not secreted. Treatment is with liver transplantation.

Idiopathic, autoimmune chronic hepatitis Idiopathic, autoimmune chronic hepatitis (IACH) is an uncommon condition predominantly affecting women. It is characterised by the presence of progressive liver disease and a polyclonal hyperglobulinaemia associated with a variety of autoantibodies. Responsiveness to corticosteroid therapy is also typical. The onset of IACH is usually insidious with progressive fatigue, anorexia and jaundice. Seventy-five per cent of patients are female, mostly between 10 and 40 years of age. In the more aggressive forms, there is progression to cirrhosis and eventually liver failure. Untreated, more than 50% of patients die in 3–5 years. The aetiology of this condition is unclear, but once established there is progressive cytotoxic T-cell-mediated injury of hepatocytes. In certain circumstances, it appears that viral hepatitis could be the initiating event of IACH. Autoantibodies, commonly anti-actin (antismooth muscle) and antinuclear antibodies, are present. There is a prominent polyclonal hypergammaglobulinaemia. In an often aggressive variant that usually affects young females, the smooth muscle antibody and

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Clinical gastroenterology: a practical problem-based approach a steroid-sparing agent. In some the corticosteroid can be withdrawn and remission maintained with azathioprine. A positive response to treatment supports the diagnosis. Mortality is reduced, hepatic inflammation and fibrosis are suppressed and symptoms improve on steroids. Sufficient therapy is required to keep the serum transaminase levels below twice the upper limit of normal, preferably normal, and normalised IgG concentration. Slower progression of the disease may continue, however. Although some patients can cease therapy after several years, treatment will need to be lifelong in the majority of cases. If the disease progresses, liver transplantation will eventually need to be considered. The benign, generally non-progressive, milder form of autoimmune hepatitis may not require therapy. Especially when long-term corticosteroid therapy is required, weight control and protection of bone density (calcium and vitamin D supplementation with or without a bisphosphonate) are particularly important. Chronic infection with strongyloides (stool examination) and tuberculosis (chest x-ray) and currency of vaccination could help prevent significant infectious complications.

Primary biliary cirrhosis Figure 24.11  Autoimmune hepatitis. The portal infiltrate consists of lymphocytes and plasma cells. The interlobar duct is partially infiltrated by lymphocytes. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

antinuclear antibody can be absent while an antiliver/kidney microtonal antibody (anti-LKM1) is found. On liver biopsy in aggressive disease, the chronic inflammatory infiltrate, including plasma cells, typically expands the portal areas and extends into the liver lobule, causing erosion of the limiting plate (interface necrosis, Fig 24.11). Varying degrees of fibrosis may be present. Fibrotic linkages between portal tracts or cirrhosis are markers of aggressive disease. Corticosteroid treatment is appropriate when liver biopsy shows more aggressive chronic hepatitis, gammaglobulin levels are greater than twice normal, and ALT levels are greater than five times normal. Corticosteroids (tapering from 30 mg/day to 60 mg/day) with or without azathioprine improve the clinical syndrome and survival. Azathioprine (1–2 mg/kg) may be used to supplement corticosteroid therapy or to act as

In primary biliary cirrhosis there is an immunemediated destruction of the small intrahepatic bile ducts. This illness follows a prolonged course with eventual development of cirrhosis and liver failure. Primary biliary cirrhosis typically presents in a middle-aged female with pruritus, a raised alkaline phosphatase level and a positive antimitochondrial antibody (AMA) result. ALP and, to a lesser extent, serum transaminase levels are usually elevated in patients with primary biliary cirrhosis. AMA is present in the serum in 95% of cases. Its presence is highly suggestive of the diagnosis. IgM levels are often elevated. Differentiation between AMA-negative primary biliary cirrhosis and IACH may be difficult. Smooth muscle antibody and antinuclear antibody may be present in the former, and low titres of AMA can occur in IACH. A true overlap syndrome can occur, and will present features of both conditions. Furthermore, on liver biopsy, primary biliary cirrhosis can share features with IACH, although differentiation is usually possible (Fig 24.12). If uncertainty remains, a therapeutic trial of corticosteroids is likely to induce an improvement in IACH but not in primary biliary cirrhosis. Adverse prognostic signs in primary biliary cirrhosis include a high serum bilirubin

24 Abnormal liver function test results

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for transplantation. In the overlap syndrome a combination of ursodeoxycholic acid and corticosteroids may be required. End-stage primary biliary cirrhosis is a common indication for liver transplantation in adults, with a success rate of 80% or more. Transplantation should be considered when the serum bilirubin concentration rises progressively above 100 μmol/L, or when there is uncontrolled gastrointestinal bleeding, ascites or intractable pruritus.

Primary sclerosing cholangitis

Figure 24.12  Primary biliary cirrhosis. The interlobar bile duct is slightly hyperplastic and exhibits lymphocytes within the duct wall. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

concentration (over 100 μmol/L), a low serum albumin concentration, ascites, gastrointestinal bleeding, advanced age, cirrhosis or central cholestasis on liver biopsy and low serum IgM levels. Pruritus is a common clinical feature of primary biliary cirrhosis. This will often respond to ursodeoxycholic acid. Alternative therapy includes cholestyramine. Fat-soluble vitamin deficiency (A, D, E and K), which is secondary to cholestasis, should be sought and treated accordingly. Osteopenia due to osteoporosis may result in disabling fractures. There may be evidence of autoimmune disorders involving other organs such as the eyes, joints and thyroid. Hypercholesterolaemia with xanthelasmas and xanthomas are further features of primary biliary cirrhosis. Ursodeoxycholic acid (13–15 mg/kg/day) is effective therapy for primary biliary cirrhosis, improving survival and delaying the need

Primary sclerosing cholangitis (PGS) is characterised by the inflammatory destruction of bile ducts larger than those involved in primary biliary cirrhosis. This condition is considered to be due to an autoimmune process. Approximately 70% of cases of PSC occur in patients with inflammatory bowel disease. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) are common, especially in those with associated ulcerative colitis (up to 90% of cases). The diagnosis of primary sclerosing cholangitis relies on cholangiography identifying focal biliary strictures with associated beadlike dilatations. Liver biopsy is of limited diagnostic value (Fig 24.13). Because of the presence of portal inflammation, there may be difficulty in differentiating primary sclerosing cholangitis from other chronic inflammatory conditions on liver biopsy. The progression of primary sclerosing cholangitis is difficult to predict. Advanced age, severe changes on liver histology, splenomegaly and high serum bilirubin concentrations are adverse prognostic features. When localised strictures occur, endoscopic therapy can be considered. Placing stents across strictures or balloon dilation may be of value. The risk of bacterial contamination of the biliary tract needs to be considered, especially if foreign bodies (stents) are left in situ. Recurrent cholangitis is a problem, with and without intervention. Liver transplantation is the only effective treatment for primary sclerosing cholangitis. A successful outcome is expected in more than 70% of well-selected cases. The use of high doses of ursodeoxycholic acid has been reported in PSC. This treatment is of no proven value and may shorten the patient’s survival time. Primary cholangiocarcinoma complicates 10– 20% of cases of primary sclerosing cholangitis. Sudden rapid progression of pruritus, jaundice and weight loss suggest malignancy. However,

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Figure 24.13  Primary sclerosing cholangitis. Periductal fibrosis is striking with fibro-obliterative ‘onion-skinning’ a common feature. Eventually duct depletion occurs. From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

this diagnosis can be difficult and may not be made until postmortem. Brush cytology on ERCP provides a positive result in only 20% of patients with cholangiocarcinoma. If transplant takes place, the outcome is poor when primary cholangiocarcinoma is present.

Drugs and the liver A careful history of medication use is vital in the assessment of the patient with abnormal liver function test results. Toxic or idiosyncratic adverse reactions may occur with many therapeutic agents (Table 24.11). Immune mechanisms are responsible for many of these reactions. The contraceptive pill may be associated with a number of liver diseases including hepatic adenoma (rare—usually single), hepatocellular carcinoma (very rare), peliosis hepatis (large blood-filled cavities), Budd-Chiari syndrome (see below), cholestasis and cholesterol gallstones (because of more lithogenic bile).

Paracetamol overdose, deliberate or accidental, is a relatively common cause of severe acute liver disease. In this case toxic metabolites of the drug are generated by cytochrome p450s and damage hepatocytes. The induction of these enzymes, as occurs with chronic alcohol consumption, may enhance paracetamol toxicity. Polymorphisms of certain p450s may also influence an individual’s risk of drug-induced liver injury by affecting the rate of production of toxic metabolites (e.g. nefazodone). The generation of toxic metabolites may also be responsible for liver damage associated with non-steroidal antiinflammatory drugs. Liver injury may follow idiosyncratic druginduced metabolic modification. For example, the statins may induce a mild asymptomatic rise in liver enzymes, but occasionally cause more severe, acute cholestatic hepatitis. The effect seems to be mediated by changes in mevalonic acid metabolism. Jaundice and other symptoms of drug-induced liver injury generally persist for a limited period after the withdrawal of the offending agent but long-term abnormalities in liver function tests and of hepatic histology may not be as unusual as previously believed. However, late liver failure is not expected. In particular, hepatic injury associated with methyldopa, amiodarone, nitrofurantoin, diclofenac and clavulanic acid/ amoxicillin may be followed by chronic, ongoing liver disease.

Vascular and perfusion disorders of the liver Vasculitis and thrombotic disorders can affect the vessels of the liver. These conditions often produce portal hypertension with varying degrees of hepatocellular dysfunction. Obstruction of the portal vein may occur in association with sepsis or thrombotic disorders and presents usually with bleeding from varices, or splenomegaly is detected on examination. This results in portal hypertension, often with preservation of hepatocyte function. Portal vein thrombosis can also complicate cirrhosis. Veno-occlusive disease of the liver is associated with obstruction of the terminal hepatic venules. Precipitating events include bone marrow transplantation and exposure to chemotherapeutic agents and certain plant alkaloids. Clinically, there is right upper quadrant tenderness, hepatomegaly, ascites and jaundice. Progression to liver failure may occur.

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Table 24.11 Drugs and the liver Liver disease

Clinicopathological features

Drug examples

Due to microsomal enzyme induction

No clinical features; raised GGT and ALP; ground glass cells

Phenytoin, warfarin

Hyperbilirubinaemia

Jaundice rare

Rifampicin

Focal necrosis

Lobular hepatitis, resembles viral hepatitis

Isoniazid, cloxacillin, halothane (mild)

Bridging necrosis

Traces of necrosis connect adjacent portal and/or central veins

Isoniazid, alpha-methyldopa

Zonal necrosis

Well-demarcated zone of necrotic hepatocytes; less conspicuous inflammation

Paracetamol, halothane (severe)

Massive necrosis

Entire hepatic acini necrotic; fulminant hepatic failure

Halothane (fatal), valproic acid NSAIDs

Acute fatty change

Usually microvesicular; clinical features of hepatitis, liver failure

Tetracycline, valproic acid, corticosteroids, NSAIDs, L-asparaginase

Steatohepatitis

Resembles alcoholic hepatitis histologically; clinical features of chronic liver disease

Perhexiline maleate, amiodarone

Varying lobular hepatitis, cholestasis or pericholangitis; usually mixed LFT results, may be hepatocellular

Allopurinol, chlorpromazine, chlorothiazide, isoniazid, phenytoin, sulfonamides

1. Altered LFTs without liver disease

2. Hepatocellular necrosis: hepatocellular necrosis with varying inflammatory change, ALT > 5 × normal

3. Fatty liver

4. Granulomatous reactions Non-caseating granulomas

5. Acute cholestasis Cholestasis without hepatitis

Cholestasis, no inflammation; pruritus with OCS, anabolic androgens minimal systemic symptoms ALP > 2 × normal

Cholestasis with hepatitis

Cholestasis with portal and lobular inflammation; systemic symptoms; ALT elevated as well as ALP

Chlorpromazine, erythromycin estolate, flucloxacillin

Cholestasis with bile duct injury

Destructive lesions of bile duct epithelium; clinically similar to acute cholangitis

Flucloxacillin, chlorpromazine

Paucity of small bile ducts, varying fibrosis; clinically resembles primary biliary cirrhosis; AMA negative

Chlorpromazine, amitriptyline, flucloxacillin

Chronic hepatitis

Periportal and/or bridging necrosis, fibrosis or cirrhosis; clinical and biochemical features of chronic liver disease; liver failure may occur

Alpha-methyldopa, nitrofurantoin, dantrolene

Fibrosis and cirrhosis

Portal hypertension; LFTs often normal

Methotrexate, hypervitaminosis A

6. Chronic cholestasis: cholestasis > 3 months Vanishing bile duct syndrome

7. Chronic parenchymal liver disease: abnormalities present > 3 months

Continued

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Table 24.11 Drugs and the liver — Continued Liver disease

Clinicopathological features

Drug examples

Sinusoidal dilatation

Isolated finding or adjacent to tumours; hepatomegaly is the only clinical feature

OCS

Peliosis hepatis

Destructive lesions of sinusoids resulting in blood-filled lakes

Anabolic androgens

8. Vascular disorders

Non-cirrhotic portal hypertension Portal and perisinusoidal fibrosis; splenomegaly, oesophageal varices

Vinyl chloride, azathioprine, hypervitaminosis A

Hepatic venous outflow obstruction

6-thioguanine, OCS, pyrrolizidine alkaloids

Budd-Chiari syndrome, veno-occlusive disease and overlap syndromes

Nodular regenerative hyperplasia Regeneration nodules with minimal fibrosis; portal hypertension

Azathioprine, dactinomycin

9. Hepatic tumours Focal nodular hyperplasia

Hamartoma, associated vascularity attributable to oestrogens

OCS

Hepatocellular adenoma

Benign neoplasm of hepatocytes

OCS, androgens

Hepatocellular carcinoma

Primary liver cancer (hepatoma)

OCS, androgens

Rarer carcinomas

Fibrolamellar variant, hepatoblastoma, cholangiocarcinoma, cholangiohepatocellular tumours, carcinosarcoma

OCS

Angiosarcoma

Malignant tumour, possibly arises from sinusoidal lining cells

Arsenic, vinyl chloride, thorium dioxide

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMA = anti-mitochondrial antibody; LFTs = liver function tests; NSAIDs = non-steroidal anti-inflammatory drugs; OCS = oral contraceptive steroids. From Farrell G. Drug induced liver disease. Edinburgh: Churchill Livingstone; 1994, with permission.

Budd-Chiari syndrome involves thrombosis of the hepatic veins. It presents with pain, hepatomegaly and ascites (Ch 4). There is portal hypertension and loss of hepatocyte function. There are acute and chronic forms of this syndrome. Progression to liver failure is not unusual. Thrombotic conditions involving the portal and hepatic vessels are associated with hypercoagulable states such as paroxysmal nocturnal haemoglobinuria, polycythaemia rubra vera, pregnancy, the contraceptive pill, lupus anticoagulant, malignancy (e.g. renal, adrenal, testicular and thyroid), a fibrous membrane, amoebic abscess or hydatid cyst and drugs (e.g. azathioprine). The diagnosis of portal and hepatic vein obstruction can often be established with ultrasonography and Doppler flow studies. Portal venography may be necessary. The definitive diagnosis of veno-occlusive disease requires liver biopsy although the diagnosis is often made clinically. Cardiac disease may cause an abnormal liver function profile. Hepatic ischaemia in association

with hypotension, as occurs during cardiac arrest, will result in a marked elevation of serum transaminase levels, often to several thousand units per litre. Unlike other conditions, the serum lactate dehydrogenase level is also markedly elevated. Recovery of the liver is prompt. Liver dysfunction does not interfere with the clinical course of the cause of the hypotension nor the prognosis. Moreover, the final prognosis is determined by the underlying illness. Right-sided heart failure and tricuspid regurgitation cause hepatic congestion, and associated abnormalities in liver function test results are not unusual. Elevations in alkaline phosphatase levels are common and will improve with control of the cardiac failure. Persistent hepatic congestion can eventually lead to fibrosis and cirrhosis.

Hepatocellular carcinoma Both the incidence of and mortality from hepatocellular carcinoma are increasing in Australia and other Western countries, primarily as a consequence of chronic viral hepatitis. Treatment

24 Abnormal liver function test results options depend on the size and location of the tumour and as such early detection is important. The diagnosis of hepatocellular carcinoma can be made on good quality imaging, such as triple phase CT scan or MRI, without the need for biopsy. Surgical resection of single lesions less than 2 cm in diameter leads to a 80% 5-year survival. This approach is appropriate when the liver disease is compensated without significant portal hypertension. It is important to have an understanding of the liver segments. There are eight segments. Each has a separate blood supply from the hepatic artery and portal vein, and a segmental bile duct drains into the right or left hepatic ducts. Removal of separate segments of the liver is feasible and this is important when considering surgical resection of a malignancy. When there is a single hepatocellular carcinoma (less than 5 cm) or up to three lesions less than 3 cm in diameter, liver transplantation can be potentially curative and should be considered. If transplantation is contraindicated local ablative therapy (radiofrequency ablation or ethanol injection) can be of value. With advanced hepatocellular carcinoma transarterial chemoembolisation and for those with more severe underlying liver disease, oral sorefenib can slow the progression of the disease. Patients with terminal disease should be managed symptomatically (see Ch 28). Cirrhosis is an important predisposing factor in the development of hepatocellular carcinoma. Cirrhosis of any cause may be considered potentially premalignant. However, the most significant aetiological factors include hepatitis B or hepatitis C infection, haemochromatosis and alcohol consumption. Hepatitis B infection and possibly hepatitis C can induce hepatocellular carcinoma without prior cirrhosis. Symptomatic hepatocellular carcinoma carries a poor prognosis. Screening of groups at high risk should be performed routinely. Ultrasonography can identify small, potentially curable lesions and should be performed in cirrhotic patients at 6-monthly intervals. The fibrolamellar variant, usually found in young Caucasian females, responds well to local resection.

Benign tumours Benign hepatic mass lesions are often identified incidentally during investigation (imaging) for unrelated symptoms. Adenomas, focal nodular hyperplasia and focal fatty change produce ‘masses’. Normal liver function test results are

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expected. Intervention is not required for focal nodular hyperplasia or fatty change. Hepatic adenoma may bleed (50% risk), may be difficult to differentiate from low-grade hepatocellular carcinoma and can progress to carcinoma. Imaging is often non-specific in the differentiation between focal nodular hyperplasia and adenoma. If an adenoma is suspected, segmental resection is usually indicated (Ch 26). Haemangiomas and hepatic cysts are common benign conditions often found incidentally during hepatic imaging. Simple fluid-filled cysts need no further investigation. If a lesion is typical of haemangioma on ultrasound or computed tomography, again no further tests should be necessary. If, however, there remains uncertainty as to the nature of the lesion, a nuclear-labelled red cell scan or MRI can be helpful. Angiography is not usually necessary. Small lesions require no treatment but large symptomatic lesions may need segmental resection (Ch 26).

Acute fatty liver of pregnancy This condition occurs in approximately 1 in 13,000 pregnancies. It carries with it a high fetal and maternal mortality. A brief non-specific prodrome may rapidly progress to fulminant hepatic failure. The onset is in the third trimester, generally after 32 weeks of gestation. Twin, male and primipara pregnancies are at greater risk of acute fatty liver. Nausea and vomiting are features of the clinical illness. Polydipsia may occur in association with diabetes insipidus. There may be abdominal pain. This can be epigastric or centred in the right upper quadrant. Malaise and fatigue is followed by pruritus and jaundice that rapidly progresses to liver failure. Ascites occurs in 50% of cases. Encephalopathy, hypoglycaemia, coagulopathy and renal failure follow. The mortality, without hepatic transplantation, is greater than 80% in advanced cases. Commonly there is mild hypertension, oedema and proteinuria, suggesting a possible relationship to preeclampsia. Haematology reveals leucocytosis, thrombocytopenia and evidence of microangiopathic haemolysis. Creatinine is elevated with a greater elevation in uric acid levels. Bilirubin and ALP levels are raised, while serum transaminase levels are between 300 U/L and 500 U/L. Hypoglycaemia and coagulopathy may be severe and represent significant management problems. Abdominal ultrasound scans have poor sensitivity in identifying acute fatty liver but are

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of use in excluding Budd-Chiari syndrome and gallstones. If necessary, a fine-needle aspiration biopsy will confirm the diagnosis. However, once the clinical diagnosis is made, performing a biopsy could waste valuable time and in so doing adversely affect the outcome. The treatment of acute fatty liver of pregnancy is emergency delivery of the fetus. This reduces the mortality to approximately 20%. It is of note that the mother’s condition may worsen after delivery. Liver transplantation may be required. There is no chronic disease following recovery. Recurrent acute fatty liver with subsequent pregnancies is not expected, but has rarely been reported.

Benign intrahepatic cholestasis of pregnancy This condition presents with pruritus and jaundice, often in the third trimester of pregnancy. Liver function tests are ‘cholestatic’, but the mother is otherwise well. Occasionally there may also be a significant rise in serum transaminase levels. The condition resolves with delivery. There is a strong genetic predisposition. Recurrence with subsequent pregnancy and during oestrogen therapy is likely. Cholestasis of pregnancy is associated with increased fetal loss. Severe symptomatic cases with progressively rising levels of serum bile acids or abnormal liver function results should be considered for early delivery. Symptomatic treatment of the pruritus has limited success. Ursodeoxycholic acid has been shown to be effective in relieving the maternal symptoms and appears to reduce fetal mortality. Numerous other measures have been tried in the control of the pruritus. These include cholestyramine, evening primrose oil, antihistamines, rifampicin, opiate antagonists, phenobarbitone and S-adenosylmethionine. The effectiveness and safety in pregnancy of all these agents has not been objectively established.

A special case of preeclampsia is the HELLP syndrome. This syndrome consists of Haemolysis, Elevated Liver function tests and Low Platelets. There is a microangiopathic haemolytic anaemia. Early aggressive management with delivery is appropriate.

Key Points ll

ll

ll

ll

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Preeclampsia and the HELLP syndrome Liver disease occurs in approximately 10% of cases of preeclampsia. In general, hepatic injury is secondary to the underlying condition, and reflects advanced disease. Preeclamptic signs may be mild. Symptoms include right upper quadrant and epigastric pain, nausea and vomiting. Jaundice, often mild, occurs in 40% of those affected. ALT levels are, in general, greater than 500 U/L. Most maternal deaths are cerebral, but hepatic involvement may contribute to death when infarction, haemorrhage or haematoma formation (with or without rupture) occurs.

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Liver function tests reflect liver function and injury. Patterns may be a guide to the underlying pathology, although they cannot be specific. Further blood tests are applied to assess for specific livers disorders, including those for viral, metabolic and autoimmune diseases. Liver biopsy may be required to confirm the diagnosis, but also to provide information regarding prognosis and to guide therapy. The pattern of presentation of liver disease varies widely, from the well patient with abnormal blood tests to those with a severe lifethreatening illness. History and physical examination will often need to be combined with specific blood tests and imaging to evaluate a patient and plan treatment. Regardless of the underlying illness patients with advanced liver disease can present in hepatic failure with jaundice, ascites, renal impairment, encephalopathy and or the complications of portal hypertension. Cirrhosis represents a situation in which the architecture of the liver is disrupted by fibrosis that has developed following hepatic injury. Hepatocyte regeneration leads to the development of nodules as the fibrosis prevents the restoration of normal microanatomy. As a consequence, blood flow through the liver is impeded. For patients with decompensated liver disease, management needs to address the consequences of the hepatic failure, any precipitating illness and the underlying condition. The management for end-stage chronic liver disease is liver transplantation.

Further reading Amin J, Law MG, Bartlett M, et al. Causes of death after diagnosis of hepatitis b or hepatitis C infection: a large community-based linkage study. Lancet 2006; 48:938–945. Bambha K, Kim WR, Talwalker J, et al. Incidence, clinical spectrum and outcome of primary sclerosing cholangitis in a United States community. Gastroenterol 2003; 125:1364–1369.

24 Abnormal liver function test results Black M, ed. Drug hepatoltoxicity. Clin Liver Dis 2003; 7:295–512. Buster E, Hansen B, Lau G, et al. Factors that predict response of patients with hepatitis B e antigenpositive chronic hepatitis B to peginterferon-alfa. Gastroenterology 2009; 137:2002–2009. Cabre E, Rodriguez Iglesias P, Caballeria J, et al. Short and long term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology 2000; 32:36–42. Chitturi S, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35:373–379. Deugnier Y, Brissot P, Loreal O. Iron and the liver: update 2008. J Hepatol 2008; 48:S113–S123. Farrell GC, Larter CZ. Non-alcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006; 43(suppl 1):S99–S112. Ferenci, P, Lockwood A, Mullen K, et al. Hepatic Encephalopathy—definition, nomenclature,diagnosis, and quantification: final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35:716–721. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002; 123:1367–2384.

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Hay JE. Liver disease in pregnancy. Hepatology 2008; 47:1067–1076. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. NEJM 2009; 360(18):1839–1850. Lok ASF, MaMahon BJ. Chronic hepatitis B. Hepatology 2007; 45:507–539. Munoz SJ. The hepatorenal syndrome. Med Clin N Am. 2008;92:813–837. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterol 2000; 118:1117– 1123. Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with hepatitis C and treatment failure. Gastroenterology 2010; 138;1338–1345. Roberts EA, Schilsky ML. Practice guideline on Wilson’s disease. Hepatology 2003; 37:1475–1492. Runyon BA. Care of patients with ascites. N Eng J Med 1994; 330:337–342. Sherlock S. Alcoholic liver disease. Lancet 1995; 345:227–229. Sorrell MF, Edward A. Belongia, et al. National Institutes of Health consensus development conference statement: management of Hepatitis B. Ann Intern Med 2009; 150:104–110.

25 Management of end-stage liver disease and liver transplantation

Case A 57-year-old female with primary biliary cirrhosis presents with new onset peripheral oedema and abdominal swelling. Her husband has noticed increasing jaundice and mild attention and concentration changes. Vital signs reveal a mild fever of 37.3° Celsius. The examination is notable for mild confusion, scleral icterus, asterixis, peripheral oedema and a distended abdomen with shifting dullness. Initial laboratory work reveals a total bilirubin of 9.5 mg/dL (normal range 0.1 – 1.0), alanine amino-transferase of 68 U/L (7–45), aspartate amino-transferase of 87 U/L (8–43) and alkaline phosphatase of 322. The International Normalized Ratio (INR) is elevated at 1.3 (0.9–1.2) as is the creatinine at 1.5 mg/dL (0.6–1.1), both of which had been previously normal. The patient has decompensated liver disease as evidenced by new onset ascites, progressive jaundice and hepatic encephalopathy. Additionally, acute kidney injury has developed. There are many possible causes of decompensation, though infection and gastrointestinal bleeding are among those that should be considered first. This patient has a low grade fever, though many cirrhotic patients with infection may not develop the typical signs and symptoms of infection. Evaluation for infection in this patient should include a complete blood count, blood cultures, urinalysis, a chest radiograph and a diagnostic paracentesis with cell count, differential, and culture. After ordering the aforementioned tests, the patient’s ascitic fluid cell count and differential results return, showing 335 polymorphonuclear cells/mm3, which is diagnostic for spontaneous bacterial peritonitis. Treatment with intravenous cefotaxime, intravenous albumin, and lactulose per rectum is initiated and the patient is transferred to the regional liver transplant centre. This vignette highlights the need to be vigilant for

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infection in all decompensated cirrhotic patients, and that decompensation necessitates referral to a liver transplant centre.

Introduction Liver transplantation has become the treatment for a variety of liver diseases including acute liver failure, end-stage chronic liver disease, metabolic liver diseases, and specific hepatic malignancies. This chapter reviews end-stage liver disease as well as giving a brief overview of liver transplantation.

End-stage Liver Disease Compensated cirrhosis The most common severity assessment tools in use are the Child-Turcotte-Pugh (CTP) score and the Model for End Stage Liver Disease (MELD) score. The CTP score was originally devised to risk stratify cirrhotic patients in need of portocaval shunt surgery due to oesophageal variceal bleeding and incorporates bilirubin, albumin and prothrombin time as well as encephalopathy and ascites measurements (see Table 24.6). The MELD score was first developed to predict short-term prognosis in patients undergoing TIPS. The MELD score (http://www.unos.org/ resources/meldpeldcalculator.asp) is based on three continuous, objective variables: bilirubin, creatinine and the INR of prothrombin time. Patients are assigned a score based on these three variables, from 6 through 40, corresponding to a 3-month survival of nearly zero and over 80% respectively. The MELD score has been validated as an accurate predictor of survival in acute liver failure, alcoholic hepatitis, a variety of chronic liver diseases and variceal bleeding, amongst others. A patient with cirrhosis who has not developed jaundice or portal hypertensive complications of hepatic encephalopathy, ascites or variceal

25 Management of end-stage liver disease and liver transplantation bleeding is ‘well compensated’, meaning he or she has adequate hepatic reserve. These patients are often categorised as Child-Turcotte-Pugh class (CTP) A. The median survival age in this group is 9–12 years. Since there are no available medical treatments to reverse cirrhosis, most management strategies are directed towards prevention.

Oesophageal varices Approximately 50% of cirrhotic patients will have gastro-oesophageal varices with the likelihood being higher in more advanced disease. The risk of haemorrhage is approximately 5–15% per year with a 15–20% risk of mortality per episode. Therefore, all patients with a new diagnosis of cirrhosis should undergo oesophagogastroduodenoscopy to screen for varices. If large varices are noted, oral non-selective beta-blockers and/or variceal band ligation are indicated. Findings of red wale markings— longitudinal dilated venules on the variceal surface—and large varices (greater than 5 mm) signify an increased risk of spontaneous haemorrhage. Advanced liver disease (CTP B or C) also places the patient at a higher risk of variceal bleeding. For large varices and other high-risk features (CTP C or red wale markings) variceal banding is preferred whereas non-selective betablockers are preferred for large varices without other high-risk features. Small varices require only primary prophylaxis with non-selective beta blockers. When varices are absent at the initial endoscopy, primary prophylaxis is not recommended, but screening should be repeated in 2–3 years if the patient remains compensated. Options for non-selective beta-blockade include propranolol, which is typically initiated at 20 mg twice daily, or nadolol which can be started at 20– 40 mg once daily. Beta-blockers should be titrated to the maximally tolerated dose. A decrease in heart rate does not correlate with a decrease portal pressures, though it is also a common practice to titrate beta-blocker doses to a heart rate of 55–60 beats per minute.

Nutrition Cirrhotic patients are often catabolic and suffer from severe muscle wasting and cachexia. Cirrhotic patients are often wrongly counselled to restrict protein intake, thus exacerbating this process. Patients with cirrhosis should eat 1.2–1.5 g/kg of protein daily with a well-balanced diet. Many patients require vitamin supplementation, with assessment specifically for vitamins A, D, E and K and zinc deficiency. Patients with fluid

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retention (ascites, pleural effusions or peripheral oedema) require a sodium restriction outlined below. Obesity is seen in epidemic proportions in developed countries. Morbid obesity is a relative contraindication to transplant. Ideally a patient’s BMI should be below 35 before transplantation in many centres, although exceptions are made. Patients with a BMI over 35 have increased risk of wound complications and longer hospital stays. All cirrhotic patients should abstain from alcohol completely and permanently. Continued alcohol use can result in earlier decompensation, increased risk of hepatocellular carcinoma, synergistic effects with hepatitis C on disease progression, an attenuated effect of interferon therapy, secondary psychiatric conditions and denial of liver transplantation. For patients with alcohol addiction issues, many transplant centres require 6 months of alcohol abstinence before liver transplantation can be considered. All cirrhotic patients should be counselled on avoidance of raw seafood due to risk of Vibrio vulnificus septicaemia, which carries a particularly high rate of mortality in cirrhotic patients (about 50%). Swimming in contaminated water can also result in wound infections or cellulitis, and should be avoided.

Osteoporosis Chronic liver disease predisposes patients to the development of hepatic osteodystrophy by multiple pathways that cause decreased bone formation and increased bone resorption. Patients with chronic liver disease plus one of the following: prolonged corticosteroid use (over 3 months), low-trauma fracture, a postmenopausal female or male older than 50 years or hypogonadism should be screened for osteoporosis with a dual energy x-ray absorptiometry. All patients should receive calcium supplementation 1200–1500 mEq/day and vitamin D 1000 IU/day. Counselling on smoking cessation and weight-bearing exercise is appropriate. Bisphosphonates should be considered for patients with known osteoporosis, non-traumatic fractures or inability to withdraw from corticosteroids.

Medication counselling Paracetamol (acetaminophen) can be hepatotoxic above a dose of 4 g/day. Certainly, patients with concurrent alcohol use or malnutrition can experience additional liver injury at lower doses of paracetamol. In this subset of patients, it is probably safest to avoid chronic dosing of

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paracetamol, but a low dose (2 g/day) one time or infrequent dosing appears safe. In other cirrhotic patients, paracetamol at doses under 4 g/day for short periods of time appear safe, but less than 2.6 g/day is now the standard of care. The chronic use of paracetamol has not been studied in cirrhotic patients, thus most hepatologists will recommend dose reduction (2 g/day in divided doses) for longer term dosing. Many over-the-counter herbal medications can be hepatotoxic and can cause acute liver failure and thus should be avoided.

Surgery counselling Patients with cirrhosis are at an increased risk of complications and mortality from surgery. Reasons for this are multiple, but include altered drug metabolism and preexisting hyperdynamic circulation that responds atypically to the stress of surgery and pharmacologic support. The MELD and CTP scores are reasonably accurate in predicting operative risks. In a retrospective study, the risk of 30-day mortality in patients undergoing intraabdominal non-transplant surgery was 5% at a MELD under 10 and 14% for a MELD over 15. In the interpretation of this study, it was suggested that for each increase in MELD score from 6–20 there is a 1% increase in 30-day mortality, and MELD scores over 20 give an additional 2% risk per point. For example, a patient with a MELD score of 7 has an approximately 7% risk of death whereas a MELD score of 25 would correlate to an approximate 30-day mortality of 50% It has been suggested that patients with CTP class A or MELD score less than 10 are acceptable candidates for elective surgery. Elective surgery for patients with CTP class B or MELD over 10 but under 15 should be approached with caution and, if surgery is necessary, work-up for transplant should be completed; performing the operation in a transplant centre is optimal. Elective surgery should not be performed on cirrhotic patients with CTP class C cirrhosis or a MELD score over 15.

Hepatocellular carcinoma Approximately 80–90% of hepatocellular carcinomas (HCCs) occur in patients that have cirrhosis. Patients with cirrhosis, regardless of aetiology should have HCC surveillance every 6 months with an ultrasound of the liver. The alpha-fetoprotein test has recently fallen out of favour for use in HCC surveillance programs. Non-cirrhotic patients with hepatitis B are also at risk of developing HCC and should also undergo screening if they are in one of the following categories: Asian females over 50 years old, Asian

males over 40 years old, Africans over 20 years old, or with a family history of HCC. The alpha-fetoprotein measurement for screening of HCC is an imperfect test. An alphafetoprotein level over 20 ng/mL alone has a sensitivity of 60%. However, in the setting of a liver lesion over 2 cm in diameter, this carries a very high positive predictive value for the diagnosis of HCC. Ultrasonographic findings in HCC are variable, ranging from an echogenic lesion in small HCCs (due to tumoural fat) to hypoechoic in larger lesions. These findings can be difficult to distinguish from those seen in macronodular cirrhosis and a CT scan is recommended for further evaluation. CT findings of arterial enhancement and venous wash-out are highly specific for HCC. An algorithmic approach to diagnosing HCC has been recommended by the American Association for the Study of Liver Diseases. For lesions smaller than 1 cm in diameter identified by ultrasound, surveillance ultrasound should be performed every 3 months and, if stable over 1–2 years, reversion to standard 6–12-month surveillance interval is recommended. If a lesion over of 1 cm diameter is identified by ultrasound, it is recommended that a CT or MRI be obtained. If an atypical vascular pattern is noted on one imaging test (CT or MRI), the other imaging modality should be used for further clarification. If a typical vascular pattern (arterial phase enhancement with venous phase washout) is seen on both CT and MRI, the lesion should be treated as HCC, and biopsy is not needed. If imaging does not provide diagnostic features, a biopsy should be pursued. If biopsy results are non-diagnostic, ultrasound on 3-month intervals is recommended. Biopsy confirmation is rarely needed if imaging is characteristic and may cause needle-tract seeding, spreading the cancer. If a liver biopsy is considered under any of the aforementioned circumstances, the authors recommend that this be discussed with a hepatologist before proceeding. Several treatment options are available for HCC including resection, locoregional therapy such as transarterial chemoembolisation (TACE), radiofrequency ablation (RFA) and liver transplantation. Radiofrequency ablation technique utilises a probe inserted percutaneously into the tumour with ultrasound or CT guidance and induces coagulative necrosis from heat generated by electromagnetic radiation. TACE delivers small embolic particles and a chemotherapeutic agent (cisplatin or doxorubicin commonly) to deprive the tumour of its vascular supply and

25 Management of end-stage liver disease and liver transplantation concomitantly deliver cytotoxic therapy, resulting in tumour hypoxaemia and necrosis. The optimal use of conventional strategies and novel therapies is evolving. A careful multidisciplinary approach involving a transplant surgeon, transplant hepatologist, interventional radiologist, and oncologist results in the best outcome. A system to guide HCC treatment, known as the Barcelona Clinic Liver Cancer staging system, has been adopted at many centres and takes into account the number and size of tumours, liver function, comorbidities, and performance status of the patient, which is summarised below. An otherwise healthy patient with a small solitary lesion, without portal hypertension or bilirubin elevation, is a candidate for resection and has the highest rate of cure. The optimal size parameters for resection remain undefined, but a lesion less than 2 cm in diameter has been suggested. The presence of portal hypertension or elevated bilirubin portends a poor outcome in resection due to subsequent liver decompensation. Patients with similar tumour characteristics, but with underlying portal hypertension or elevated bilirubin, may be candidates for RFA, TACE or liver transplantation. Generally speaking, a patient with HCC and without other contraindications (listed below) can be considered for liver transplantation if they fulfil the Milan criteria, which is 3 lesions smaller than 3 cm or one lesion smaller than 5 cm in diameter. It is very important to note that some centres carry out successful transplantation for HCC with characteristics exceeding those of the Milan criteria and discussion with the transplant centre is crucial. In patients with an expected waiting time for the transplant greater than 6 months, it is recommended that locoregional therapy be performed before transplantation although there is little evidence to support the benefit of this practice. In patients who are not candidates for resection or transplantation, Child-Turcotte-Pugh (CTP) status, location and size of the tumours, ascites and portal vein thrombus are some of the important factors in deciding whether to perform RFA or TACE. Optimal outcomes for RFA are seen in patients with an HCC less than 3 cm in diameter. Technical challenges may prevent use of RFA in patients with ascites, lesions near the surface of the liver, or lesions near the hilum or gallbladder. Guidelines have recommended that TACE should ideally be performed in CTP class A patients with multifocal involvement confined to the liver. However, TACE can be used in a variety

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of different circumstances including in solitary tumours, depending on the centre. Performing TACE in patients with CTP class B or C cirrhosis or those with portal vein thrombus increases the risk of decompensation and is not recommended. Recently, transarterial radioembolisation (TARE) has garnered attention as an alternative to TACE and RFA. This modality is under continued investigation and its role in treatment of HCC is not yet defined. For patients with advanced disease with good underlying liver function (CTP class A), sorafenib, a multikinase inhibitor, has shown modest improvement in survival and time to progression.

Decompensated cirrhosis Compensated cirrhosis eventually decompensates, manifested by progressive jaundice, hepatic encephalopathy, gastro-oesophageal variceal bleeding or ascites. Decompensation may arise as a natural progression of disease, or be triggered by events such as infection, hepatoma, medications, other organ failure or surgery. Decompensation heralds a major change in the prognosis of the cirrhotic patient with a 5–year survival rate of 20–50%. Any decompensating event warrants a referral to a transplant hepatologist.

Jaundice Jaundice can be a result of the natural progression of disease or a manifestation of acute or chronic liver failure. A careful search for infection, gastrointestinal bleeding or HCC is warranted. Cirrhotic patients are also not exempt from other common problems, such as choledocholithiasis, as a cause for jaundice. Biliary obstruction should be ruled out with an ultrasound. A history of recent alcohol use or new medications and over-thecounter drugs should be elicited, as superimposed alcoholic hepatitis or drug hepatotoxicity should be considered.

Hepatic encephalopathy Hepatic encephalopathy is a set of potentially reversible neuropsychiatric symptoms seen in patients with liver dysfunction. The symptoms can range from mild inattention and disorientation to coma. Hepatic encephalopathy may also be accompanied by an elevation in venous ammonia values, but these values have not been found to correlate well with the presence, absence or grade of encephalopathy. Treatment requires correction of precipitating factors such as gastrointestinal haemorrhage, uraemia, hypoxia, use of psychoactive medication, infection, constipation,

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electrolyte disturbance and, very rarely, high protein intake. Treatment should include lactulose (oral, nasogastric or rectal) until the bowels begin to move, and then titrated to 2–3 loose stools per day. An alternative therapy is neomycin, but this is rarely used due to the risk of ototoxicity and nephrotoxicity. For lactulose refractory cases, rifaximin has been used with some success. Rifaximin is not superior to lactulose, and is much more expensive. Nonetheless, some data suggest that use of rifaximin (when added to lactulose) is effective for secondary prophylaxis of acute hepatic encephalopathy and may prevent recurrent hospitalisation for hepatic encephalopathy. L-ornithine L-aspartate (LOLA) is another option for lactulose refractory hepatic encephalopathy, and stimulates the urea cycle, leading to decreased ammonia levels. Administration of LOLA for treatment of overt hepatic encephalopathy has been shown to be superior to placebo although the beneficial effects when combined with lactulose remain unknown. Diet is thought to play an important role in hepatic encephalopathy, although it is rare to see a high-protein meal trigger worsening encephalopathy. Skeletal muscle is important for removing ammonia from the blood stream and low protein intake may result in muscle mass loss. Vegetable proteins produce less ammonia than animal proteins and may be preferred. As a rule, protein restriction is rarely required.

Oesophageal variceal haemorrhage Cirrhotic patients with gastrointestinal bleeding are assumed to have an oesophageal variceal bleed until proven otherwise, due to the 15–20% mortality per episode of variceal haemorrhage. Management should begin with admission to an intensive care unit, the establishment of two large bore intravenous lines (18 gauge or greater), fluid resuscitation, correction of significant coagulopathy, endotracheal intubation for massive bleeds or the inability to protect the airway, and preparation for upper endoscopy. Overreplacement of packed red blood cells is a common mistake as this can lead to increased portal pressure and an increased risk of re-bleeding. The goal haemoglobin level should be about 8 g/dL. Bacterial infections can complicate up to 50% of variceal bleeds and therefore ceftriaxone (or norfloxacin) is recommended for infection prevention. Octreotide, vasopressin, terlipressin or somatostatin may be used to decrease portal inflow. All are equivalent in their efficacy, but the risk of side effects is higher with vasopressin.

Oesophageal variceal band ligation should be performed for active bleeding or a clot from a varix, or a non-bleeding varix in the absence of other causes of upper gastrointestinal bleeding. In 10–20% of patients, bleeding cannot be controlled by these measures and salvage measures include balloon tamponade with a Sengstaken-Blakemore or Linton tube, transjugular intrahepatic portal systemic shunt or a surgical shunt. To reduce recurrent bleeding, octreotide or similar agents should be continued for 3–5 days as 50% of early re-bleeding occurs during the first 5 days. Nonselective beta-blockers should be initiated when haemodynamically feasible. After the initial oesophageal variceal band ligation, the patient should undergo repeat oesophageal variceal band ligation every 4–6 weeks until varices are obliterated and then every 6–12 months thereafter.

Ascites The diagnosis of ascites is suggested if flank dullness, bulging flanks, shifting dullness or a fluid wave is present. Ultrasound is the safest and most inexpensive modality to confirm or dismiss ascites. The 1-year survival rate is approximately 50% once ascites has developed. Treatment of ascites does not influence this survival. Treatment should begin with dietary sodium restriction of less than 2 g/day. Spironolactone (starting at 50–100 mg/day) is the most effective diuretic in patients without acute renal failure or hyperkalaemia. The dose may be titrated every 4–7 days, to a weight loss of 0.5 kg/day in patients without oedema, or 1.0 kg/day in those with oedema. If desired results are not achieved or hyperkalaemia develops, furosemide should then be added at 20–40 mg/day. Maximum recommended dosing is 400 mg/day of spironolactone and 160 mg/day of furosemide. Dose adjustments or diuretic ‘breaks’ are commonly needed due to hyperkalaemia, hyponatraemia or renal dysfunction. If diuretics are maximised, and a patient is not losing fluid weight, a 24-hour urine collection revealing more than 78 mmol/day of sodium indicates dietary non-compliance. The term ‘refractory ascites’ encompasses diuretic resistant and diuretic intractable (intolerable) ascites. Diuretic resistant ascites fails to resolve despite maximal medical therapy whereas diuretic intractable ascites refers to failure to control ascites due to medication side effects. In this setting, intermittent large volume paracenteses are the next step. Diuretics, if tolerated, should be continued if urinary excretion of sodium is more than 30 mEq/L. A transjugular intrahepatic portal

25 Management of end-stage liver disease and liver transplantation systemic shunt procedure is second-line therapy for refractory ascites, but should be considered in patients requiring over one or two large volume paracenteses per month and is more likely to be effective in the setting of normal renal function. Contraindications for transjugular intrahepatic portal systemic shunt are shown in Table 25.1. Ascitic fluid from a diagnostic paracentesis should always be sent for cell count, albumin levels, total protein levels and culture. Blood culture bottles should be inoculated with fluid at the bedside to improve the sensitivity for detecting an organism. A serum albumin–ascitic fluid albumin gradient (SAAG) greater than 1.1 g/L is consistent with portal hypertension. A SAAG less than 1.1 g/L merits consideration of other causes for ascites. Therapeutic paracentesis need only be sent for cell count if the patient is well otherwise. If more than 5 litres of fluid is removed, 6–8 g of intravenous albumin per litre removed should be administered. If there is any concern for spontaneous bacterial peritonitis (see below) or renal dysfunction, smaller volumes of fluid may be extracted to avoid postparacentesis circulatory dysfunction, which can worsen renal failure and hasten the re-accumulation of ascitic fluid.

Spontaneous bacterial peritonitis Spontaneous bacterial peritonitis (SPB) can complicate ascites and historically resulted in mortality greater than or equal to 80%. With

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heightened clinical suspicion for SBP and early antibiotic therapy, mortality can be reduced drastically. Blood cultures may be positive in about 50% of cases and should be obtained around the time of paracentesis. The diagnosis of SBP is made if the cell count reveals more than 250 polymorphonuclear cells per mm3 or the patient has positive ascitic fluid cultures in addition to clinical symptoms/signs of SBP. Symptoms and signs of SBP include worsening hepatic encephalopathy, fever, elevated/reduced white count, abdominal pain or tenderness, and renal dysfunction. It is important to note that patients with this infection may also be asymptomatic. Once the diagnosis is made, treatment should be initiated with intravenous cefotaxime or the equivalent. Intravenous albumin infusions should be administered at 1.5 g/kg on the day of diagnosis followed by 1.0 g/kg on day 3 to prevent further renal dysfunction. Reassess after 5 days of therapy. If symptoms or white count persist, repeating paracentesis and the cell count will determine whether or not the infection has been eradicated. Primary antibiotic prophylaxis for patients with low ascitic fluid total protein (under 1.5 g) is recommended. Secondary prophylaxis (after first episode) is recommended for all patients due to the high (about 70%) 1-year recurrence rate. Norfloxacin 400 mg/day is the most studied in this setting, but other quinolones (ciprofloxacin) or sulfamethoxazole/trimethoprim can be used.

Table 25.1 Transjugular intrahepatic portal systemic shunt Indications

Contraindications

Major

Minor

Absolute

Relative

2° prevention of variceal bleeding

Refractory acutely bleeding varices

Primary prevention of variceal bleeding

Hepatoma

Congestive heart failure

Portal vein thrombus

Bleeding gastric varices

Multiple hepatic cysts

Severe coagulopathy

Gastric antral vascular ectasia

Uncontrolled systemic infection

Platelet count < 20,000/cm3

Refractory hepatic hydrothorax

Unrelieved biliary obstruction

Moderate pulmonary hypertension

Hepatorenal syndrome 1 or 2

Severe pulmonary hypertension

Refractory cirrhotic Portal hypertensive ascites gastropathy

Budd-Chiari syndrome Veno-occlusive disease—rarely INR = International Normalized Ratio. From Boyer T, Haskal Z. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology 2005; 41(2):386-400. © 2005 American Association for the Study of Liver Diseases. Used with Permission.

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Hospitalised patients with cirrhosis

ARF/AKI 19%

Chronic renal failure 1%

Prerenal 68%

Volume-responsive 66% • Infection • Hypovolemia • Vasodilators • Other

Intra-renal (ATN, GMN) 32%

Postrenal (obstructive) (< 1%)

Not volume-responsive

HRS type 1 25%

HRS type 2 9%

Figure 25.1  Acute kidney injury in hospitalized cirrhotics. ARF = acute renal failure; AKI = acute kidney injury; ATN = acute tubular necrosis; GMN = glomerulonephritis; HRS = hepatorenal syndrome. * Volume-responsive prerenal failure is precipitated by infection in 51% of cases. From Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008; 48(6):2064-2077. © 2008 American Association for the Study of Liver Diseases.

Renal failure Renal failure in the cirrhotic patient is an important prognostic sign. Evidence consistently shows that renal failure, now called acute kidney injury, predicts early mortality in cirrhotic patients and is one of three variables used in the Model for End Stage Liver Disease (MELD) score. Aetiologies of acute kidney injury include hypovolaemia, sepsis, acute tubular necrosis, nephrotoxic drugs, and hepatorenal syndrome (Fig 25.1). Evaluation of acute kidney injury should begin by ruling out infection, and urinalysis and urine sodium measurement should also be performed. In all forms of acute kidney injury, the clinician should discontinue diuretics, lactulose and nephrotoxic agents. Hypovolaemia should not be overlooked as it accounts for approximately 70% of acute kidney injury in cirrhotic patients; thus all patients should receive volume expansion with 1 g/kg of albumin. Additional colloid or crystalloid fluid may be necessary in addition to the minimum requirement. Sepsis or systemic inflammatory response syndrome will result in systemic vasodilation and a further decrease in effective

circulating volume resulting in acute kidney injury. If sepsis is suspected, broad spectrum antibiotic coverage and aggressive fluid resuscitation should be commenced. Patient with spontaneous bacterial peritonitis are at increased risk of hepatorenal syndrome requiring specific measures outlined below. Acute tubular necrosis may be the result of sustained hypovolemia, severe sepsis or exposure to nephrotoxic agents. Patients with acute tubular necrosis will not respond to fluid resuscitation and may require renal replacement therapy, usually better tolerated as continuous renal replacement therapy rather than intermittent haemodialysis due to haemodynamic instability. Patients with hepatorenal syndrome also do not respond well to intravascular volume expansion. This syndrome is unique to liver disease patients and occurs due to renal vasoconstriction in reaction to systemic vasodilation (decreased effective circulating volume). Type 1 hepatorenal syndrome occurs in patients with advanced liver disease and ascites. It is by definition rapidly progressive and results in a median survival of approximately 4 weeks without liver transplantation. Diagnostic criteria are listed in Box 25.1. Type 2 hepatorenal syndrome is a

25 Management of end-stage liver disease and liver transplantation Box 25.1  Diagnostic criteria for hepatorenal syndrome type 1 ll ll

ll

ll

ll ll

ll

Cirrhosis with ascites Serum creatinine over 1.5 mg/dL (133 μmol/L) No improvement in creatinine (under 1.5 mg/dL) after 2 days of diuretic withdrawal and administration of IV albumin 1 g/kg/day (max: 100 g/day) Absence of spontaneous bacterial peritonitis (SBP) Absence of shock Absence of current/recent treatment with nephrotoxic drugs or vasodilators Absence of parenchymal kidney disease (as indicated by proteinuria (500 mg/day), microhaematuria (over 50 RBCs/hpf) and/or abnormal renal ultrasound)

IV = intravenous; max = maximum; RBC = red blood cell; hpf = high power field. Adapted from Salerno et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56(9):1310–1318.

milder form of renal failure that occurs over a period of months. Hepatorenal syndrome is potentially reversible. There is usually a precipitating event (spontaneous bacterial peritonitis, gastrointestinal bleeding). If this inciting factor is addressed, and adequate intravenous albumin has not resulted in improvement in the creatinine (and other causes are ruled out), then hepatorenal syndrome treatments should be initiated. Terlipressin or the combination of octreotide plus midodrine is initiated in conjunction with intravenous albumin infusions. The goal is to increase the mean arterial pressure by 15 mmHg. Treatment should be continued for 7–14 days or until liver transplantation. Liver transplantation is the only definitive treatment for type 1 hepatorenal syndrome.

Orthotopic Liver Transplantation The most common indications for liver transplantation differ by country, but include alcoholic liver disease, hepatitis C, hepatitis B and non-alcoholic fatty liver disease. Patients with a CTP score of 7 or more will achieve a survival benefit from transplantation, and thus is a threshold for referral for transplant evaluation in many centres. Variceal bleeding, progressive jaundice and hepatorenal syndrome are not factors in the CTP score, but are decompensating events that also merit transplant referral.

353

Patients with a MELD score of 10 or more should be referred for liver transplant evaluation but, again, decompensation such as encephalopathy and recurrent bleeding or refractory ascites are not reflected in the score and warrant referral as well. Liver transplantation is a major operation and requires a thorough evaluation for candidacy that differs from centre to centre. A careful determination of obvious contraindications may help to avoid unnecessary referrals. Absolute contraindications that may be encountered include uncontrolled infection and severe intracranial hypertension (intracranial pressure over 50 mmHg) or brainstem herniation. Other contraindications include a current or recent (less than 2 years) extrahepatic malignancy (depending on the origin), severe comorbid illness (especially cardiopulmonary), active substance abuse and persistent noncompliance. Relative contraindications include advanced age, current smoking and morbid obesity, with centre-dependent restrictions. If there is in doubt, the referral centre should be called. Patients who eventually receive liver transplantation enjoy 1- and 5-year survival rates of 85–90% and 75%, respectively. With this success has come growing disparities between the demand and the availability of donor livers. Significant morbidity and mortality occur while patients are on the transplant waiting list. Good medical management of the end-stage liver disease patient can improve upon the morbidity and mortality, but cannot fix the underlying organ failure. All efforts are needed to increase the supply of donor organs for this life-saving procedure. After a liver transplant, patients are generally followed closely by the transplant centre, particularly with respect to immunosuppression and graft-related issues. Most patients are discharged home between 2 and 4 weeks after transplant, depending on the distance they must travel. Patients have regular blood work at least weekly for the first 4–8 weeks until liver and renal functions are stable and immunosuppression levels are satisfactory. After the first 8 weeks, blood work may be performed less frequently with longer intervals between blood draws as per transplant centre protocols. Most patients will return to the transplant centre between 3 and 6 months for a follow-up appointment. Many centres will see the patient at least annually, but every centre may be different. Most transplant programs will adjust all transplant immunosuppression medications. Transplant programs will follow the patient for

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many of their ongoing medical issues, but most transplant centres rely heavily on the family practitioner to manage the patient’s chronic care issues. These issues include diabetes, hypertension, hyperlipidaemia, bone disease and other chronic ailments, as well as acute issues such as infections or even pregnancy. Treatment of all of these issues is generally similar to that of the general population, but with careful choices for medications, as many drugs interact with immunosuppression medications (Box 25.2). If there is any doubt, discussing the case with the transplant centre physicians is the best choice. Generally, transplant centres utilise two to four immunosuppressive medications in the days to months after transplantation to prevent acute and chronic allograft rejection. These vary according to transplant centre, but may include a calcineurin inhibitor (tacrolimus or cyclosporine), corticosteroids (prednisone), antimetabolites (mycophenolate mofetil or azathioprine), or newer immunosuppressants such as rapamycin or daclizumab. As a rule of thumb, these are tapered down to one or two agents over the 3 months or more after transplantation with one of the calcineurin inhibitor medications being retained as the cornerstone of long-term immunosuppression. These medications carry risk for significant side effects that can result in acute illness, such as hyperkalaemia, renal failure, severe cytopenias and organ rejection. Thus, it is best to check serum drug levels where applicable (cyclosporine, tacrolimus and mycophenolate mofetil) in all acutely ill transplant patients. The immunosuppression program should be exclusively managed by the transplant centre and all abnormal drug levels should be communicated immediately to that centre. Long-term immunosuppression results in approximately 50% of post-transplant deaths from complications of cardiovascular disease, renal failure, infection and malignancy. Many conditions commonly encountered in the general population are more prevalent in the post-transplant setting due to immunosuppressive medications, including diabetes, hypertension, hyperlipidemia, chronic kidney disease and skin cancer. Any abnormal or unexpected liver tests should be brought to the attention of the transplant program. Basic work-up includes ultrasound of the liver for biliary dilation and, more importantly, a Doppler exam for hepatic artery patency is crucial. If a cholestatic liver enzyme pattern is noted, ultrasound may not show dilation of the biliary tree. Thus, magnetic resonance cholangiopancreatography or

Box 25.2  Drug interactions with calcineurin inhibitors Increase levels of calcineurin inhibitor Calcium channel Antimicrobial blockers Others Caspofungin Diltiazem Danazol Azoles* Verapamil Grapefruit juice Terbinafine Amlodipine Diazepam, (less) alprazolam Macrolides† Chloroquine Felodipine Allopurinol (less) Protease Sertraline, inhibitors Nicardipine nefazodone Decrease levels Antimicrobials Rifampin Rifabutin

of calcineurin inhibitor Anticonvulsants Others Carbamazepine Orlistat Phenobarbital St John’s wort Phenytoin

*Azoles = ketoconazole, fluconazole, miconazole, voriconazole † Macrolides = clarithromycin, erythromycin, azithromycin (less so)

endoscopic retrograde cholangiopancreatography may be warranted and should be discussed with the transplant centre before proceeding with any invasive procedure. Periprocedure antibiotics are mandatory for any biliary manipulation or transhepatic needle track in a patient with a Rouxen-Y anastomosis. If liver tests reveal a rise in transaminases (and the patient is otherwise well), then serum analysis for cytomegalovirus infection is necessary along with immunosuppression drug levels and a review for new medications or symptoms of infection. Acute cellular rejection can present with non-specific elevation of transaminases, alkaline phosphatase, gammaglutamyl transpeptidase or bilirubin and requires a liver biopsy for diagnosis. A liver biopsy may be warranted but should be discussed with the transplant centre.

Key Points ll

ll

ll

Cirrhosis cannot be reversed; management focuses on prevention and treatment of consequences of portal hypertension. Compensated cirrhosis is defined by stable clinical status with a lack of encephalopathy, ascites or bleeding oesophageal varices. Decompensated cirrhosis is marked by development of encephalopathy, ascites, spontaneous bacterial peritonitis, progressive jaundice or hepatorenal syndrome.

25 Management of end-stage liver disease and liver transplantation ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

ll

Patients with cirrhosis should eat 1.2–1.5 grams/kilogram of protein daily with a wellbalanced diet. Many cirrhotics require fatsoluble vitamin supplementation. All patients with a new diagnosis of cirrhosis should undergo an oesophagogastroduodenoscopy to screen for varices. If varices are found, treatment depends on their size and appearance and the severity of the underlying liver disease. Patients with chronic liver disease and additional risk factors for osteoporosis should undergo osteoporosis screening with a dual energy x-ray absorptiometry scan. Elective surgery should not be performed on cirrhotic patients with Child-Turcotte-Pugh class C cirrhosis or a MELD score over 15. Patients with cirrhosis, regardless of aetiology, should be screened for hepatocellular carcinoma every 6–12 months with an ultrasound or computed tomography scan. There are multiple treatment options for hepatocellular carcinoma, including resection, locoregional therapies, liver transplantation and chemotherapy. Hepatic encephalopathy is treated with lactulose after reversible causes have been addressed. Rifaximin and L-ornithine L-aspartate can be used in lactulose refractory cases. Intravenous fluid resuscitation, packed red blood cell support (goal haemoglobin = 8 g/dL), vasoactive medications (octreotide or terlipressin), antibiotics and oesophagogastroduodenoscopy are recommended for acute variceal bleeding. Spontaneous bacterial peritonitis can be diagnosed when the ascitic fluid polymorphonuclear cell count exceeds 250/ mm3. This infection may be asymptomatic or present as new or worsening hepatic encephalopathy or renal failure. Approximately 70% of acute kidney injury seen in the setting of renal failure is volume responsive. Liver transplantation should be considered for patients with a Child-Turcotte-Pugh score ≥ 7 or MELD score ≥ 10, or features of decompensated liver disease including encephalopathy, ascites, and oesophageal variceal bleeding. Patients who eventually receive liver transplantation enjoy 1- and 5-year survival rates of 85–90% and 75%, respectively.

ll

ll

355

All liver transplant patients who are starting new medications, are acutely ill, have abnormal lab or imaging studies, or abnormal drug levels should be discussed with the transplant centre. When in doubt call your transplant centre.

Further reading Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362:1071–1081. Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol 2001; 96:1968–1976. Boyer TD, Haskal ZJ. American Association for the Study of Liver Diseases practice guidelines: the role of transjugular intrahepatic portosystemic shunt creation in the management of portal hypertension. J Vasc Interv Radiol 2005; 16:615–629. Boyer TD, Haskal ZJ: The role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology 2009; 51:306. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42:1208–1236. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44:217–231. Fernandez J, Ruiz del Arbol L, Gomez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006; 131:1049–1056. Garcia-Tsao G, Lim JK. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol 2009; 104:1802–1829. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008; 48:2064–2077. Gonzalez R, Zamora J, Gomez-Camarero J, et al. Metaanalysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008; 149:109–122. Hanje AJ, Patel T. Preoperative evaluation of patients with liver disease. Nat Clin Pract Gastroenterol Hepatol 2007; 4:266–276. Kamath PS, Kim WR. The model for end-stage liver disease (MELD). Hepatology 2007; 45:797–805. Korenblat KM, Mazariegos GV, Moonka D, et al. Longterm management of the liver transplant patient: recommendations for the primary care doctor. Am J Transplant 2009; 9:1988–2003. McGuire BM, Rosenthal P, Brown CC, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56:1310–1318. Murray KF, Carithers RL, Jr. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 2005; 41:1407–1432.

26 Abdominal incidentalomas

Case Mrs AI, a slim, previously well 65-year-old woman presented to her general practitioner with dysuria. There was a trace of blood in her urine and erythrocytes were seen on urine microscopy, so a renal ultrasound scan was carried out. This did not detect any renal abnormality, but did reveal a 1-cm solitary, mobile gallstone in an otherwise normal, thin-walled gallbladder. A complete ultrasound scan assessment of the liver, biliary tree and pancreas was carried out and no other pathology was identified; in particular, there was no evidence of choledocholithiasis. Following first principles, her doctor first of all revisited her medical history and found no symptoms other than the dysuria and in particular no biliary symptoms. No abnormality was detected on physical examination, in particular no biliary signs. Her liver function tests were normal. Mrs AI was referred to a general surgeon who explained the risks and benefits of a policy of observation and intervention if symptoms developed as opposed to elective intervention by laparoscopic cholecystectomy. The surgeon did not recommend surgical intervention as her gallstones were asymptomatic, there were no bile duct stones and her liver function tests were normal. Mrs AI decided against a cholecystectomy, was advised to avoid fatty meals in the hope of reducing the likelihood of developing biliary colic and was referred back to her general practitioner for ongoing care and observation. This short case summary illustrates the principles of assessment and management of incidentally detected abdominal mass as outlined in the rest of this chapter.

Diagnosis and Management For the purposes of this chapter, an incidentaloma is defined as an abdominal mass unexpectedly detected on abdominal imaging carried out for an

356

unrelated purpose. Abdominal incidentalomas are usually detected on cross-sectional imaging; ultrasound scans (US), computed tomography scans (CT) and magnetic resonance imaging scans (MRI), in decreasing order of frequency. As imaging techniques become more sensitive and readily available, incidentalomas will be discovered more often and will continue to pose diagnostic and management dilemmas. In this chapter, issues around further diagnostic tests and treatment will be discussed in the context of a mass that has been discovered unexpectedly, may not be related to the reasons the index investigation was done and may be minimally symptomatic or asymptomatic. Most patients and their relatives associate the discovery of an incidentaloma with cancer. In fact, the majority of lesions encountered this way are benign, unrelated to the problem that triggered the scan in the first place and are of little or no risk to health. Vigorous investigation of clearly harmless findings is likely to do more harm than good. In most, the diagnosis is immediately apparent. Though some will require further investigations, only a minority will require treatment. Those that do require further investigation or treatment often pose quite complex management challenges and most should be managed in a multidisciplinary setting in which the safest and most effective investigation and treatment plans can be generated and implemented. In women, unexpected pelvic mass lesions are common. However, these are not covered here. Dystrophic calcification (normal serum calcium, abnormal tissue) is a very common incidental finding on abdominal imaging. Dystrophic calcification is often seen in malignancies but is most commonly due to age-related degeneration or inflammation and scarring and will not be treated as an incidental mass in the context of this chapter.

26 Abdominal incidentalomas Abdominal masses that may present as incidental scan findings and discussed in this chapter include gallbladder stones (cholecystolithiasis), gallbladder polyps, stones in the bile ducts (choledocholithiasis), dilated bile ducts (including choledochal cysts), solid and cystic pancreatic masses, solid and cystic liver masses and masses in the retroperitoneum and in the small bowel mesentery.

The investigation plan The investigation of incidentalomas is a twostage process. The first stage is non-invasive and includes a thorough review of the clinical history and examination with particular focus on the organ systems and the most likely disease processes (see Box 26.1). Disease risk factors and symptom patterns may suggest a particular diagnosis or disease process and may help focus the diagnostic plan. A thorough physical examination, including a careful and complete examination outside the system involved looking for signs of primary or secondary involvement elsewhere, may similarly shorten the time to diagnosis. After this review and focusing of the history and clinical examination, a few simple, non-invasive investigational tests will be indicated. These stage 1 investigations are usually non-specific, including an office urine analysis (urinalysis), a full blood count and general biochemical screen (liver function tests, urea, creatinine and electrolytes). More specific investigations should be evidencebased and used selectively as the field of diagnostic possibilities is progressively narrowed. Non-invasive specific disease investigations may include tumour marker and immunological studies Box 26.1  Investigation of an incidental, scan-detected abdominal mass. Stage 1: non-invasive investigations ll

ll

ll

ll

ll

ll

Review history: focus on processes that arise in or affect abdominal organs. Repeat the physical examination with an abdominal focus as for history. Non-specific blood tests: full blood count, biochemistry Specific blood tests: tumour markers, immunological markers and hormone assays Non-invasive imaging to clarify anatomy and function: plain and cross-sectional radiology and ultrasound scans Other non-invasive anatomical or functional scans to clarify relevant anatomy and function.

357

or endocrine assays looking for the evidence of products secreted by the mass. Clarification of anatomical details and differentiation of cystic from solid are crucial imaging issues, but may not have been possible on the original scan due to lesion size, scan quality or scan type and technique. Simple cysts are frequent incidental findings on abdominal imaging, especially in the liver and kidneys, but are also commonly seen in the pancreas and small bowel mesentery and less frequently in the pancreas and adrenals. Ultrasound scanning is adequate for assessment of most simple cysts. CT and ultrasound are often complementary to one another in the phase of non-invasive investigations. Simple cysts rarely require further investigation or treatment. Parasitic cysts, posttraumatic cysts and pseudocysts need careful assessment, although not all will require treatment. All solid or mixed solid and cystic lesions require investigation to exclude neoplasia although only a few will be malignant. Other non-invasive contrast radiology techniques such as barium meal, small bowel series, barium enema, magnetic resonance cholangiopancreatography (MRCP), CT cholangio­ graphy and nuclear scans may also be useful in diagnosing the nature of an incidentally detected abdominal mass, as well as for assessing the degree of functional compromise caused to the organ system involved. These tests should be selected on their relevance to the organ or site implicated in a focused clinical history and physical examination as well as in the original scan that detected the lesion. Though technically non-invasive, they can be expensive, disruptive if not easily and locally available and may still entail some risk if complex preparations such as bowel preparation are required. It will not always be necessary to proceed to the second stage, that of invasive investigations (Box 26.2). The indications for this and the pattern of investigations chosen in stage 2 will depend on Box 26.2  Investigation of an incidental, scan-detected abdominal mass. Stage 2: invasive investigations ll ll ll ll ll

Invasive imaging Endoscopy ± biopsy Laparoscopy ± biopsy Ultrasound- or CT-guided biopsy Imaging requiring complex preparation or physiological risk

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Clinical gastroenterology: a practical problem-based approach

the findings from the non-invasive investigations of stage 1. Invasive or physiologically disruptive diagnostic procedures may include imaging guided biopsies, arteriography, barium enema, endoscopic procedures and associated biopsies or, less frequently, diagnostic laparoscopic or open surgery. All invasive investigations incur some risk, discomfort and expense. The patient must be fully informed about this and must be able to comply with the requirements of the investigation. Hence, a patient who cannot remain still may not be suitable for a percutaneous biopsy. A patient who suffers from claustrophobia may not be suitable for an MRI scan.

Biliary Incidentalomas Asymptomatic gallstones Calcification renders gallstones detectable on x-ray examinations. However, only about 10% of gallstones are calcified, so the detection rate on abdominal x-ray examinations is low. However, the sensitivity and specificity of ultrasound scanning for the detection of stones in the gallbladder (cholelithiasis) is high (over 90%) so the majority of incidentally detected gallstones are found on abdominal ultrasound scans. In this situation, further imaging is not usually required as in this situation ultrasound is the optimal imaging investigation in any case. If the stones are calcified and have been seen on CT scan, again no further investigation will be required. However, if stones are detected on CT but are not clearly seen as they are not calcified, an abdominal ultrasound will usually be required to be certain of the diagnosis. Other non-invasive tests such as liver function tests will not usually be required and invasive tests will similarly not be indicated for asymptomatic gallstones. The question will arise: should a patient with asymptomatic gallstones be referred for surgical management? The answer is: usually not. Most truly asymptomatic gallbladder stones (asymptomatic cholelithiasis) remain asymptomatic. Approximately 10% of patients with asymptomatic cholelithiasis will develop symptoms attributable to their gallstones within 5 years of diagnosis, and approximately 20% by 20 years. The rate of symptom development is maximal in the early years after diagnosis. This then tapers off to 1–2% becoming symptomatic per year. In general, the risks of surgery for asymptomatic gallstones outweigh the benefits, so prophylactic cholecystectomy is not usually recommended.

Though the risk of gallbladder cancer is increased by gallbladder stones, it remains very low and should not be used as a justification for a patient with asymptomatic gallstones to undergo a prophylactic cholecystectomy. If previously asymptomatic gallstones do become symptomatic, cholecystectomy will usually be indicated. Biliary colic is the most common presenting symptom; only 10% of those developing symptoms will present with acute cholecystitis. Many mild cases of cholecystitis probably resolve quickly without a hospital admission. In such cases the stones are then diagnosed after the acute event has settled, allowing elective surgical referral and cholecystectomy. However, those cases of acute cholecystitis that present to a general practitioner or that result in hospital admission are best treated by immediate cholecystectomy. Prophylactic cholecystectomy may be justifiable for gallstones larger than 2.5 cm; the risk of acute cholecystitis may be higher due to a higher risk of gallstone impaction in Hartmann's pouch causing gallbladder outflow obstruction and acute cholecystitis. Prophylactic cholecystectomy may also be justified for diabetic patients with asymptomatic gallstones as acute cholecystitis may be more dangerous in these patients. Other situations where prophylactic cholecystectomy may be justified for asymptomatic gallstones include the very young, haemolytic disease, nonhepatic transplantation and porcelain gallbladder, where chronic infection associated with gallstones has resulted in calcification of the gallbladder wall (Figs 26.1 and 26.2). In all such cases, the clinical decision making should include appropriate specialist advice.

Incidentally detected gallbladder polyps Polyps in the gallbladder are usually asymptomatic and are frequently detected by upper abdominal ultrasound carried out for other reasons. On ultrasound scanning, gallbladder polyps are differentiated from gallstones by their lack of mobility within the gallbladder (as they are attached to the gallbladder wall), and by the lack of acoustic shadowing that is a usual ultrasound scan feature of gallstones. Gallbladder polyps may be non-neoplastic or neoplastic. Non-neoplastic gallbladder polyps are made up of cholesterol and attached to the gallbladder epithelium so they do not move. Neoplastic (or adenomatous) gallbladder polyps arise from the gallbladder epithelium. Most gallbladder polyps are small (less than 1 cm) and most small gallbladder polyps are non-neoplastic. The risk that a polyp

26 Abdominal incidentalomas

359

Figure 26.1  CT scan. Incidentally detected porcelain gallbladder (circled).

Box 26.3  Causes of a dilated bile duct ll ll ll ll ll ll ll ll

ll

Figure 26.2  Plain abdominal x-ray. Porcelain gallbladder.

is an unsuspected gallbladder carcinoma is very low but increases with increasing polyp size. For this reason, polyps greater than 1 cm are generally removed by cholecystectomy. For polyps less than 1 cm the possibility of a small carcinoma is addressed by repeating the ultrasound in 3–6 months. If the lesion is stable the ultrasound is repeated at 12 months. A carcinoma would be expected to increase in size whereas small adenomatous polyps and cholesterol polyps are unlikely to change. Polyps larger than 1 cm or that enlarge should be regarded as suspicious,

Normal variant Choledochal cyst Previous bile duct dilation Previous bile duct injury Post cholecystectomy Unsuspected bile duct stone Sphincter of Oddi stenosis Early carcinoma of the pancreas, bile duct or ampulla Extrinsic compression of the bile duct by a primary or secondary neoplasm

removed by cholecystectomy and submitted for histopathology.

Asymptomatic common bile duct dilatation In normal patients younger than 60 years of age the upper limit of common bile duct size on ultrasound is 6 mm. This limit increases by 1 mm per decade after 60 years of age. The bile duct tends to be a little wider in women and also after cholecystectomy. Other causes of bile duct dilatation are listed in Box 26.3. The likelihood that incidentally detected common bile duct dilation is due to significant pathology and is revealing extrahepatic cholestasis is increased if the liver

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function tests, especially the serum bilirubin and alkaline phosphatase levels, are abnormal, so these are usually performed first. The likelihood of a malignant cause such as pancreatic head carcinoma or cholangiocarcinoma is increased if the tumour marker CA-19-9 is elevated, so this too should be checked in the phase of noninvasive investigations, especially if the serum bilirubin and serum alkaline phosphatase level are raised. When a patient has presented with obstructive jaundice, endoscopic retrograde cholangiopancreatography (ERCP) for definitive diagnosis and relief of the jaundice will be a priority. However, when bile duct dilation has been an incidental finding on a scan one of the noninvasive modalities, usually CT cholangiography or MRCP, will be generally be carried out first to make sure that a subsequent ERCP with its attendant risks is really necessary. ERCP will not usually be indicated if the liver function tests are normal and no mass lesion, stone or stricture is seen on non-invasive imaging of the pancreas and biliary tree. ERCP will usually be required if biliary imaging does reveal significant pathology. Though ERCP is invasive it has the advantage of allowing tissue sampling seeking a definitive diagnosis (brushings for cytology and biopsy for histopathology) and therapeutic interventions to treat cholestasis including clearance of bile duct stones, endoscopic sphincterotomy, dilatation of a benign stricture or placement of a biliary stent to achieve bile drainage past impacted bile duct stones, a malignant stricture or a tight benign stricture.

Asymptomatic choledocholithiasis Asymptomatic choledocholithiasis may be detected incidentally on scans or through investigation of incidentally detected extrahepatic biliary dilation where the stones were not seen on the signal investigation. Common bile duct stones can be difficult to detect on abdominal ultrasound scanning even when the common bile duct is dilated as they may be obscured from detection on ultrasound scan by overlying gas in the duodenum, small bowel or colon. Small stones may do no harm and may pass spontaneously. However, the risks associated with common bile duct stones should not be ignored. The incidence of complications of common bile duct stones is around 20% over 5 years, including serious problems such as obstructive jaundice, cholangitis and acute pancreatitis. Consequently, removal of stones in the common

bile duct is generally recommended even if they are asymptomatic. Where it is available, ERCP with endoscopic sphincterotomy and endoscopic stone extraction is the most common treatment for common bile duct stones that do not pass spontaneously (Fig 26.3). If ERCP is not available the duct is usually cleared by laparoscopic or open surgery. If the gallbladder is still present it is usually removed at the same operation. Thus, if ERCP is not readily available or, in patients not needing urgent clearance of the bile duct, a two-stage treatment (ERCP and subsequent surgical removal of the gallbladder) can on occasion be condensed into a single phase treatment by omitting the ERCP and utilising a single surgical procedure to remove the gallbladder and clear the bile duct, usually laparoscopically.

Choledochal cysts Choledochal cysts are most commonly congenital and most commonly present with cholestasis during infancy. However, 20% present in adulthood, frequently as incidental scan findings in individuals with no biliary symptoms. Women are more commonly affected than men (80%; 4:1 female/male ratio). The development of some choledochal cysts may be explained by anomalous union of the common bile duct and pancreatic duct during embryogenesis. The resulting anatomy allows mixing of pancreatic juice and bile within the bile ducts. Exposure of the pancreatic exocrine proenzymes to bile activates the pancreatic digestive enzymes within the bile ducts, perhaps in turn leading to weakening and dilation of the duct and inducing epithelial changes predisposing to bile duct cancer (cholangiocarcinoma). Choledochal cysts may occur anywhere in the biliary tree. They may be focal or diffuse, single or multiple. They are classified on the number of cysts present and on their position in the intraor extrahepatic biliary tree (Table 26.1). Though not primarily caused by bile duct obstruction or by strictures, tumours or stones, all these problems may develop in association with them and may in turn lead to complications such as cholestasis (obstructive jaundice), infection in the biliary tree (cholangitis), impaired hepatic function (liver failure), hepatocellular loss and hepatic fibrosis (cirrhosis) and bile duct cancer (cholangiocarcinoma). The discovery of intrahepatic or extrahepatic bile duct dilation consistent with choledochal cysts necessitates further investigation, initially by assessment of liver function and by MRCP

26 Abdominal incidentalomas

361

Table 26.1  Todani classification of choledochal cysts Site of cyst

Classification

ERCP findings

Extrahepatic

I

Solitary fusiform cyst

II

Supraduodenal diverticulum

III

Intraduodenal diverticulum (choledochocoele)

IVB

Multiple extrahepatic cysts

Extrahepatic and intrahepatic

IVA

Extra and intrahepatic cysts

Intrahepatic

V

Multiple intrahepatic cysts (Caroli's disease)

ERCP = endoscopic retrograde cholangiopancreatography.

or CT cholangiography. Masses associated with choledochal cysts anywhere in the biliary tree may be due to cholangiocarcinoma and should be assumed to be so until proven otherwise. Extrahepatic choledochal cysts usually require excision of the extrahepatic ducts and reconstruction for biliary drainage with a choledochoenterostomy (anastomosis of the end of the remaining bile ducts to a loop of jejunum). Multiple intrahepatic cysts may not be amenable to surgery and are usually treated with endoscopic or percutaneous tubes (stents) in the bile ducts if biliary drainage is impaired. In such cases the cycle of chronic biliary obstruction and recurrent biliary sepsis may lead to liver failure and necessitate hepatic transplantation.

Pancreatic Incidentalomas

Figure 26.3  ERCP demonstrating stones in the bile duct. These had been difficult to see on ultrasound scan due to overlying bowel gas.

Unexpected imaging detected masses in the pancreas may be cystic or solid and may be derived from stromal, exocrine or endocrine elements of the pancreas. Lymph glands lying in or adjacent to the pancreas may also be responsible for incidentally detected asymptomatic pancreatic masses. As with incidentalomas elsewhere, the first step in noninvasive investigation of pancreatic incidentalomas is always to revisit the clinical history and examination. A past history of epigastric pain may correspond to a previous episode of pancreatitis. Epigastric pain associated with back pain may be consistent with pancreatic cancer, as would

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Clinical gastroenterology: a practical problem-based approach

a history of nausea or weight loss. A palpable epigastric mass is possible and should be looked for but is unlikely unless a pancreatic lesion is very large. An enlarged supraclavicular lymph node, an umbilical nodule or a hepatic mass may betray previously unsuspected metastatic disease. Managing pancreatic masses usually requires referral to a specialist multidisciplinary pancreatic unit. The first step in non-invasive imaging of unexpected pancreatic masses is to differentiate cystic from solid. This is most simply done with ultrasound scanning. However, CT and MRI scans are often needed, especially if a mixed cystic and solid mass is suspected. If invasive investigations are indicated, endoscopic ultrasound scanning is very useful to differentiate a simple cyst from a complex cyst and to achieve cyst fluid aspiration for cytology, biochemistry and tumour marker levels or to achieve a tissue diagnosis by fine needle aspiration biopsy and cytology.

Focal pancreatitis Focal pancreatitis can result in incidentally detected solid pancreatic masses which on closer investigation are often associated with previous symptoms that were not recognised as caused by pancreatitis. Some of these focal pancreatitis lesions will settle during investigation but they may persist for a long time and their true nature can be very difficult to sort out. Endoscopic ultrasound scanning and needle aspiration cytology may resolve the issue. Rarely, autoimmune pancreatitis will present clinically as a focal pancreatic mass in which case serum IgG4 levels may be elevated. Pancreatic resection may be considered on a working diagnosis of pancreatic cancer. But surgery for focal pancreatitis of any sort should be avoided and pancreatic cancer should, if possible, be excluded non-surgically. The services of a specialised multidisciplinary pancreatic service should be enlisted.

Pancreatic cysts Most asymptomatic cystic lesions of the pancreas are simple cysts. Simple cysts of the pancreas are usually unilocular, lined by simple one-layered epithelium and contain serous fluid. They do not enlarge and do not become malignant or cause complications and they require no treatment. The difficulty is establishing a firm diagnosis of simple cyst while excluding the possibility of a cystic neoplasm or a pseudocyst. Endoscopic ultrasound scanning may provide more detailed images and facilitate needle aspiration of the cyst fluid. Simple cysts will contain fluid with cytologically

benign cells and low levels of carcinoembryonic antigen and CA 19-9. Mucinous cystadenoma fluid may show cytologically atypical cells and elevated tumour marker levels. Amylase and lipase levels will be high in fluid from pancreatic pseudocysts, but they have no epithelial lining so no epithelial cells should be seen on cytology from pancreatic pseudocyst fluid. Most incidentally detected pancreatic pseudocysts are small (less than 5 cm) and uncomplicated. These usually resolve and, although continued observation with follow-up scans may be warranted until resolution is demonstrated, very few require any intervention. Large pseudocysts are rarely incidental findings. Spontaneous resolution becomes less reliable as pseudocysts become larger than 5 cm and is unlikely to occur for pseudocysts over 10 cm. Accordingly, larger pseudocysts will usually require drainage. Endoscopic, percutaneous and laparoscopic or open surgical techniques can be used for this. Selection of a pseudocyst drainage technique should be individualised for each case and specialist advice should always be sought. Hydatid disease can involve the pancreas and cause cysts just as it does in the liver. Hydatid disease in the pancreas is a marker of disease dissemination and while it may be an unexpected finding in the context of a particular case of hydatid disease, it is rarely a truly incidental finding. The radiological features are curved plates of calcification in cyst walls and grape-like daughter cysts within large cysts.

Cystic neoplasms of the pancreas These are usually multilocular and commonly have solid elements or irregular thickening of their walls. They are often asymptomatic and so are liable to present as incidental imaging findings. The most common pancreatic cystic neoplasms are serous cystadenoma and mucinous cystadenoma. Less common mixed solid and cystic pancreatic neoplasms include microcystic adenomas and papillary and cystic tumours (Ch 17). Though it may be difficult, distinguishing between these neoplastic lesions is important as they have quite different malignancy risks. If a lesion can be demonstrated to be a serous cystadenoma by detection of tiny flecks of calcium in the cysts wall on CT or MRI scanning and on endoscopic ultrasound suggestive cytology features and elevated cyst fluid tumour marker levels, then no treatment is required as pancreatic serous cystadenomas are benign with no malignant potential. Conversely, if the lesion

26 Abdominal incidentalomas

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Table 26.2 Endocrine tumours of the pancreas Type

Clinical features

Hormone secreted

Malignancy rate (%)

Gastrinoma

Dyspepsia (Ch 5) Diarrhoea

Gastrin

60–90

VlPoma

Diarrhoea Flushing Weight loss

VIP

> 60

Glucagonoma

Diarrhoea Dermatitis (necrolytic migratory erythema) Diabetes mellitus Weight loss

Glucagon

50–80

Somatostatinoma

Diarrhoea

Somatostatin

> 70

Insulinoma

Symptoms of hypoglycaemia: fasting confusion, irritability, weakness, palpitations, sweating

Insulin

< 10

VIP = vasoactive intestinal polypeptide.

is a mucinous cystadenoma and the patient is fit, resection should be considered as some of these are malignant (cystadenocarcinoma) even though they may look histologically benign on biopsy. Pancreatic cystadenocarcinoma carries a much higher chance of cure than does the more common pancreatic adenocarcinoma, especially if detected early and resected completely (see Ch 17).

Pancreatic adenocarcinoma By far the most common malignant pancreatic neoplasms are adenocarcinomas derived from the exocrine pancreas. They can occur anywhere in the pancreas, but those that develop in the head of the gland are rarely detected at an asymptomatic stage as they tend to involve the bile duct and cause obstructive jaundice. Cancers of the body and tail of the pancreas are well away from the bile duct and are more likely to be detected incidentally on abdominal scans where they are usually seen as solid or mixed cystic and solid masses. It can sometimes be difficult to differentiate pancreatic cancer from lymphoma, focal pancreatitis or rarely, focal autoimmune pancreatitis. Lymphoma can usually be identified on a biopsy and autoimmune pancreatitis by presence of elevated serum IgG4 levels. Focal pancreatitis may resolve during investigation or observation, but can persist for quite long periods and can result in misguided resection for what was thought to be pancreatic cancer. Lymphoma and autoimmune pancreatitis are treated by nonsurgical means. If possible, pancreatic masses should be biopsied by endoscopic or endoscopic

ultrasound scanning guided routes if there is any diagnostic doubt. Cure rates for pancreatic adenocarcinoma are dismal, but perhaps the best chance of cure will be for the occasional small, asymptomatic, incidentally detected case. All such cases should be referred promptly for specialist evaluation. Most will require some form of invasive investigation to secure the diagnosis, most commonly endoscopic ultrasound scanning and ERCP. Those that are malignant will also require staging investigations before pancreatic resection is considered (see Ch 17).

Endocrine pancreatic neoplasms Endocrine neoplasms of the pancreas may be functional (secretory) or non-functional (nonsecretory). Functional endocrine tumours of the pancreas usually present with symptoms caused by an excess of the secreted hormone and are rarely incidental. Non-functional endocrine neoplasms of the pancreas are more prone to be detected as incidental findings (incidentalomas) on intravenous contrast CT scans (Table 26.2) where they appear as small, well-vascularised, mass lesions (Fig 26.4). In general, endocrine neoplasms of the pancreas grow very slowly or not at all and, as with lymph nodes, investigation and management can be problematic as their true nature can be very difficult to determine with certainty. Transgastric endoscopic ultrasound scanning may help clarify the diagnosis, especially if endoscopic ultrasound scanning guided fine needle aspiration biopsy and cytology can be carried out (see Ch 17).

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Figure 26.4  CT scan. Incidentally detected vascular pancreatic tail mass. Initial diagnosis: pancreatic neurendocrine tumour. Lesion is isodense with spleen. Final diagnosis: splenunculus.

Hepatic Incidentalomas As with the pancreas, incidentally found masses of the liver may be due to congenital or acquired causes and may be cystic, solid or mixed cystic and solid. They may be non-neoplastic or neoplastic. Neoplastic hepatic incidentalomas may be benign or malignant and the malignant lesions may arise in the liver (primary hepatocellular carcinoma) or they may be metastatic from an extrahepatic primary site.

Cystic hepatic incidentalomas Hepatic cysts are frequent incidental findings on abdominal cross-sectional imaging (ultrasound and CT). The great majority are non-neoplastic. Most are simple cysts requiring no further investigation or treatment unless they are symptomatic or there is diagnostic doubt.

Simple hepatic cysts Simple hepatic cysts are more common in women than men, are lined by thin, smooth, epithelium and contain serous fluid. They do not connect with the biliary tree and they vary in size, ranging from only just detectable on scan (5 mm) to greater than 20 cm and palpable. These rarely require treatment although very large cysts may be symptomatic (abdominal discomfort or pain) and very occasionally they may cause abnormal liver function tests or even obstructive jaundice

Figure 26.5  Abdominal CT. Incidentally detected simple hepatic cysts.

by compression of the bile duct. Simple cysts may be multiple, but this finding should raise the possibility of polycystic liver disease (Fig 25.5). Polycystic liver disease If the problem is true hepatic polycystic disease, there may be many, many cysts replacing most of the liver. An autosomal-dominant inherited disease, polycystic liver disease causes multiple hepatic cysts. Full expression of the defect also results in associated polycystic renal disease. Hepatic polycystic disease may cause enormous hepatomegaly, pain, jaundice and impaired liver function. Abdominal ultrasound scanning is the usual diagnostic tool. Needle biopsy is rarely indicated and should be utilised only in the context of a specialist, multidisciplinary unit.

Hepatic hydatid cysts Viable (containing live hydatids) or non-viable (dead) hydatid cysts may be encountered as incidental scan findings, particularly in people from hydatid disease endemic rural areas. A history of contact with sheep and dogs is common, especially in a rural setting during childhood, and may not be clearly remembered. Plate-like or curvilinear calcification cyst wall calcification may be clearly visible on plain abdominal x-rays or CT scans of hepatic hydatid cysts. Dead hydatid cysts tend to calcify and to collapse and may then show up on scans or on plain x-rays as amorphous, coarse, heavily calcified

26 Abdominal incidentalomas

Figure 26.6  Photograph taken during an operation on an hepatic hydatid cyst. Large liver hydatid cyst open to show daughter cysts within it. Hydatid daughter cysts cause the circular shadows seen within larger hydatid cysts on US and CT scans (see Fig 26.7).

lesions with little or no residual cystic component. Provided other potentially viable hydatid cysts are excluded on the abdominal scan and chest x-ray examination, further diagnostic investigations are not usually required and calcified, non-viable hydatid cysts rarely require treatment. Viable hydatid cysts show no calcification or incomplete calcification and non-uniform internal density due to daughter cysts or hydatid debris within the main cyst (Figs 26.6 and 26.7). Potentially viable hydatid cysts require careful investigation, even if they are truly asymptomatic, because of the risk of rupture into the peritoneal cavity. Hepatic hydatid disease must always be excluded before needling of hepatic cysts is considered as this procedure may result in leakage of hydatid cyst fluid containing viable hydatid protoscolices and cause intraperitoneal dissemination of the disease. Leakage of hydatid fluid into the peritoneal cavity may also cause acute hypersensitivity reactions. Hydatid serology may be positive in the presence of a non-viable cyst and is occasionally negative in the presence of a viable cyst. However, a positive test is a useful way of confirming that a patient has had hydatid disease at some time, but is not diagnostic of active hydatidosis. Potentially viable hydatid cysts that are completely intrahepatic may safely be kept under observation after treatment with an antihelminthic agent such as albendazole. Cysts that discharge into the biliary tree may present with jaundice and are usually treated by endoscopic drainage to clear the bile duct. Further invasive treatment is not usually needed in these cases as bile contamination of the cysts kills the organisms, rendering the residual hepatic hydatid cyst non-viable. Cysts that are large

365

Figure 26.7  Abdominal ultrasound scan. Daughter cysts in a large hepatic hydatic cyst.

involve the surface of the liver, become infected, are associated with compromise of liver function or are symptomatic usually do need treatment. This is usually surgical evacuation of the cyst plus an antihelminthic agent given before and after surgery to reduce the risk of postsurgical recurrence. See Table 26.3 for treatment of hepatic hydatid cysts.

Neoplastic hepatic cysts Hepatic cystadenoma and their malignant form, hepatic cystadenocarcinoma, tend to be asymptomatic until quite large and so some will be detected incidentally on abdominal imaging. Surgical resection of hepatic cystadenomas, with clear resection margins achieved, should be curative. The hepatic cystadenocarcinoma is one of the few forms of hepatic malignancy with strong potential for cure if completely resected. Accordingly, though both these lesions are very uncommon, any patients in whom mixed cystic and solid hepatic cysts are detected require referral to a multidisciplinary specialist hepatic unit. The same advice applies to any other incidentally hepatic lesion in which there is diagnostic doubt or where invasive investigations or treatment modalities are required.

Solid hepatic incidentalomas Solid hepatic lesions are more likely to be malignant than are cystic hepatic lesions. However, approximately 75% of solid liver lesions presenting as incidentalomas will be benign and the majority will also be non-neoplastic. The chance of a solid hepatic lesion being malignant does increase with age (especially over 55 years), if the lesion is palpable, if the liver function tests are abnormal and if known risk factors for primary or metastatic liver disease are present (Fig 26.8). These factors should be taken into consideration in

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Clinical gastroenterology: a practical problem-based approach

Table 26.3 Treatment of hepatic hydatid cysts Management phases Disease presentation

Management approach

Ruptured into bile duct. Obstructive jaundice

ERCP Sphincterotomy

Heavily calcified. Non-viable

No therapy

Small, intrahepatic, uncomplicated

No invasive therapy

Albendazole

Yearly ultrasound

Most eventually calcify and become non-viable

Symptomatic Large

Combination therapy

Pre- and postoperative albendazole

Surgical evacuation

Monitor for recurrence

1

2

3

Albendazole

Surgery not usually needed

Bile in cyst kills organisms

No follow-up imaging needed

Liver mass detected Review scan details carefully

Review history and examination

No diagnostic findings outside liver SOLID

CYSTIC

Liver function tests Hepatitis B & C serology Tumour markers (AFP, CEA)

All normal/ negative + Haemangioma on labelled red cell scan or triple phase CT Reassure No treatment

Abormal/ or Scan not c/w haemangioma

CXR normal

Small (< 5 cm)

Large (> 5 cm)

Single smooth, thin wall fluid density

Single/multiple layered walls septations internal cysts cyst floor sediment partially calcified

Simple cyst

Positive hydatid serology

Reassure No treatment

Refer to surgeon for treatment of hydatid cyst

Densely calcified Minimal/nil cyst left

Dead hydatid Reassure No treatment

Specialist referral to exclude malignancy

Figure 26.8  Investigation of the incidental, scan-detected space-occupying lesion in the liver. AFP = α fetoprotein, CEA = carcino embryonic antigen; c/w = consistent with; CXR = chest x-ray; CT = computed tomography.

26 Abdominal incidentalomas assessing the risks associated with any particular solid hepatic incidentaloma. Hepatic haemangioma Most solid hepatic incidentalomas are haemangiomas. These are not neoplasms and, unless large and involving the surface of the liver, are usually asymptomatic. Large haemangiomas can thrombose, causing episodes of upper abdominal discomfort. Spontaneous rupture of hepatic haemangiomas or rupture of them due to external violence is rare. Most instances of bleeding from hepatic haemangiomas have been iatrogenic, resulting from ill-advised attempts at needle biopsy. On ultrasound scanning, haemangiomas are usually very echogenic. This may not show clearly in small lesions (smaller than 2 cm). This reduces the diagnostic sensitivity and specificity of ultrasound scanning for small hepatic haemangiomas. Large haemangiomas (greater than 4 cm) often show quite variable, non-diagnostic echo patterns on ultrasound, perhaps due to the thrombosis and fibrosis that tends to occur in them as they enlarge. Radiolabelled red cell scanning is diagnostic in most cases, though lesions smaller than 2 cm may be too small to resolve, and those that are partly calcified or in which thrombosis has occurred may give equivocal results. Triple phase, dynamic CT or contrast enhanced MRI may then be diagnostic, showing slow filling of the lesion from its periphery followed by retention of contrast within it. Angiography is no longer indicated for diagnosing hepatic haemangiomas. Fibronodular hyperplasia Another benign solid lesion of the liver is fibronodular hyperplasia. This may not be neoplastic, has no malignant potential and can safely be observed provided the diagnosis is made with confidence. However, achieving sufficient certainty to safely advise observation rather than intervention can be difficult as the imaging diagnosis is not always certain and there are no non-imaging tumour markers associated with the lesion. Good quality dynamic intravenous contrast CT scanning or MRI scanning with contrast may reveal features characteristic of fibronodular hyperplasia including a solid and homogeneous tumour except for a central scar with radiating prongs, a central feeding vessel and a delayed vascular blush in the rest of the mass after filling of the central feeding vessel. This appearance must be distinguished from that of the fibrolamellar variant of hepatocellular carcinoma. A percutaneous or

367

a laparoscopic liver biopsy may be required to confirm that the lesion is fibronodular hyperplasia, but this is not usually indicated, should be used only within the context of a multidisciplinary group and should not be done at all until the situation has been discussed with a liver surgeon. Hepatic adenoma and hepatocellular carcinoma Formerly called ‘pill adenoma’ because of an association with prolonged oral contraceptive use, hepatic adenomas are also uncommon, often asymptomatic and are subject to incidental discovery on abdominal scanning. Like fibronodular hyperplasia, these are also solid but are more uniformly vascular and homogeneous in appearance on cross-sectional imaging as they lack the central feeding vessels and the central scar that are characteristic of fibronodular hyperplasia. The absence of a central scar or dominant central feeding vessel should swing the diagnosis more towards hepatic adenoma than fibronodular hyperplasia. Surgical excision of hepatic adenomas is usually recommended as they are prone to rupture and bleeding (spontaneously or after minimal trauma), they may become malignant, and they may be very difficult to differentiate from primary hepatic cancer (hepatocellular carcinoma). Percutaneous biopsy of suspected hepatic adenomas should be avoided, because the histological picture can be very hard for the pathologist to interpret, the diagnosis may remain indeterminate and bleeding or iatrogenic tumour rupture may result. If the tumour is actually hepatocellular carcinoma, spillage of tumour into the peritoneal cavity or along the biopsy track may complicate subsequent surgery and may compromise the chances for cure. Hepatocellular carcinoma may not have been suspected in the absence of satellite lesions on the CT scan and lack of identifiable hepatocellular carcinoma risk factors such as intravenous drug use, hepatitis B or C history or positive serology, haemochromatosis, chronic liver disease and cirrhosis. Alpha-fetoprotein, the usual tumour marker used in the diagnosis of hepatocellular carcinoma, may also be misleadingly low in non-viral hepatocellular carcinoma. Hepatic metastases Solid hepatic incidentalomas identified on scanning may not be primary liver lesions at all. They may be metastases acting as the diagnostic clue for a primary malignancy elsewhere. This should be suspected in all cases of solid hepatic incidentaloma and the finding of one or more solid hepatic incidentalomas mandates exclusion of this

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Clinical gastroenterology: a practical problem-based approach

possibility. Multiple solid lesions are more likely to be malignant than benign and are more likely to be metastases than primary liver tumours. A careful history and physical examination are required. Physical examination should include the skin (for melanoma), breasts, lungs, lymph nodes (especially supraclavicular nodes), genitals, anus and

Figure 26.9  Abdominal CT scan. Fifty-five-yearold patient. Initial investigation for vascular disease. Unexpected right hepatic mass. Elevated CEA. Final diagnosis colonic adenocarcinoma.

rectum as well as the abdomen for other abdominal masses. A chest x-ray examination should be carried out looking for a lung primary or pulmonary metastases. Upper and lower gastrointestinal tract endoscopy should be considered, particularly if the serum carcinoembryonic antigen level is elevated, looking for stomach or colon cancer (Fig 26.9). If a lesion can be found outside the liver, the diagnostic problem may be more simply and safely solved by biopsy of that lesion than of the liver lesion. Summary of solid hepatic incidentalomas Hepatic haemangiomas are common, generally harmless and asymptomatic, rarely require treatment and should not be biopsied. The majority of solid lesions remaining after hepatic haemangioma has been excluded are also benign. However, all must be regarded as possibly malignant, particularly in older people, when the liver or a liver mass is palpable, when liver function is disturbed, when there is a history of hepatitis B or C or when metastatic disease is possible. The index of suspicion of a malignant mass rises according to the number of risk factors present (Fig 26.10). Clinical, biochemical and imaging characteristics are useful in assessing the risk of malignancy, but none of these can reliably distinguish benign from malignant neoplasms in the liver. The final diagnosis is usually made on a combination of findings, but may depend on histopathology, either from a biopsy or on excision of the whole lesion. Biopsy

RISK FACTORS: Age > 55 years Palpable liver and/or Hepatomegaly Raised serum alkaline phosphatase

No. risk factors for malignancy present

Risk that the mass is malignant

Nil

Unlikely

1

Low

2

Moderate

3

High

Figure 26.10  Solid hepatic mass detected: indicators of malignancy. Used as a simple screen, these factors allow a reasonable assessment of the likelihood that an incidentally detected, solid hepatic mass is malignant. The more positive risk factors identified, the higher the likelihood that the mass is malignant.

26 Abdominal incidentalomas should not be undertaken without prior surgical consultation.

Hepatic fat deposition and rare tumours Focal irregularities in distribution of fat (focal excess or absence) detected within the liver on ultrasound or CT scanning can give the appearance of a mass lesion (in this context, a hepatic incidentaloma). Focal fat deposition is most commonly seen in segment four of the liver, adjacent to the ligamentum teres. This characteristic location and other radiological characteristics mean that most focal fat deposits in the liver are recognised as such by the radiologist. Rare liver lesions which may be asymptomatic and detected unexpectedly include teratomas, large biliary adenomas and myxomas. The imaging findings are unlikely to be conclusively diagnostic and will usually mandate other investigations for which referral to a multidisciplinary hepatic unit will be required.

Radioactive pharmaceutical imaging in the investigation of hepatic masses Radionuclide scans exploit the capacity of certain tissues to selectively concentrate a radioactive labelled tracer. However, these tests are often not specifically diagnostic and the information gathered is usually functional rather than anatomical. The need for precise anatomical and diagnostic information in the detection and anatomical assessment of abdominal masses has led to a decline in the use of radioisotope scanning in favour of cross-sectional imaging (ultrasound, CT and MRI) to detect liver masses and to characterise them anatomically. However, the ability of some radionuclide scans to reveal the functional characteristics of an abdominal mass or to exploit specific functional characteristics (such as glucose avidity) to reveal the presence of anatomically undetectable masses is still useful in characterising some hepatic masses, in staging some malignancies that have presented as hepatic masses or that have a propensity to spread to the liver, for assessing treatment responses and in surveillance for post-treatment recurrences. Liver/spleen scan This scan may be useful in characterising hepatic adenomas. The radiopharmaceutical is bound to a colloid. The colloid facilitates uptake by hepatic reticuloendothelial (Kupffer) cells to give an outline of the whole of the liver. This whole-organ affinity for the colloid carrying the radioactive marker can then be used to delineate masses that

369

do not contain Kupffer cells. Such masses (e.g. colon carcinoma metastases) will then appear on the scan as ‘cold’ or ‘photopaenic’ areas in the liver scan. Liver cell adenomas lack Kuppfer cells and so also tend to be photopaenic. Labelled red cell scan This scan is particularly useful in the diagnosis of hepatic haemangiomas. Venous blood is drawn from the patient and mixed with a radioactive marker that attaches to the red cells. The blood, now tagged with the radioactive marker, is then injected back into the patient and the patient is scanned. Haemangiomas typically show progressive accumulation of radiolabelled red blood cells. This causes slowly evolving focal ‘hot’ spots on the labelled red cell scan consistent with slow venous flow into a haemangioma, into the periphery of the lesion first, then to the centre of the lesion. Biliary scan Usually named according to the tracer used (HIDA or DisHIDA), this scan is occasionally requested for diagnosing cystic duct obstruction (especially suspected acute cholecystitis), checking flow of bile out of the liver through a bilioenteric anastomosis or stent and in characterising focal nodular hyperplasia. The injected contrast agent is taken up by hepatocytes and is then rapidly excreted from the hepatocyte into the bile duct radicals and transported out of the liver in the bile ducts to be discharged from the common bile duct into the duodenum. Biliary scanning is still occasionally useful in assessing patency of the cystic duct to help establish a diagnosis of acute cholecystitis and to demonstrate non-function of the gallbladder due to chronic cholecystitis (gallbladder fibrosis). In the normal biliary tree, in the fasting state, the sphincter of Oddi will be closed and bile will be diverted into the gallbladder where water will be reabsorbed across the gallbladder mucosa to concentrate the gallbladder bile. If the cystic duct is obstructed by a gallbladder stone (as in acute cholecystitis) or if the gallbladder is scarred and contracted due to fibrosis from previous cholecystitis, bile will not enter the gallbladder and the gallbladder will not appear on the scan. If a stent in the bile duct has become obstructed, the tracer will accumulate in the liver and in the biliary tree above the stent, but will not appear in the duodenum or will be very slow to do so. Biliary scanning can also be useful in characterising liver masses when the diagnosis remains unclear after cross-sectional imaging,

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Clinical gastroenterology: a practical problem-based approach

liver-spleen scanning and labelled red cell scanning. Masses caused by fibronodular hyperplasia contain functioning hepatocytes, but have few biliary drainage radicals. Fibronodular hyperplasia will therefore tend to take up and hold a radiolabelled tracer excreted into the bile. Therefore, fibronodular hyperplasia will initially appear isodense with the rest of the liver. But, due to its deficiency of biliary drainage radicals, fibronodular hyperplasia will hold the tracer and therefore appear as a delayed hot spot on the biliary scan after the normal liver has cleared the radiolabelled tracer into the biliary tree. Positron emission tomographic scan The positron emission tomographic scan (PET) is not specifically a liver mass scan. The bio-window exploited in this scan is the high glucose uptake and metabolism exhibited by some malignancies. A glucose analogue radiopharmaceutical will accumulate in the glucose pathway, and tissues utilising this pathway more than surrounding tissues do will stand out as hot spots on the scan. This is particularly useful for staging some malignancies, for confirming that a mass is malignant, for assessing treatment results and for surveillance for post-treatment recurrence. Other radionuclide scans for liver masses Gallium scans can highlight lymphoma, metastatic melanoma, hepatoma and inflammatory collections. However, as gallium is also taken up by normal liver parenchyma it is of limited value in assessing liver masses. Scanning for neurendocrine tumours (e.g. carcinoid) can be more specific and can be useful for characterising the primary tumours and their liver metastases by utilising 111-indium pentetreotide (octreotide) as the scanning tracer or indicator. Other radionuclide scans for other abdominal masses A number of racers are available for specific circumstances but are uncommonly used as initial investigations. These include radioiodine-labelled MIBG (iodine-131-meta-iodobenzylguanidine) for phaeochromocytoma and paraganglioma and labelled white cell scans for inflammatory bowel disease and inflammatory collections.

Invasive diagnostic procedures in the diagnosis of hepatic masses The highest order diagnosis possible should be sought for potentially treatable lesions in patients likely to be able to tolerate and benefit from

treatment. Achieving a confident diagnosis may require invasive investigations. The risks of these must be outweighed by the potential benefits. Invasive investigations require fully informed consent by the patient and family and should be undertaken only with appropriate specialist advice as part of an overall management plan. Such investigations include: ll endoscopy: this is of particular value when the hepatic lesion is thought to be a metastasis from an upper or lower gastrointestinal tract primary cancer; ll endoscopic ultrasound of the pancreas: this may be appropriate if a liver lesion is thought to be a pancreatic metastasis. Pancreatic cancer with hepatic or other visceral metastatic spread is incurable, treatment intent is palliative and surgical intervention is usually contraindicated; ll biopsy: finalising the diagnosis and treatment plan often requires biopsy for cytopathology or histopathology. Even though the procedural risks are generally low, biopsy of a liver mass by any method will always entail some risk. Risks include bleeding from vascular lesions, tumour rupture and spread by seeding of tumour along a biopsy track or into the peritoneal cavity. Needle biopsy of liver masses should be avoided if the lesion is cystic, if there is any likelihood that the tumour might be malignant and amenable to potentially curative surgical excision, might be vascular and prone to bleeding and/or rupture or the patient has comorbidity likely to be associated with bleeding. Surgical excision biopsy should be considered for liver adenomas, some hepatomas and some liver metastases. Liver biopsy should not be undertaken until these possibilities have been considered. This will usually require a multidisciplinary approach including surgical consultation; ll angiography: selective cannulation of the coeliac or superior mesenteric arteries is only occasionally required. Modern cross-sectional imaging yields high quality images of liver lesions. All the information required for clinical decision making should be available from the arterial and portal venous phases of triple-phase CT scans; ll laparoscopy: this is occasionally useful when the imaging diagnosis remains uncertain. Direct visualisation of the liver mass may help clarify this or permit safer biopsy than by the percutaneous route.

26 Abdominal incidentalomas

Figure 26.11  Retroperitoneal mass (circle). CT taken at time of needle biopsy. Histopathology diagnosis lymphoma.

Retroperitoneal Masses Tissues of origin for retroperitoneal incidentalomas may include lymph nodes, mesenchyme and nerves of the sympathetic chain or of the somatic neural network.

Lymph node masses Retroperitoneal lymphadenopathy may be reactive (inflammatory) or neoplastic (malignant). Reactive lymphadenopathy is usually a response to inflammation somewhere in the draining field of that lymph node but can also be part of a diffuse inflammatory response. Reactive nodal enlargement is usually modest, non-progressive and temporary. Malignant retroperitoneal lymphadenopathy tends to be progressive and may be quite bulky, particularly when due to malignant lymphoma (Fig 26.11). Lymphadenopathy due to metastatic carcinoma is usually slowly but inexorably progressive whereas that due to lymphoma may fluctuate, particularly early in the course of the disease. Close questioning of lymphoma patients may uncover systemic symptoms (e.g. fever, rash, pruritus) and careful examination may detect enlarged lymph nodes in the groin, axilla or neck. In patients with metastatic skin cancer (squamous cell carcinoma or melanoma), there may be a history of a mole or lump, which may have been ignored, may have regressed or may have been previously removed. Some of the more common visceral primary sites leading to unexpected retroperitoneal

371

masses (usually nodal) include the colon, stomach, pancreas and testis. There may be previously unrecognised or undetected symptoms arising from the nodal mass or from the primary lesion, or there may be signs in the organ draining to the site. There may also be non-specific symptoms consistent with malignancy, such as lethargy or weight loss. Metastatic carcinoma in retroperitoneal nodes denotes disseminated disease that usually cannot be cured by surgery. The aim here should be to carry out and to take into consideration the findings from all investigations that may advance the diagnosis and development of the treatment plan, but to avoid unhelpful investigations and inappropriate or misguided treatments that could be instituted on the basis of inadequate or inappropriate investigations. Other simple investigations such as a tumour marker screen and a chest x-ray may help characterise and stage the disease, but will not be specifically diagnostic (see Ch 15). Definitive diagnosis is generally based on histopathology, established by biopsy of a metastasis or of the primary tumour and treatment is generally non-surgical. An unexpected abdominal mass in lymph nodes may be associated with blood count changes. These may be consistent with infection or a lymphoproliferative disease so the initial, noninvasive phase of investigations should include a full blood count, erythrocyte sedimentation rate and a chest x-ray.

Benign mesenchymal tumours Benign mesenchymal tumours, such as lipomas, are slow-growing and are often asymptomatic, sometimes in spite of considerable bulk. However, all must be suspected of being malignant (sarcoma). Most retroperitoneal tumours are silent until they become large enough to be palpable or to produce local symptoms by their bulk or until they metastasise and cause a symptom or mass leading to their detection elsewhere.

Extraadrenal endocrine tumours These can be functional or non-functional and should be particularly thought of for those retroperitoneal incidentalomas that are close to the kidney. A family history of an endocrine neoplasm, a past history of hypertension and symptoms such as episodic palpitations (e.g. phaeochromocytoma) or flushing and diarrhoea (e.g. carcinoid) should also arouse suspicion of an endocrine neoplasm. If an endocrine tumour is a possibility (Fig 26.12), a search for other endocrine tumours (multiple endocrine neoplasia; Box 26.4) should also be undertaken, particularly

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Clinical gastroenterology: a practical problem-based approach Table 26.4  Unexpected retroperitoneal mass: basic diagnostic possibilities

Figure 26.12  CAT scan. Unexpected right adrenal mass: carcinoma. Box 26.4  Multiple endocrine neoplasia (MEN) All these syndromes are autosomal-dominant. Men I Hyperplasia, adenoma or carcinoma of: ll parathyroid; ll pituitary; ll pancreatic islets (adrenal cortex and thyroid may also be involved). Men II ll Parathyroid ll Medullary carcinoma of thyroid ll Phaeochromocytoma (frequently bilateral) Men III Features of MEN II and dysmorphic features: ll neuromas on conjunctiva, tongue, buccal mucosa; ll marfanoid habitus; ll pigmentation.

in the thyroid, parathyroid and adrenal glands (see Table 25.4). Invasive investigations must be avoided until the secretory status of the tumour has been ascertained.

Biopsy of retroperitoneal incidentalomas Biopsy should be approached with caution and specialist advice should be sought first. If the lesion is a carcinoma, a needle biopsy will usually be diagnostic. Biopsy of a retroperitoneal mass

Tissue of origin

Benign neoplasm or process

Malignant neoplasm

Retroperitoneal tissue

Benign

Malignant

Lymph nodes

Reactive lymphadenopathy

Metastatic cancer Malignant lymphoma

Lymph vessels

Lymphocele



Fat

Lipoma

Liposarcoma

Nervous system Paraganglioma

±

Adrenal

±

Extraadrenal tumour Functional or non-functional

may be indicated if the history, examination and index scan do not suggest an endocrine tumour or a sarcoma; the mass does not involve the vascular tree; there is no diagnostic evidence of a lymphoproliferative disease on the haematological screen; the chest x-ray examination is clear; and there is no more easily accessible mass to biopsy such as a node in the groin or axilla. Scans can occasionally eliminate the need for a biopsy. However, although lymphomas are commonly gallium avid, gallium scans are not specific for lymphoma. Several other conditions including inflammation and malignant melanoma may also cause a positive gallium scan. Other manoeuvres such as bone marrow biopsy or lymph node biopsy in the neck, axilla or groin may remove the need for an abdominal operation to make the diagnosis of lymphoma after the discovery of a retroperitoneal mass. However, if the lesion is a lymphoma or a mesenchymal tumour, needle biopsy may well be non-diagnostic. The pathologist may still not be able to differentiate benign reactive changes from a lymphoma unless an incisional or excisional node biopsy is done. If the lesion is a sarcoma, needle aspiration cytology may be non-diagnostic in very well differentiated sarcoma as the cells may not look particularly abnormal, particularly on cytology. Core biopsy will be more accurate, but care in selecting the appropriate case and biopsy site is essential as a needle biopsy of a sarcoma may compromise subsequent treatment by seeding along the needle track. Detailed staging scanning should be undertaken for all suspected mesenchymal tumours, but biopsy of potentially sarcomatous

26 Abdominal incidentalomas

373

Figure 26.13  Mesenteric desmoid tumour detected on CT.

lesions is best deferred until the advice of a surgical oncologist has been sought.

Mesenteric Masses Mesenteric cysts These are benign and generally of no clinical consequence. They are uncommon but, of those that are diagnosed, an increasing number are discovered incidentally during abdominal scanning. They must be differentiated from solid mesenteric masses and from aneurysms of the mesenteric vessels. Mesenteric cysts can usually be diagnosed as such on ultrasound.

Mesenteric lymph node masses and neoplasms The investigation of these may be approached in the same way as for retroperitoneal masses. Like the retroperitoneum, the mesentery contains many lymph nodes and unexpected masses in the mesentery most commonly arise in these lymph nodes. Non-lymphatic mesenchymal neoplasms are less common. A rare form of fibrotic mass known as a desmoid tumour (also known as ‘aggressive fibromatosis’) can also present as an unexpected mass in the small bowel mesentery or occasionally, in the pelvis, on CT or ultrasound scanning (Fig 26.13). Diagnosis of mesenteric masses, especially desmoid tumour, can be difficult to secure as small biopsies are often inconclusive. Final diagnosis may rest on tissue obtained by surgical excision. Metastatic carcinoma in a mesenteric mass should trigger a search for a primary site as outlined for metastatic disease found in the liver or in

retroperitoneal nodes. Mesenteric desmoid tumour may be associated with Gardner's syndrome (Ch 22) in which case there should be other features of that syndrome identifiable and a relevant family history should be sought. Desmoid tumours that arise in the pelvis are often asymptomatic until they become very large.

Vascular mesenteric masses Duplex ultrasound will identify most mesenteric artery aneurysms by demonstrating the blood flow within them. If doubt persists after duplex ultrasound has been performed, triple-phase CT scanning may be diagnostic if a good quality arterial phase is achieved.

Peritoneal masses The majority of these are metastases due to transcoelomic spread of pelvic (especially ovarian) or abdominal (especially gastric) adenocarcinomas but any intraabdominal cancer can be the primary site. Primary malignancies of the peritoneum are uncommon conditions that occur in two forms: mesothelioma and primary peritoneal carcinoma. A background history of asbestos exposure should be sought if mesothelioma is suspected. Primary peritoneal carcinoma is very similar to ovarian carcinoma. These two malignancies usually present with abdominal or pelvic symptoms and signs, particularly palpable masses and ascites. A careful history may also reveal non-specific symptoms such as mild abdominal discomfort, weight loss, malaise and lethargy. They are rarely incidental scan findings. A definitive diagnosis may be made on cytology from samples of peritoneal fluid or needle biopsy, but open biopsy is still occasionally required.

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An incidentaloma is an abdominal mass unexpectedly detected on abdominal imaging carried out for an unrelated purpose. Most lesions encountered this way are benign, unrelated to the problem that triggered the scan in the first place and are of little or no risk to health. Incidental, imaging-detected abdominal masses discussed in this chapter include those arising in: – gallbladder—stones and neoplasms; – bile ducts—stones, dilation and cysts; – pancreas—cystic, solid, inflammatory, neoplastic and non-neoplastic; – liver—cystic, solid, infective, parasitic, neoplastic and non-neoplastic; – retroperitoneum—nodal, mesenchymal, neoplastic, non-neoplastic and inflammatory; – small bowel mesentery—cystic, solid, inflammatory, non-neoplastic and neoplastic; – peritoneal—neoplastic, malignant, primary and secondary. The investigation of incidentalomas is a twostage process (Boxes 25.1 and 25.2): – stage 1—non-invasive investigations: ■  focused history and examination; ■  non-invasive tests; – stage 2—invasive investigations: ■  specialist referral; ■  multidisciplinary setting. Initial investigations should identify the functional significance (e.g. jaundice) and should differentiate cystic from solid (for which abdominal ultrasound is usually the most useful first investigation). Vigorous investigation of clearly harmless findings is likely to do more harm than good.

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In most cases, the diagnosis is immediately apparent. Though some will require further investigations, only a minority will require treatment. Asymptomatic gallstones do not usually require treatment. Calcified dead hydatid cysts usually require no treatment. Hepatic haemangiomas are very echogenic on ultrasound, whereas fibronodular hyperplasia usually has a central scar on CT; these are benign liver lesions.

Further reading Carling T. Multiple endocrine neoplasia syndrome: genetic basis for clinical management. Curr Opin Oncol 2005; 17:7–12. Friedel DM, Abraham B, Georgiou N, et al. Pancreatic cystic neoplasms. South Med J 2010; 103(1):51–57. Garcea G, Ong SL, Rajesh A, et al. Cystic lesions of the pancreas. A diagnostic and management dilemma. Pancreatology 2008; 8(3):236–251. Levy MJ, Clain JE. Evaluation and management of cystic pancreatic tumors: emphasis on the role of EUS FNA. Clin Gastroenterol Hepatol 2004; 2:639–653. Metcalfe MS, Wemyss-Holden SA, Maddern GJ. Management dilemmas with choledochal cysts. Arch Surg 2003; 138:333–339. Petrov MS, Savides TJ. Systematic review of endoscopic ultrasonography versus endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis. Br J Surg. 2009; 96(9):967–974. Rubens DJ. Hepatobiliary imaging and its pitfalls. Radiol Clin North Am 2004; 42:257–278. Schipper HG, Kager PA. Diagnosis and treatment of hepatic echinococcosis: an overview. Scand J Gastroenterol Suppl 2004;241:50–55. Strasberg SM. Clinical practice. Acute calculous cholecystitis. N Engl J Med 2008; 358(26):2804–2811. Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 2009; 266(1):43–52.

27 Obesity and anti-obesity medical and surgical management

Case, Part 1 SB is a 48-year-old woman with type 2 diabetes mellitus, hypertension and hyperlipidemia who presents for weight loss. She reports struggling with weight since childhood but started gaining most significantly after her pregnancies, the last of which was at 28 years of age. She has tried several popular diets, including diet books and diet centres. She has also tried pills for weight loss, both ‘over the counter’ and ordered from television without success. Her current diet consists of a fast food sandwich and large diet soda in the mid-morning ‘on the run’, a piece of fruit with cheese and crackers at home in the midafternoon, and large meal with a meat, starch and vegetable for dinner with her family at home four nights a week and eating out the other three. In the evening, she snacks on a piece of cake, icecream or popcorn. She craves sweets, especially when stressed, and struggles with large portion sizes. She wants to avoid surgery if possible, but is open to hearing more about it. Her family history is significant for obesity in her mother and two of her three siblings, and hyperlipidaemia in her father and mother. She takes rosiglitazone 2 mgmetformin 1000 mg twice daily, insulin aspart 20 units with each meal, insulin glargine 45 units at bedtime, simvastatin 40 mg daily and lisinopril 20 mg twice daily. Pertinent physical exam findings include a weight of 126 kg, height of 162 cm, and body mass index (BMI) of 48.0 kg/m2. She has a waist of 42 inches. Her labs are unremarkable.

Introduction Obesity has reached epidemic proportions in the United States of America and Australia, affecting over 30% of the population. In the USA, the prevalence of obesity has increased from 22.9% in 1988 to 30.5% in 2002. This disease affects all ages, races and genders. Obese individuals suffer

not only from obesity and its social stigma, but also from medical comorbidities. Over 300,000 deaths each year are attributable to obesity. For people with a BMI over 30, the relative risk of developing diabetes is 12.7 in women and 5.2 in men. The risk of death from cancer may be 40–80% higher in the heaviest men and women. These obesity-associated health problems result in repeated physician office visits, time lost from work, and escalating healthcare costs. In 2000, the economic cost of obesity was $117 billion. If the obesity epidemic continues to grow, scientists predict a decrease in life expectancy by 2050. It is clear that obesity is a significant issue for our national health.

Medical Management Pharmacotherapy and behaviour modification are the mainstays of non-surgical treatment of obesity, with behaviour modification being the oldest approach to weight loss. Most commonly applied as a program of decreased caloric intake coupled with increased physical activity, behavioural programs have been effective in curtailing weight gain and improving overweight and moderate obesity; however, these behaviour changes and resultant weight loss are difficult for patients to sustain. Additionally, the magnitude of weight loss only modestly improves the health of patients with morbid obesity, those in the greatest need for weight management. Behaviour modification programs usually result in loss of 5–10% of body weight over a 6-month period, but this loss is rarely maintained beyond 6–12 months. High protein, low-carbohydrate diets have had some recent popularity, but a study has shown that at 1 year there was little difference in outcome when such a diet was compared with a conventional diet. Very-low-calorie diets result in more rapid weight loss, but are not a long-term solution without

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significant, sustained behaviour modification. The risk of malnutrition and need for frequent changes to medication make medical supervision imperative, increasing the cost and decreasing the ease of access to this type of program. Many pharmacological therapies exist for assistance with weight loss. The two medications approved for long-term use, orlistat (which inhibits dietary fat absorption) and sibutramine (which suppresses appetite), have been shown to produce modest weight loss. However, these medications have many unwanted side effects (such as diarrhoea with orlistat) that lead to non-compliance. When patients stop taking the medication, they often regain their lost weight. Finally, these medications are expensive and a considerable burden economically. Whether behaviour modification, pharmacotherapy or a combination of these approaches, the bottomline issue with non-surgical weight management remains failure to achieve clinically significant weight loss for morbidly obese patients and failure to sustain weight loss for most patients. For many obese individuals, continued pursuit of these programs leads to recidivism, incremental weight gain, and the negative psychological and physiological consequences of repeated failures. Recently, there has been interest in several putative gut hormones and their role in appetite, glucose metabolism and overall metabolism. Levels of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), ghrelin, cholecystokinin (CCK), gastric inhibitory peptide (GIP), oxyntomodulin (OXW) and pancreatic polypeptide have all been shown to have anorexigenic or orexigenic effects, and some degree of change after various weight loss operations. This has renewed interest in the gut–brain axis and the regulating peptides, and their potential role in future weight management strategies.

Case, Part 2 SB is provided with information about both nonsurgical and surgical options. She elects to pursue a non-surgical treatment regimen. She is placed on a 1200 calorie American Diabetes Association diet, which includes a regular eating schedule. Her dietitian also assists her with meal planning and preparation improvements. She increases her activity to incorporate 3 or 4 days per week of 30– 60 minutes of aerobic exercise and on the other days uses a pedometer to accumulate an increasing number of steps. She works with a clinical health psychologist to improve her stress management, decrease her eating out and manage her cravings.

Over a 6-month period, she is able to reduce her weight by 11% to 112 kg, yielding a BMI of 42.7. She has discontinued her rosiglitazone and decreased her insulin aspart to 15 units with meals, insulin glargine to 30 units at bedtime and lisinopril to 20 mg daily. However, she continues to require her metformin 1000 mg twice daily and simvastatin 40 mg at bedtime. After maintaining her weight within 2.27 kg for another 6 months, she decides to pursue gastric bypass surgery for additional weight loss and improvement of her diabetes.

Surgical Management The rapid increase in the prevalence and morbid consequences of obesity combined with failure of those weight-loss strategies outlined earlier has led to increased interest in surgical management of obesity. Various operations to induce weight loss have been available and used for nearly 40 years. The epidemic of obesity combined with the use of laparoscopy in performing weightloss operations has led to a dramatic rise in the number of procedures performed. It is estimated that in 2004 140,000 morbidly obese individuals underwent weight-loss surgery, an increase of over 300% when compared with the 40,000 similar procedures performed in 1999. Today, three procedures are most commonly offered: the roux-en-Y gastric bypass (GBP), the laparoscopic adjustable gastric band (LGB) and the sleeve gastrectomy, with the roux-en-Y gastric bypass remaining the most commonly performed weightloss operation. The vertical gastric band (VBG) is now largely of historic interest since up to 25% of patients require revisional surgery after this operation, and durable weight loss is insufficient when compared to the other procedures. The biliopancreatic bypass with duodenal switch (BPO-DS) continues to have limited use in select patients at select centres.

Roux-en-Y gastric bypass The Roux-en-Y gastric bypass (GBP) (Fig 27.1) is the most commonly performed procedure in the United States of America and works in three ways. A small pouch of 30-mL volume is created along the lesser curve of the stomach, resulting in restriction to food intake. A 100- to 150-cm Roux limb drains this proximal gastric pouch, resulting in malabsorption. Finally, because ingested food bypasses the main portion of the stomach, certain foods (e.g. sweets) induce the dumping syndrome, which limits patients’ consumption of these foods. After a GBP, 90% of patients lose 50–75% of their

27 Obesity and anti-obesity medical and surgical management

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Figure 27.2  Anatomy of laparoscopic adjustable gastric band. Figure 27.1  Anatomy of Roux-en-Y gastric bypass.

excess weight, and this loss is maintained for at least 14 years.

Laparoscopic adjustable gastric band The laparoscopic adjustable gastric band (LGB) (Fig 27.2) procedure places an adjustable Silastic™ band around the gastric cardia, thereby creating a small proximal gastric pouch with a restricted outlet to the distal stomach. The LGB has essentially replaced the vertical banded gastroplasty as an effective restrictive-only procedure. While the GBP remains the most commonly performed procedure in the USA, the LGB is the most commonly performed weight-loss procedure in the world. Five-year outcomes reveal that most patients lose 50% to 60% of their excess weight.

Sleeve gastrectomy Sleeve gastrectomy (Fig 27.3) has recently become an increasingly common and popular operation. This procedure developed as part of the duodenal switch operation and was used as a staging procedure for extremely obese or high-risk patients. These patients would undergo an initial operation consisting of the sleeve gastrectomy only with the plan to later undergo another surgery to complete the duodenal switch. Weight loss with sleeve gastrectomy only induced sufficient and durable weight loss, making the sleeve gastrectomy alone a reasonable operation. This operation achieves

Figure 27.3  Anatomy of sleeve gastrectomy.

50–75% excess weight loss without the perioperative risks of the more complex anatomic reconstruction of the GBP.

Outcomes of surgery Minimally invasive techniques have been used for weight-loss surgery since the first laparoscopic GBP was performed in 1994. Since that time laparoscopic techniques have increasingly dominated weightloss surgery, with patients realising the expected

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results regardless of the method of access (open or laparoscopic). These overall results include sustained weight loss with either improvement or complete resolution of comorbidities after surgery. In a recent systematic review of the literature, 22,094 patients were included and the results were as follows: the mean percentage weight loss was 61.2% for all patients, with the most excess weight loss observed with GBP (68.2%). Diabetes resolved in 76.8% of patients, hypertension in 61.7% of patients, and obstructive sleep apnoea in 85.7% of patients. Furthermore, an economic advantage with surgical weight loss has been suggested (see pros and cons below). One study demonstrated that with the resolution of many of these comorbidities the cost per patient of pharmaceuticals after weight-loss surgery was significantly decreased. Furthermore, a recent study has demonstrated that patients who underwent weight-loss surgery experienced lower mortality than those who remained obese. Obesity has been identified as the second most common cause of preventable death in the United States of America. This elevated death rate will revert back to that of the normal population with return to a non-obese weight. Another area of impact has been cancer; obesity may account for 14% of cancer deaths in men and 20% in women. With weight loss, one in six cancer deaths may be prevented in the United States.

Pros and Cons of Weight-loss Surgery With such positive outcomes from weight-loss surgery, the question could be asked: why hasn't everyone with morbid obesity undergone weightloss surgery? Currently, over 16 million Americans are potential candidates for weight-loss surgery (BMI over 40 or BMI over 35 with comorbidities). At the rate of just over 140,000 procedures being performed in 2004, it will take at least 150 years to address the current population. Several factors limit the number of weight-loss operations performed. First, there are not enough surgeons who perform weight-loss surgery to operate on all of these people even within the next decade. Also, weight-loss surgery is not appropriate for all obese individuals. Several surgical and non-surgical factors influence the outcome after weight-loss surgery. For example. weight regain at 18–24 months after surgery is noted in up to 30% of patients. One factor identified in weight regain is binge-eating disorder. Patients with a history of

binge-eating behaviour frequently revert to their old habits after surgery, and this could explain weight regain in some patients. In contrast, patients with the most success after weight-loss surgery have an overall improved eating behaviour and also have greater physical activity. For success with surgery, patients need to be willing to accept these lifestyle changes and be able to modify their eating habits in accordance with the surgery. Not all patients are willing to comply with such changes, and therefore not all patients are proper candidates for surgery. Many of the patients seeking weight-loss surgery are young and have a life expectancy of at least 30 years after their weight-loss procedure. We do not know the long-term (over 20 years) effects of the gastrointestinal anatomic alterations of current weight-loss procedures. We do know that 7–29% of patients will require cholecystectomy after any weight-loss surgery, and 10–15% of LGB patients will require more surgery for band erosion, leakage or slip. There are also concerns about longterm nutritional and micronutrient deficiencies, especially with the GBP where a significant portion of the GI tract has been bypassed. Patients who undergo this malabsorptive procedure must be monitored for life, in particular for iron, vitamin B12 and calcium deficiencies. Vitamin B12 and calcium supplementation is indicated lifelong in all GBP patients, and foods rich in protein can be a challenge, thereby often necessitating protein supplementation.

Case, Conclusion SB undergoes gastric bypass after preparation by her bariatric team, incorporating appropriate dietary changes and supplementation. Over her first year she meets with her dietician and physician regularly and continues her aerobic exercise while adding resistance exercise. She is able to reduce her weight to 79 kg, yielding a BMI of 30.1. Her lisinopril, insulin aspart and insulin glargine metformin are discontinued, but she continues with simvastatin 20 mg at bedtime to control her persistent hyperlipidaemia. After the first year, she meets with the team annually for monitoring. With continued vigilance, she is able to maintain her weight loss with a significant improvement in her health and quality of life.

Conclusions Obesity remains a significant health concern. Weight-loss surgery is the most sustainable weight-loss option for the majority of morbidly obese adults. As long as the person is motivated

27 Obesity and anti-obesity medical and surgical management to make the lifestyle changes required by the various weight-loss options, he or she can enjoy the benefits of fewer comorbidities, fewer medications, fewer costs and an improved quality of life. In the long term, however, surgery will not be the answer. Not enough surgeons are available to address the current obese adult population, and the prevalence of obesity continues to rise. Education and public awareness are the long-term solution to decrease the incidence of obesity and prevent children from becoming obese adults. It has taken several decades for obesity to reach its current epidemic proportions. It will take many more to get the population back to a healthier weight.

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Most non-surgical obesity treatments can produce a weight loss of 5–10% over 6 months. A weight loss of 5–10% will improve health, but usually not enough for patients with morbid obesity. Sibutramine (an anorexiant) and orlistat (an intestinal lipase inhibitor) are the only medications currently approved for long-term use for the treatment of obesity. Note that the US Food and Drug Administration (FDA), as of 8 October 2010, has recommended against continued prescribing of sibutramine: see http:// www.fda.gov/Drugs/Drugsafety/ucm228746. htm#Safety_Announcement Surgical treatment produces greater weight loss that is sustained over a longer period of time than non-surgical treatments. Gastric bypass produces more weight loss than gastric banding and may be comparable to sleeve gastrectomy. Gastric bypass resolves up to 80% of type 2 diabetes mellitus. Those who undergo a malabsorptive procedure must be closely monitored for nutritional deficiencies for life (e.g. B12, calcium).

References Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004; 292:1724–1737. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 2003, 348:1625–1638. Calle EE, Thun MI, Petrelli JM, et al. Body mass index and mortality in a prospective cohort of US adults. N Engl J Med 1999; 341:1097–1105.

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Centers for Disease Control and Prevention. Prevalence of overweight and obesity among adults with diagnosed diabetes. United States, 1988–1994 and 1999–2002. MMWR Morb Mortal Wkly Rep 2004; 53:1066–1068. Christou NV, Sarnpalis JS, Liberman M, et al. Surgery decreases long-term-mortality, morbidity, and health care use in morbidly obese patients. Ann Surg 2004; 240:416–424. Clegg AJ, Colquitt J, Sidhu MK, et al. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation. Health Tech Assess 2002: 6:1–153. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 2003; 348:2082–2090. Glazer G. Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety. Arch Intern Med 2001; 161:1814–1824. Hsu L, Benotti P, Dwyer J, et al. Nonsurgical factors that influence the outcome for bariatric surgery: a review. Psychosom Med 1998; 60:338–346. Hall JC, Watts JM, O'Brien PE, et al. Gastric surgery for morbid obesity. The Adelaide Study. Ann Surg 1990; 211:419–427. Howard L, Malone M, Michalek A, et al. Gastric bypass and vertical banded gastroplasty—a prospective randomized comparison and 5-year follow up. Obes Surg 1995; 5:55–60. Martin LF, Tan TL, Horn JR, et al. Comparison of the costs associated with medical and surgical treatment of obesity. Surgery 1995; 118:599–606. Mun EC, Blackburn GL, Matthews JB. Current status of medical and surgical therapy for obesity. Gastroenterology 2001; 120:669–681. National Audit Office. Tackling Obesity in England: Report by the Controller and Auditor General. London: Stationary Office, 2001. No. HC 220 Session 2000–2001. Norris SL, Zhang X, Avenell A, et al. Efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med 2004; 164:1395–1404. O'Meara S, Riemsma R, Shirran L, et al. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity. Health Technol Assess 2001; 5:1–81. Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 2005; 352:1138–1145. Pories W, Swanson M, MacDonald K, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995; 222:339–350. Potteiger C, Paragi P, Inverse N, et al. Bariatric surgery: Shedding the monetary weight of prescription costs in the managed care area. Obes Surg 2004; 14: 725–730. Pournaras DJ, le Roux CW. Obesity, gut hormones, and bariatric surgery. World J Surg 2009; 33:1983–1988. Sjostrom L, Lindroos A, Peltonen M, et al. Lifestyle, diabetes and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351:2683–2693.

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Smith CD, Herkes SB, Behrns KE, et al. Gastric acid secretion and vitamin B12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity. Ann Surg 1993; 218:91–96. Steinbrook R. Surgery for severe obesity. N Engl J Med 2004; 350:1075–1079.

Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity. Available at http://surgeon general.gov/topics/obesity/. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346:591–602.

28 Patient preparation and principles of sedation in gastrointestinal endoscopy

Case A 67-year-old male with a past history of mitral valve stenosis and insulin-dependent diabetes mellitis with moderate renal impairment requests his primary care physician to organise colon cancer screening. An open-access colonoscopy is arranged. The patient presents for the procedure with moderate dehydration following preparation with three sachets of sodium phosphate solution. The patient is noted to be hypoglycaemic, having taken his usual dose of insulin that morning. He requests antibiotic prophylaxis for the procedure (as he has been told always to request this prior to invasive procedures). He is angry when this is refused and becomes more agitated when the consultant acquiesces and asks the nurse to prepare 1 g of ampicillin. He is sedated with midazolam and fentanyl. During the procedure he receives oxygen supplementation but no capnography or pulse oximetry. He is uncomfortable during the procedure and complains that he is not ‘asleep’. He is given three further doses of midazolam, initially becoming more agitated, but eventually settling. After several minutes the nurse notes that he does not appear to be breathing. The medical emergency team is called but takes 5 minutes to respond. He is given flumazenil and becomes extremely agitated and tremulous. It is then noted that he takes valium for anxiety and temazepam at night. This patient, although an extreme example, illustrates some of issues of appropriate preparation for an endoscopic procedure. The patient was given inappropriate bowel preparation, no instruction on the management of his insulin and no information about what to expect during the procedure. The proceduralist was correct not to recommend antibiotics, but his reasoning should have been explained and discussed rather than

simply agreeing with the request and ordering penicillin without discussion. He had not had a chance to adequately discuss his history with the proceduralist, who did not know that he was allergic to penicillin, nor that he was on regular benzodiazepines. He was subsequently oversedated for the procedure and had inadequate non-invasive monitoring. ‘Open access’ endoscopic services are relatively common, but if this type of service is to utilised it is paramount that the proceduralist have effective measures in place in order to obtain appropriate informed consent and identify patients for whom special issues regarding preparation are required. In short, the patient must understand the procedure and the proceduralist must understand the patient.

Introduction Gastrointestinal endoscopy is an important tool in the diagnosis and treatment of many diseases. A broad range of endoscopic procedures are now commonly performed in addition to conventional diagnostic gastroscopy and colonoscopy, including endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound, and insertion of percutaneous endoscopic gastrostomy. In addition, gastrointestinal haemorrhage is often managed endoscopically, and colonic or upper gastrointestinal tract polyps can be resected via endoscopic mucosal resection. The volume of endoscopic procedures performed demands that these procedures are as safe as possible. The American Society of Gastrointestinal Endoscopy has published excellent guidelines covering all aspects of patient preparation and sedation. This chapter deals with several of the most important aspects of providing a safe endoscopic practice: preprocedure patient assessment, management of anticoagulation, antibiotic prophylaxis and intraprocedural sedation.

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Preparing Patients for Endoscopy Informed consent Law suits against gastroenterologists are not uncommon, and in many Western countries most endoscopists can expect to be sued during their career. Endoscopic procedures are inherently dangerous and complications will occur. However, a poor clinical outcome of itself does not equate to negligence or malpractice. Many actions could be prevented (or at least effective defended) by the gastroenterologist taking care to obtain informed consent. Although this does not defend against poor medical practice, it ensures that the patient is responsible for key management decisions. Informed consent is a process, not a signed piece of paper. It requires that the patient understands the procedure, likely outcomes, potential complications and alternative management strategies. Provision of information to patients prior to the procedure is an important step, but never supplants the opportunity to discuss the procedure with the proceduralist. The type of sedation planned should also be discussed, including the risks of sedation. With regard to conscious sedation many patients will complain about awareness during the procedure unless forewarned that the aim is comfort and not unconsciousness. The patient's expectations should be explored, and the possibility mentioned that the procedure may not be successful or solve the patient's problem (missed lesions at colonoscopy are a relatively frequent cause of litigation).

Bowel preparation for colonoscopy The quality of the bowel preparation prior to colonoscopy is critical in order to provide good views during endoscopy, and thus minimise the risk of missed lesions due to poor endoscopic views. The importance of this is illustrated by the fact that adequate bowel preparation is often included as a quality indicator in colonoscopy. The preparation is often regarded as unpleasant, and many patients are more concerned about the preparation than the actual procedure. As such, detailed explanation both verbally and written is important in order for this to be performed correctly and safely. If the bowel preparation is inadequate, the procedure may need to be deferred. It is important for patients to be informed that they should drink clear fluids only on the day prior to the procedure in addition to the bowel preparation

in order to prevent dehydration, and to improve the effectiveness of the bowel cleansing. In addition, mobilising during the preparation may improve the effectiveness of the preparation, especially in the elderly. The two main constituents widely used for bowel preparation are non-absorbed, isotonic solutions such as polyethylene glycol and low volume hypertonic solutions such as sodium phosphate and sodium picosulfate. Polyethylene glycol is an osmotic laxative that contains electrolytes in order to balance electrolyte shifts; as such it can be regarded as isoosmotic. It is mixed in a large quantity of water; for example the patient may need to drink a total of 3–4 L of fluid. This is usually taken the day prior to the procedure, but if a morning procedure it should be given as a ‘split’ preparation, where part of the preparation is given on the morning of the procedure. This may improve the effectiveness and tolerability of the preparation; however, it needs to be taken at least 4 hours prior to the procedure in order for the stomach to be empty, to reduce the risk of gastric aspiration. Sodium phosphate (NaP)-based solutions work via a hyperosmotic mode of action, and can be given in much smaller volumes of water. As such, NaP is often tolerated better by patients. It can be combined with a polyethylene glycolbased regimen in order to improve tolerability and reduce volume. The NaP-based solutions do have some risks, including sudden fluid shifts within the body and precipitating acute phosphate nephropathy. Therefore, it should be avoided in the elderly and in patients with congestive heart failure or renal failure. In addition, caution is required if patients have an increased risk of electrolyte disturbance such as those with cirrhosis, small or large bowel dysmotility or other preexisting electrolyte imbalances. The sodium picosulfate (Picoprep) preparation has no risk of phosphate nephropathy. Patients should be encouraged to drink fluids liberally during hypertonic-based bowel preparation. Patients with known or suspected inflammatory bowel disease may not be suitable for NaPbased preparations, due to an increased risk of causing preparation-related colonic inflammation compared to polyethylene glycol-based solutions.

Endoscopic retrograde cholangiopancreatography Patients undergoing ERCP will be exposed to ionising radiation. Therefore women of childbearing age should have pelvic shielding

28 Patient preparation and principles of sedation in gastrointestinal endoscopy during the procedure. If there is any possibility of pregnancy a serum or urinary β-human chorionic gonadotropin should be checked. Contrast medium in the bowel lumen can obstruct views of the biliary system, so patients who have recently had a CT scan with contrast or a barium study should have a plain abdominal x-ray to ensure the biliary system is not obscured. As iodinated contrast is used to inject into the biliary system, a history of iodine allergy or hyperthyroidism should be elicited, though history of a contrast allergy is not an absolute contraindication as the risk of an allergic reaction during ERCP is extremely low. Patients with biliary obstruction should receive prophylactic antibiotics prior to the procedure. Due to the risk of bleeding with sphincterotomy of the ampulla of Vater, elective patients on clopidogrel should ideally withhold this medication for 7–10 days if feasible. The risk is lower with aspirin (all therapeutic endoscopy can be performed on aspirin). Discussion with the patient's cardiologist is prudent if there is uncertainty whether it is safe to withhold these medications. Coagulopathy should be reversed if present; patients on warfarin may need to change to low-molecular-weight heparin prior to the procedure depending upon the indication. The decision when to reinstitute anticoagulant therapy following therapeutic procedures such as ERCP and colonic polypectomy is a difficult one and should be individualised in consultation with the patient's cardiologist.

Antibiotic prophylaxis Advice regarding antibiotic prophylaxis prior to endoscopic procedures was significantly updated in American Society for Gastrointestinal Endoscopy guidelines (2008) based on the recognition from the American Heart Association that bacterial endocarditis from endoscopic procedures was exceedingly rare. For the majority of patients undergoing endoscopic procedures, including those with prosthetic heart valves or congenital cardiac abnormalities, antibiotic prophylaxis to prevent bacterial seeding was no longer recommended. There are however, certain situations in which the risk of infective complications (which may be local rather than systemic) is increased and antibiotics are warranted; these are listed in Box 28.1. All patients with cholangitis require antibiotics; patients with biliary obstruction without cholangitis undergoing ERCP require antibiotics only if incomplete drainage is anticipated. Similarly, patients with diffuse sclerosing cholangitis

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Box 28.1  Antibiotic prophylaxis for endoscopy All patients prior to insertion of percutaneous endoscopic gastrostomy Endoscopic ultrasound: ll guided puncture of cystic lesions; or ll pseudocyst drainage. ERCP: ll bile duct obstruction in absence of cholangitis, only if incomplete drainage is anticipated (e.g. hilar stricture, primary sclerosing cholangitis). All patients with cirrhosis with acute GI bleeding (intravenous ceftriaxone from admission)

should receive periprocedural antibiotics. There is insufficient evidence to recommend antibiotic prophylaxis for endoscopic ultrasound-guided aspiration of solid lesions, though it is warranted for cystic lesions or pseudocyst drainage.

Disease-specific issues Patients can take their normal medications several hours prior to the procedure with a sip of water. The management of patients taking antiplatelet agents or anticoagulants is a complex issue, and should be in accordance with published guidelines. These guidelines take into account whether the procedure is elective or an emergency procedure, the indication for the antiplatelet agent or anticoagulant, and the bleeding risk related to the procedure. A suggested algorithm for management of patients requiring anticoagulation is outlined in Figure 28.1. The management of patients with diabetes mellitus will depend upon whether they have type 1 or type 2 diabetes, and on whether they are diet-controlled or on diabetic medications or insulin. Patients with type 2 diabetes are more easily managed as they can generally withhold their medications or insulin on the morning of the procedure. If undertaking bowel preparation on the previous day, similar withholding or reduction in dosage is appropriate. For type 1 diabetes the management is more complicated as some maintenance insulin is required in order to avoid the risk of precipitating ketoacidosis. Involvement of the patient's diabetic specialist may be useful, and in some situations admission to hospital early on the day of the procedure or even the night before the procedure for an insulin/dextrose infusion

Clopidogrel

Continue warfarin Check INR 1 week before endoscopy If INR within therapeutic range continue usual daily dose If INR above therapeutic range but < 5 reduce daily dose until INR returns to therapeutic range

Continue clopidogrel

High-risk procedure Polypectomy ERCP with sphincterotomy EMR Dilation of strictures Therapy of varices PEG EUS with FNA

Warfarin

Clopidogrel

Low-risk condition Prosthetic metal heart valve in aortic position Xenograft heart valve AF without valvular disease > 3 months after VTE

High-risk condition Prosthetic metal heart valve in mitral position Prosthetic heart valve and AF AF and mitral stenosis < 3 months after VTE Thrombophilia syndromes

Low-risk condition Ischaemic heart disease without coronary stent Cerebrovascular disease Peripheral vascular disease

High-risk condition Coronary artery stents

Stop warfarin 5 days before endoscopy Check INR price to procedure to ensure INR < 1.5 Restart warfarin evening of procedure with usual daily dose Check INR 1 week later to ensure adequate anticoagulation

Stop warfarin 5 days before endoscopy Start LMWH 2 days after stopping warfarin Omit LMWH on day of procedure Restart warfarin evening of procedure with usual daily dose Continue LMWH until INR adequate

Stop Clopidogrel 7 days before endoscopy Continue aspirin if already prescribed If not on aspirin, then consider aspirin therapy while clopidogrel discontinued

Liaise with cardiologist Consider stopping clopidogrel 7 days before endoscopy if: > 12 months after insertion of drug-eluting coronary stent > 1 month after insertion of bare metal coronary stent Continue aspirin

Figure 28.1  Guidelines for the management of patients on warfarin or clopidogrel undergoing endoscopic procedures. AF = atrial fibrillation; EMR = endoscopic mucosal resection; ERCP = endoscopic retrograde cholangiopancreatography; EUS = endoscopic ultrasound; FNA = fine needle aspiration; INR = international normalised ratio; LMWH = low-molecular-weight heparin; PEG = percutaneous endoscopic gastroenterostomy; VTE = venous thromboembolism. From Veitch AM, Baglin TP, Gershlick AH, et al. Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures. Gut 2008; 57:1322–1329.

Clinical gastroenterology: a practical problem-based approach

Warfarin

384

Low-risk procedure Diagnostic procedures ± biopsy Billiary or pancreatic stenting Diagnostic EUS

28 Patient preparation and principles of sedation in gastrointestinal endoscopy may be appropriate. Diabetic patients should be first on elective morning endoscopy lists in order to minimise fasting and disruption of glycaemic control.

Principles of Anaesthesia for Endoscopy Introduction The anaesthetic management of a patient undergoing an endoscopic procedure should take into account a number of factors including the type of procedure, the patient characteristics and their wishes, and the expertise and preferences of the proceduralist and staff members. Patients may have comorbidities that increase the risk of sedation, especially in the older age group. Gastroenterologists need to be comfortable assessing patients for their anaesthetic requirements prior to a procedure in addition to managing their primary gastroenterological problem. Depending upon the facility in which procedures are performed, the anaesthetic (which may also be referred to as ‘sedation’ with the exception of general anaesthesia) may be given by the proceduralist with the assistance of nursing staff, a nurse anaesthetist or by a dedicated anaesthetist. There is wide variation between different countries regarding sedation management; it is a reflection of cultural expectations, health insurance structure and workforce training (e.g. nurse anaesthetists are common in some countries but not others). The aim of anaesthesia is to provide a comfortable experience for the patient during the procedure, and to keep the patient still to enable the procedure to be performed. Sedation can be divided into different categories according to the depth of sedation. The American Society of Anaesthesiologists provides the following categorisation (see Table 28.1). The term ‘moderate sedation’ is being increasingly used instead of the potentially confusing term ‘conscious sedation’. Note that patients can move between different sedation states quickly, and proceduralists targeting a level of sedation should be competent at managing patients who enter the next deeper level of sedation. Assessment of the depth of sedation can be difficult as there is no widely accepted objective measure of the depth of sedation. A study of 80 patients sedated for endoscopy with the view to moderate sedation with midazolam and meperidine (pethidine) showed that 68% of patients entered a period of deep sedation at some point during their procedure.

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Patient assessment The assessment of a patient initially comprises a thorough history of comorbidities, exercise tolerance and medications (including over-thecounter remedies and allergies). History of tobacco, alcohol and illicit drugs should be elicited, as should difficulties related to previous anaesthetics. A focused cardiorespiratory examination should be performed for all patients, especially to detect occult valvular disease. Of particular interest is the use of potent thienopyridine antiplatelet agents such as clopidogrel and prasugrel, and anticoagulants such as warfarin. A useful guide for assessing anaesthetic risk has been developed by the American Society for Anaesthesiology (Table 28.2). Patients with an ASA status greater than III should be managed by an anaesthetist. For some patients with significant comorbidities, liaison with the patient's treating specialist may be useful. For example, if a patient with reduced exercise tolerance due to emphysema has not been reviewed by a respiratory physician for a long period of time, it would be reasonable for the respiratory physician to review the patient in order to optimise his or her periprocedural status and to help stratify the anaesthetic risk.

Patients who should be sedated by an anaesthetist There is a group of patients in whom the risks of sedation are significantly increased, and for whom it is more appropriate for an anaesthetist to deliver sedation. This includes patients with severe comorbidities such as cardiac, pulmonary or renal disease who have an ASA grading over III (see Table 28.2). In addition, patients with abnormalities of the oropharynx, neck or airway are at increased risk of airway problems if oversedation occurs (see Box 28.2). Patients at extremes of age, who abuse alcohol or other drugs, are pregnant or who are planned for a procedure of long duration or in which deep sedation is required are also suitable to be referred to an anaesthetist. In addition, those with a high risk of having a large residual gastric content such as patients with a small bowel obstruction should be managed by an anaesthetist due to the increased risk of aspiration.

Logistics of administering sedation The logistics of administering sedation are very important, and if performed inadequately can create an unsafe situation with significant potential of an adverse event occurring. These issues include monitoring of the patient during and after the

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Clinical gastroenterology: a practical problem-based approach Box 28.2  Patients at increased risk of airway management problems

Table 28.1  Clinical states of sedation (American Society of Anaesthesiologists) Sedation level

Characteristics

Minimal sedation

Normal response to verbal stimulation.

Moderate sedation

Purposeful response to verbal or tactile stimulation. Spontaneous ventilation is adequate and no airway intervention is required.

Deep sedation

Purposeful response only after repeated or painful stimulation. Spontaneous ventilation may be inadequate, and airway intervention may be required.

General anaesthesia

Unrousable, even with painful stimuli. Airway intervention is often required and spontaneous breathing is usually inadequate. Cardiovascular compromise may occur.

Table 28.2  American Society of Anaesthesiologists (ASA) classification of anaesthetic risk Class I

The patient is normal and healthy

II

Mild systemic disease that does not limit activity (e.g. controlled hypertension)

III

Moderate or severe systemic disease that does not limit activity (e.g. stable angina, diabetes mellitus with systemic sequelae)

IV

Severe systemic disease that is a ‘constant threat to life’ (e.g. end-stage renal failure, severe cardiac failure)

V

Patient is morbid and at substantial risk of death within 24 hours (whether the procedure is performed or not)

E

Emergency status: add this as a suffix for emergency cases (e.g. IIIE)

procedure, administration of anaesthetic agents, training and level of staffing, and protocols for managing emergencies. Communication between the proceduralist and nursing staff is critical in order to clearly communicate orders relating to sedation, and also to feed back to the proceduralist changes in the patient's status that require attention. All staff should feel comfortable vocalising concerns about a patient's status if they feel that the safety of a patient has been compromised, and not feel that doing so is inappropriate due to issues of hierarchy or seniority.

ll ll

ll

ll ll

ll

History of sleep apnoea, stridor, or snoring Oral abnormalities such as loose teeth, small oral opening (less than 3 cm), or macroglossia Neck problems such as cervical spine disease or trauma, limited neck extension, obesity involving the neck and facial structures, short neck, tracheal deviation Previous airway problems in an anaesthetic Dysmorphic facial features such as in Pierre-Robin syndrome Jaw abnormalities such as micrognathia

Monitoring of patients All patients should be monitored during sedation in order to detect complications of sedation and allow early management of these problems. The most common adverse event during endoscopy is the development of respiratory depression and hypoxia due to the administration of sedative agents. In addition to respiratory effects, sedation can cause cardiovascular depression so blood pressure and heart rate should be monitored as well. Pulse oximetry Pulse oximetry is a non-invasive way of measuring arterial oxygen saturation (SaO2) by the use of a probe that measures the light signal transmitting through tissue and the pulsatile volume changes that occur. Because the oxyhaemoglobin dissociation curve is sigmoid in nature, the partial pressure of oxygen is maintained reasonably high when the SaO2 is above 90%; however, it quickly drops when the SaO2 drops below 90%. In this range, small drops in SaO2 correspond to large drops in oxygen partial pressure and are a signal that rapid attention to oxygen delivery and ventilation is required. Notably, pulse oximetry does not work as well when tissue perfusion is poor, such as when hypotension occurs during a procedure; low oxygen saturation should prompt a recheck of the blood pressure (the cuff should be on the opposite arm to avoid reducing perfusion to the pulse oximeter). Most importantly, there is a significant delay between hypoventilation (or apnoea) and reduction in SaO2. Capnography Although pulse oximetry provides some indication of when hypoxia has occurred, it is a relatively blunt tool to detect hypoventilation

28 Patient preparation and principles of sedation in gastrointestinal endoscopy and apnoea, which can be further masked by the use of supplemental oxygen. An excellent way to monitor for hypoventilation is to use non-invasive capnography, which measures CO2 concentration in the vicinity of expired air. This is graphically represented as an oscillating line as the patient breathes in and out and the CO2 concentration changes. The actual CO2 level estimated is not critical. Rather, capnography demonstrates in real time that the patient is breathing. Capnography enables hypoventilation and apnoea to be detected immediately as reflected by a lack of oscillation in expired carbon dioxide (CO2). A capnograph probe can be used attached to a Hudson mask, and even attached to nasal prongs.

Blood pressure monitoring Monitoring of blood pressure is best achieved via the use of an inflatable blood pressure cuff which is able to be automatically inflated at periodic intervals. Guidelines from the American Society of Gastrointestinal Endoscopy suggest measuring the blood pressure before the procedure, at the commencement of the procedure, at every 5 minutes during the procedure then at intervals in the recovery room. Ideally, the most recent blood pressure reading should be displayed on the screen of an electronic ‘mini-monitor’. The blood pressure cuff should not be placed on the same arm as the intravenous cannula or the pulse oximeter to prevent flow of sedation, and false pulse oximeter readings. For some patients, especially for those with a cardiac history such as arrhythmias or if deep sedation is performed, additional monitoring of an electrocardiography trace may be useful.

Medications used in sedation Drugs used for sedation have a number of common properties. These drugs are often synergistic when used together rather than being cumulative, and as such care should be taken when drugs are coadministered. A given dose of a sedative can have a wide variation in sedative effect in different patients, so careful titration of dosages is important to avoid oversedation—there is no such thing as a ‘standard dose’. In addition, the peak effect of a medication may be delayed, and over-frequent administration of doses can also lead to oversedation, especially in the recovery room. It should be remembered that the key end point of sedation is patient comfort rather than complete unconsciousness, and in some situations it is perfectly reasonable for the patient to be awake during the procedure. Patient expectation is essential here—patients often complain of

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awareness during endoscopic procedures because they had the misconception that they would undergo general anaesthesia. Unsedated endoscopy Unsedated endoscopy can be performed in patients who have a high risk related to sedation or prefer not to be sedated; in some European and Asian countries less than 25% of patients are sedated for routine upper gastrointestinal endoscopy. This may reduce costs and risks associated with procedures, and enables patients to ‘walk out’ of the procedure room without the need for a recovery period; patients can go back to work with minimal disruption. This may be particularly useful in regions where mass screening for oesophageal or gastric cancer is practised. Since most patients find unsedated endoscopy disagreeable, the use of an ultra-thin endoscope or transnasal endoscope may make this more tolerable. Benzodiazepines and opiates A combination of a benzodiazepines and an opiate is commonly used for sedation during endoscopy. These drugs have the advantage of availability of reversal agents in the event of oversedation. Commonly used benzodiazepines include midazolam and diazepam. Midazolam has a more rapid onset, shorter half-life; produces less thrombophlebitis; and has better amnesic properties compared to diazepam. It should be remembered that benzodiazepines may lead to paradoxical agitation. The amnesic effect of benzodiazepines is very useful to minimise postprocedure distress, though this effect is very variable and should not be relied upon. Commonly used opiates include fentanyl and meperidine (pethidine). Fentanyl, though more expensive, is a better agent than meperidine; it has a shorter half-life, produces less nausea and fewer allergic reactions and does not cause local injection site reactions. Propofol Propofol is an anaesthetic agent that acts by causing the release of gamma amino butyric acid in the brain. It is increasingly used in endoscopy due to its attractive properties such as rapid onset and offset, shortened recovery time, and fewer effects on neuropsychiatric functioning postprocedure. The half-life is 1–4 minutes, and the onset of sedation is within 30–60 seconds. Propofol is regarded as having a ‘narrow therapeutic window’ that can result in rapid depression to deep sedation or even general anaesthesia. In addition,

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hypotension can occur due to decreased systemic vascular resistance and negative cardiac inotropy. It has been approved by the US Food and Drug Administration for use by anaesthetists, but it is commonly used ‘off label’ by endoscopists for sedation. A meta-analysis of randomised controlled trials comparing propofol use during endoscopy to combined midazolam and opiates suggested that there were no differences in hypoxaemia, hypotension, the proportion of patients reporting pain or physician satisfaction, though patient satisfaction was higher in the propofol group. Furthermore, in contrast to benzodiazepines and narcotics there is no reversal agent. This means that a practitioner using propofol must be prepared to artificially ventilate an apnoeic patient for up to several minutes if necessary. Generally propofol should not be used as a single agent as its analgesic effects are minimal, and it combines well with use of a small dose of opiate with or without a benzodiazepine at the beginning of the procedure. Droperidol Droperidol is a dopamine receptor antagonist in the same class as haloperidol, which has been used as an adjunct in patients who are difficult to sedate. However, it has a risk of cardiac arrhythmias, especially in higher doses and in patients with prolonged Q-T duration, and should be used with caution. Furthermore, it is long-acting, requiring a long recovery phase, and causes unpleasant dysphoria in many patients. For these reasons it is rarely used. Pharyngeal anaesthesia Topical anaesthetic throat sprays are sometimes used to suppress the gag reflex and so to facilitate upper endoscopic procedures. These agents are effective for up to an hour, though they may impair pharyngeal coordination. Therefore, patients should be warned not to eat or drink for at least 1 hour postendoscopy. There is conflicting data regarding the benefit of anaesthetic throat sprays as an adjunct to conventional sedation, though some clinicians use it routinely for all procedures. There is a risk of rare but potentially severe reactions such as methemoglobinemia. One approach is to limit its use to patients in whom minimal sedation or unsedated endoscopy is performed. Intravenous cannulas and supplemental oxygen The administration of sedative agents should be by means of a conveniently and securely placed intravenous cannula. ‘Butterfly needles’ may

cut tissue out of the vein during the procedure and should not be used. Intravenous fluids can be useful in some cases, such as if the patient is dehydrated due to bowel preparation or due to fasting, if the patient has renal impairment, or if hypotension occurs during the procedure. Oxygen can be administered via nasal prongs when upper endoscopy is performed, and via a Hudson mask for colonoscopy.

Management of oversedation Oversedation as manifested by reduced conscious state and respiratory depression or apnoea may initially manifest as a drop in oxygen saturation, though ideally it should be detected earlier by the clinical assessment of responsiveness (if conscious sedation is used), respiration or capnography. Initial management depends upon the degree of respiratory depression. This includes increasing supplemental oxygen (which may be administered via a Hudson mask rather than via nasal prongs), patient stimulation, airway management with the use of a ‘jaw thrust’ manoeuvre, and possibly withdrawal of the endoscope if gastroscopy is being performed. If these measures fail to resolve the situation, bag-and-mask ventilation should be performed and reversal medication such as flumazenil (for benzodiazepines) or naloxone (for opiates) should be administered. It should be noted that the half-life of these reversal agents is shorter than the active drugs, leading to the possibility that patients can slip back into deep sedation after the procedure. In practice this is a rare phenomenon. If the situation is deteriorating or additional help is required urgently, early notification of a medical emergency team is appropriate. Staffing The level of staffing depends upon the procedure being performed, but should ideally include a nurse to assist with the procedure such as the use of biopsy forceps, and a nurse allocated to monitor the patient and administer sedation. Training of staff with regard to the principles behind the use of sedative agents and management of oversedation is important, and regular training or education sessions should be attended. There should be at least one practitioner who has advanced resuscitation skills (such as endotracheal intubation, defibrillation and usage of resuscitation medications) available within 1–5 minutes. If propofol is used, a practitioner with experience in advanced life support should be dedicated solely to sedation and patient monitoring. Recently, the Australia and New Zealand College

28 Patient preparation and principles of sedation in gastrointestinal endoscopy of Anaesthetists, Gastroenterology Society of Australia and Royal Australian College of Surgeons have prepared a statement on appropriate staffing for different patient settings and anaesthetic agents. A regularly checked resuscitation trolley or kit should be available with equipment for endotracheal intubation, and a defibrillator should be available within several minutes. However, the vast majority of adverse events are related to oversedation and will respond promptly to bag and mask ventilation. Specific situations In the case of acute upper tract gastrointestinal haemorrhage, sedation of the patient during endoscopy must take into account the increased risk of aspiration. An estimate of this risk can be made on clinical criteria such as presentation (haematemesis versus melaena), the amount of bleeding, the haemoglobin and the haemodynamic status. If the patient is thought to have a high risk of aspiration, sedation should be delivered by an anaesthetist with prophylactic endotracheal intubation. Administration of a prokinetic agent (such as intravenous erythromycin) half an hour before the procedure may aid in gastric emptying. Intensive resuscitation including administration of blood products prior to the procedure is important to minimise anaesthetic risks, though in some cases if bleeding is ongoing it may not be possible to normalise the haemodynamic status and the procedure should be performed emergently. For patients presenting with an oesophageal foreign body, the risk of pulmonary aspiration of saliva or food contents is significantly increased. As such, for most patients endotracheal intubation should be performed prior to the procedure. Alternatively, the use of an overtube in the upper oesophagus may protect the airway.

ll

ll

ll

ll

ll

ll

ll

ll

Key Points ll

ll

Informed consent is critical to any endoscopic procedure. It is not merely a signed document, but rather a process whereby the patient comes to understand the indication and nature of a procedure as well as its risks, benefits and alternatives. There must be an opportunity for questions to be addressed. Adequate bowel preparation for colonoscopy is essential to reduce missed lesions. Hyperosmolar solutions such as sodium phosphate or sodium picosulfate-based preparations are usually better tolerated, but may lead to dehydration and must be used with caution in the elderly and those with renal impairment.

ll

389

Antibiotic prophylaxis is probably overused, but is important for ‘high risk’ patients undergoing ‘high risk’ procedures as well as mandatory for a few specific procedures (such as percutaneous endoscopic gastroenterostomy placement and drainage of pancreatic fluid collections). Diabetic patients comprise a special group requiring individualisation of their preparation for procedures, especially for those taking insulin. All endoscopic procedures can be safely performed while a patient is on aspirin. Therapeutic procedures such as polypectomy of significant polyps, stricture dilation and biliary sphincterotomy should not be preformed within a setting of anticoagulants such as warfarin or the newer antiplatelet agents such as clopidogrel. The management of these patients on these agents is complex and requires balancing the risk of the procedure and the potential consequences of cessation of the medication. A specific situation of note is the management of clopidogrel in patients with a recent coronary stent (especially a drug-eluting stent). The management of these patients must be done in collaboration with their cardiologist. All patients should undergo non-invasive monitoring during any sedated procedure including pulse, blood pressure and pulse oximetry. Capnography is very useful for those undergoing deep sedation in order to detect apnoea early. During any sedation an appropriately trained health professional whose sole purpose is to monitor the patient's wellbeing must be present. The mainstay of endoscopic sedation is a combination of short-acting benzodiazepine and narcotic. For both of these drug classes an effective, immediate reversal agent is available and must be on hand. Propofol is used to provide ‘deep sedation’, never ‘conscious sedation’, and must only be used if staff are trained in advanced airway management.

Further reading [Anonymous]. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002; 96(4):1004–1017. Australia and New Zealand College of Anaesthetists, Gastroenterology Society of Australia and Royal Australian College of Surgeons. PS9: guidelines on sedation and/or analgesia for diagnostic and interventional medical or surgical procedures, February 2008. Online.

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Banerjee S, Shen B, Baron TH, et al. Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 2008; 67(6):791–798. Burton JH, Harrah JD, Germann CA, et al Does end-tidal carbon dioxide monitoring detect respiratory events prior to current sedation monitoring practices? Academic Emergency Medicine 2006; 13(5):500– 504. Carbonell N, Pauwels A, Serfaty L, et al. Erythromycin infusion prior to endoscopy for acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial. Am J Gastroenterol 2006; 101(6):1211–1215. Cohen LB, DeLegge MH, Aisenberg J, et al. AGA Institute review of endoscopic sedation. Gastroenterology 2007; 133(2):675–701. Eisen GM, Baron TH, Dominitz JA, et al. Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 2002; 55(7):775–779. Evans LT, Saberi S, Kim HM, et al. Pharyngeal anesthesia during sedated EGDs: is ‘the spray’ beneficial? A meta-analysis and systematic review. Gastrointest Endosc 2006; 63(6):761–766. Ladas SD, Aabakken L, Rey JF, et al. Use of sedation for routine diagnostic upper gastrointestinal endoscopy: a European Society of Gastrointestinal Endoscopy survey of McQuaid KR, Laine L. A systematic review and meta-analysis of randomized, controlled trials of moderate sedation for routine endoscopic procedures. Gastrointestinal endoscopy 2008; 67(6):910–923.

National Endoscopy Society members. Digestion 2006; 74(2):69–77. Patel S, Vargo JJ, Khandwala F, et al. Deep sedation occurs frequently during elective endoscopy with meperidine and midazolam. Am J Gastroenterol 2005; 100(12):2689–2695. Rex DK. Review article: moderate sedation for endoscopy: sedation regimens for non-anaesthesiologists. Alimentary Pharmacology & Therapeutics 2006; 24(2):163–171. Robin C, Trieger N. Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature. Anesth Prog 2002; 49(4):128–132. Sorbi D, Gostout CJ, Henry J, et al. Unsedated smallcaliber esophagogastroduodenoscopy (EGD) versus conventional EGD: a comparative study. Gastroenterology 1999; 117(6):1301–1307. Vargo JJ, Zuccaro G, Jr, Dumot JA, et al. Automated graphic assessment of respiratory activity is superior to pulse oximetry and visual assessment for the detection of early respiratory depression during therapeutic upper endoscopy. Gastrointest Endosc 2002; 55(7):826–831. Veitch AM, Baglin TP, Gershlick AH, et al. Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures. Gut 2008; 57(9):1322–1329.

Index Page numbers followed by ‘f’ denote figures; those followed by ‘t’ denote tables; those followed by ‘b’ denote boxes abdominal angina 92–93 abdominal aortic aneurysm, ruptured 42–43 abdominal bloating 100 abdominal catastrophe 41 clinical clues to cause of 42t abdominal colic, acute 46–50 abdominal distention 100, 104, 263–270 classification of causes: the 'six Fs' 263–264, 265t clinical features ascites (fluid) 263–264, 266–267 faecal impaction of the colon 264, 267 flatus 263–266 obesity (fat) 264, 267 organomegaly 264, 267 pregnancy (fetus) 264, 267 history 264 investigations blood tests 267–268 plain radiology 267 ultrasound or CT of abdomen 267 possible symptoms 266t preliminary examination of the abdomen 263–264 See also ascites abdominal masses asymptomatic 246–262 audible 247 bimanually palpable on rectal or vaginal examination 254–255 blood tests 261, 261t bruit or silent 253–254 clinical clues 250, 251t enlarged organs 256–261 examination of the abdomen 247 features that need to be defined 252b imaging plain radiology 255 ultrasound and CT 255–256 nuclear medicine 261 office tests 255 palpable 247 percussion note 253 pulsatile or non-pulsatile 253 tender or non-tender 253, 254t

tissue diagnosis 262 vague symptoms 255b visible 247 abdominal pain, acute 37–65 abdominal rectopexy 215 abdominal wall hernias 247, 249b abdominal wall masses 247–249 abdominal wall pain 76 abnormal intestinal mobility 159 abnormal liver function profile, patients with 312–315 examination 313 history 312–313 investigation 307 abnormal sphincter 207b acalculous cholecystitis, acute 57–58 achalasia See oesophageal achalasia acid regurgitation 2, 106 clinical management 7 complications 2–3 investigations 4–7 acute abdominal colic 46–50 bowel obstruction 46–50 causes 47b acute abdominal pain 37–65 acute abdominal colic 46–50 acute epigastric pain 50–51 clinical evaluation 40 generalised abdominal pain 40–46 left iliac fossa pain 63–64 mechanisms 38 pathological causes 38–40, 40t acute inflammation 38–39 ischaemia 39 obstruction 39 tension in a solid organ 39–40 right iliac fossa pain 61–63 right upper quadrant pain 55–61 sites and types of pain related to different organs 37t–40t acute acalculous cholecystitis 57–58 acute appendicitis 61 conditions mimicking 62 management 62 signs of 62t

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Index

acute bloody diarrhoea causes 161b, 167–171 Campylobacter jejuni 169 Entamoeba histolytica 170–171 Escherichia coli 169–170 non-typhoidal salmonellosis 168 Salmonella 168 Shigella 167 typhoid fever 168–169 Yersinia enterocolitica 169 acute cholecystitis 56–57 complications 57b acute colonic pseudo-obstruction 47–48 acute diarrhoea 158–173 antibiotic-associated and C. difficile colitis 171–172 associated with AIDS 172–173 bloody diarrhoea, causes 161b, 167–171 caused by food-borne illness 162–164 clinical approach 159–162 cryptosporidiosis 172 history 161 investigations 161–162 pathophysiology 158–159 physical examination 161 therapy 162 travellers' diarrhoea 164–165 watery diarrhoea, causes 161b, 165–167 See also chronic diarrhoea; diarrhoea acute diverticulitis 64 acute epigastric pain 50–51 causes 50b further investigations 51 initial investigations 51 radiological findings 51t acute fatty liver of pregnancy 343–344 acute fluid collection, as complication of acute ­pancreatitis 53 acute gastric dilatation 265 acute hepatitis 315–316 examination 315 history 315 investigation 315 management 315–316 acute intermittent porphyria 93 acute intravascular haemolysis 296–297 acute liver disease 315–316 acute pancreatitis 39, 51–55 aetiology 51, 51t assessment of severity 52 complications 53t diagnosis 51–52 initial management 52 prognostic factors 52t severe 52 subsequent management 54–55 acute severe gallstone pancreatitis 52 acute upper gastrointestinal haemorrhage, in portal hypertension 320–322 acute viral gastroenteritis, and vomiting 111 acute watery diarrhoea causes 161b, 165–167 cholera 166

Giardia lamblia 165–166 viral infections 166–167 adenitis, mesenteric 62 adenocarcinoma gastric 234–235 oesophagus 11–12, 233–234 pancreas 231–233 adenomatous polyps 284–287, 285f Kudo pit pattern 285, 286f malignancy risk 285, 285t Paris classification 285, 286f surveillance 290 adhesive enteropathy 91 aerophagia 104 AIDS, diarrhoea associated with 172–173 alanine aminotransferase (ALT) 309 albumin levels 308–309 alcohol dependency, CAGE screening 334 alcoholic hepatitis 315–316, 333 alcoholic liver disease 333–334 tests for 333t alkaline phosphatase (ALP) 310 allergic reactions to food See food allergy alpha-1 antitrypsin deficiency 337 alpha-fetoprotein 310 alpha-interferon 331 5-amino salicylates 194, 201 amoebic liver abscess 59 ampulla of Vater, cancer of 298 anaesthesia for gastrointestinal endoscopy 385–389 anal abscess 145–150 aetiology 146b clinical features 150 primary 146–147 secondary 147–150 surgical treatment 150 anal canal cancer 290–291 anal canal, anatomy 145–146 anal cushions 151–152, 208 anal encirclement procedures 215 anal fissure 124, 142–145 aetiology 143 pathology 144 pathophysiology 144 site 144 clinical features 144–145 examination 144–145 history 144 primary 143 secondary 143 treatment 145 conservative 145 medical 145 surgery 145 anal fistula 142–143, 146–147 aetiology 146b clinical features 150 primary 146–147 secondary 147–150 surgical treatment 150 anal incontinence See faecal incontinence anal infection, spread of 146, 147f anal mucosa, sensory mechanism 208

Index anal mucosal prolapse 212 anal sepsis 213 anal sphincter 208, 209f aneurysms 260–261 femoral artery 272 angiodysplasia 124–125 angiography 12, 370 angioneurotic oedema 93 anorectal abnormalities 212–213 anorectal manometry 134, 209–210, 210f anorectal physiological examination 208–211 diagnostic tests 209–211 electrophysiology 210–211 anorexia 220 causes 221b clinical approach 222–226 history 222–223 investigations 223–226 pathophysiology 221 physical examination 223 anorexia nervosa 235–236 laboratory findings 236t antibiotics for Crohn's disease 201 for travellers' diarrhoea 165 for travellers' diarrhoea prevention 165 in gastrointestinal endoscopy 383, 383b resistance to 71 use for diarrhoea 162 antidiarrhoeal agents 162, 165 antiemetics 112 antireflux surgery 8–10 aphthous ulceration 31 appendicitis acute 61–62, 62t perforated 42 appetite 220 arterial ischaemia 39 Ascaris lumbricoides infections, and jaundice 298 ascites 263–264, 266–267, 350–351 and cirrhosis 266, 322–323 appearance 268 biochemistry 268 cardiac 266, 270 causes 266 cells 268 chylous 267–268 classification by serum-ascites albumin gradient 268, 269t culture 269 cytology 269 diagnosis 268–269 fever and pain 323–324 malignant 266, 269 management 269–270 pancreatic 263, 267–268, 270 aspartate aminotransferase (AST) 309 asymptomatic dilatation of the common bile duct 359–360 asymptomatic gallstones 358 asymptomatic palpable abdominal masses 246–262 asymptomatic stones in common bile duct 360 audible abdominal masses 247

autoimmune liver disease, tests for 311t autoimmune pancreatitis 362 azathioprine 196–197, 202 Bacillus cereus food poisoning 163 bacterial food poisoning 163 bacterial gastroenteritis, and vomiting 111 bad breath See halitosis Barcelona Clinic Liver Cancer staging system 349 Barrett's oesophagus 4, 10–12 belching 100, 103 benign hepatic mass lesions 343 benign intrahepatic cholestasis of pregnancy 344 benign mesenchymal tumours 371 benzodiazepines 113 in gastrointestinal endoscopy 387 Bernstein testing 5–7 bile duct benign strictures, and jaundice 298 See also common bile duct bile duct obstruction management 301–303 stones 302–303, 302f tumour 301–302 biliary cirrhosis, primary 338–339 biliary colic 56, 76 differential diagnosis 59–60 biliary incidentalomas 358–361 biliary obstruction, extrahepatic 297–298 biliary scan 369–370 bilirubin levels 294–295, 308 bilirubin overproduction 296–297 bilirubin pathway 293–294, 294f biofeedback therapy 136, 156 bismuth quadruple therapy 70 black stools See melaena bladder enlargement 261 bleeding peptic ulcers 121–122 surgery role 122 bloating 100, 104 blood per rectum See rectal bleeding blood tests abdominal distension 267 abdominal masses 261, 261t positive occult 127–128 bloody diarrhoea, acute 161b, 167–171 body mass index (BMI) 181, 220, 223, 375 borborygmi 100 botulinum toxin 25, 113, 137 bowel obstruction 39, 46–50 gastric outlet 50 large bowel 48–50, 264 small bowel 43–44, 44f, 46, 264 bowel preparation for colonoscopy 382 breath hydrogen testing for lactose intolerance 101 bright red blood per rectum See rectal bleeding Budd-Chiari syndrome 60, 342 budesonide, enteric-release 201–202 bulimia nervosa 236–237 burning mouth syndrome See glossodynia/­ glossopyrosis

393

394

Index

C breath test 73, 69f C breath test 69f C-D-xylose breath test 183 14 C-glycocholate test 183 14 C1 esterase deficiency 93 caecal carcinoma 63 caecal volvulus 49–50 caeruloplasmin 310, 337 calcineurin inhibitors 354b Campylobacter jejuni infection 169 candidiasis, oesophageal 16 capnography 386–387 carbohydrate digestion and absorption 179 cardiac ascites 266, 270 central nervous system disorders, and vomiting 111 cerebral oedema 317 chest pain, non-cardiac 12–14 Child-Pugh score 318, 318t Child-Turcotte-Pugh (CTP) score 66–67, 346, 349 cholangiogram, intravenous 300–301 cholangitis 303 primary sclerosing 339–340 cholecystitis acute 56–57 acute acalculous 57–58 gangrenous 57 cholecystoduodenal fistula 57 choledochal cysts 360–361 Todani classification 361t choledocholithiasis 61, 298, 302–303, 302f cholelithiasis 76 management 58 cholera 166 cholestasis 295–296, 310 intrahepatic 297 versus hepatocellular disease 310 cholestatic jaundice 295–298 cholesterol-containing stones 56 chronic anal fissure 144 chronic diarrhoea 174–189 approach to 176 assessment 176 causes 174–176, 183–188 clinical features 311t history 174–175 physical examination 175–176 See also malabsorption chronic duodenal ulcer 79f chronic epigastric pain 73–74 chronic pancreatitis 84–86 chronic peptic ulcer 75–76, 78–80 clinical assessment 74–75 functional dyspepsia 81–84 indigestion and dyspepsia 73 chronic haemolysis 296–297 chronic hepatitis 313–315 causes 314t chronic hepatitis B 327, 330 chronic intestinal pseudo-obstruction 92, 92b chronic liver disease and portal hypertension 319–322 signs of 314f See also cirrhosis 13 14

chronic lower abdominal pain 88–99 clinical evaluation 94–95 investigations 95 physical examination 95 differential diagnosis 90–94 'functional' bowel disorders 93–94 'organic' bowel disorders 90 history 88–90 character, intensity and duration of pain 89 modifying factors 89–90 site, radiation and referral of pain 89 chronic mesenteric ischaemia 92–93 chronic pancreatitis 76, 84–86 and jaundice 298 causes 85b clinical presentation 84–85 diagnosis 85 treatment 85–86 chronic peptic ulcer aetiology and pathophysiology 78–79 and NSAIDs 75, 79–80 and Zollinger-Ellison syndrome 75, 80–81 H. pylori infection 75, 78, 80, 82 surgery 80 surgical complications 82b treatment 79–80 chronic perianal pain syndromes 155–156 chylous ascites 267–268 ciguatera fish poisoning 164 cirrhosis and ascites 266, 322–323 and hepatic encephalopathy 324–325 and portal hypertension 319–322 causes 314t compensated 346–347 medication counselling 347–348 surgery counselling 348 decompensated 349 patients presenting with 318–319 primary biliary 338–339 well patient with 319 Clonorchis sinensis infections, and jaundice 298 Clostridium botulinum food poisoning 163 Clostridium difficile infection 162 and antibiotic-associated diarrhoea 171–172 Clostridium perfringens food poisoning 163 coagulopathy 317 coccygodynia 143, 155 coeliac disease 183–185 aetiology 183 associations with 185 clinical features 183 diagnosis 183–185 serological tests 184 treatment 185 colectomy 136–137 colic acute abdominal 46–50 biliary 56, 59–60 colitis Clostridium difficile 171–172 collagenous 189 ischaemic 45–46, 64, 125, 125f

Index microscopic 189, 199 ulcerative 191–198 coloenteric fistula 64 colonic enlargement 260 colonic motility and normal small bowel 95–96 colonic pseudo-obstruction, acute 47–48 colonoscopy 132, 162, 193–194, 200, 286–287 bowel preparation for 382 colorectal cancer 149–150, 279–292 aetiology 283 chemotherapy 289 Dukes' classification 287 follow-up 289 Haggitt's level of carcinoma invasion 288, 288f, 288t history 281 incidence 279, 283 investigation 282 left-sided 281 physical examination 282 polyps and the polyp-cancer sequence 284–287 preoperative assessment 282t right-sided 281 screening 289–290 staging 287 TNM classification 287t treatment 287–289 in ulcerative colitis 197–198 colovaginal fistula 64 colovesical fistula 64 columnar lined oesophagus See Barrett's ­oesophagus common bile duct asymptomatic dilatation 359–360 asymptomatic stones 360 stones, risk factors 58b See also bile duct compensated cirrhosis 346–347 computerised tomography abdominal distension 267, 268f abdominal masses 255–256 biliary disease 299 enlarged abdominal organs 256–261 pancreatic adenocarcinoma 232 conditioned reflexes, and nausea/vomiting 111–112 conjugated bilirubin 294–295, 308 constipation 124, 130–140 and large bowel obstruction 47 and left iliac fossa pain 64 and neurological diseases 139 and perianal pain 142 and spinal cord lesions 139 autonomic neuropathy 139 classification in adults 131b clinical approach 131–132 diagnostic approach 133f endocrine and metabolic causes 139 history 131–132 hospitalised patients 137 idiopathic slow-transit 138 in diabetes mellitus 139 in elderly persons 137 investigations 132–135

395

ano-rectal manometry, sensation and balloon expulsion 134 colonic transit studies 133–134 colonoscopy 132 dynamic proctography 134 haematology and biochemistry 132 motility studies 134 radiology 132–133 rectal biopsy 134–135 management 135–136 biofeedback 136 general measures 135 surgical treatment 136–137 therapeutic agents 135–136 megacolon 138–139 physical examination 132 simple 137 spinal cord lesions 139 continence definition 206 physiology 208–209 See also faecal incontinence coronary angiography 12 corticosteroids for Crohn's disease 201 enteric-release 201 for ulcerative colitis 195 Crigler-Najjar syndrome 297 Crohn's disease 63, 91–92, 147, 198–204 aetiology 198–199 antibody testing 200 clinical presentation 199 complications 201 diagnosis 199–200 differential diagnosis 199 disease location and behaviour 199 haematology and biochemistry 199–200 malignancy risk 203 management issues 204b Montreal classification 199t pathology 200 perforating (fistulising) 202–203 radiology 200–201 stool biomarkers 199 stool culture and examination 199 surgery 203 treatment 201 cryptoglandular abscess 146–147 cryptosporidiosis 172 Cryptosporidium parvum infection 172 cyclical vomiting 113 cyclosporins 196 cystadenocarcinoma 362–363, 365 cystic hepatic incidentalomas 364 cystic neoplasms of the pancreas 362–363 cytomegalovirus oesophagitis 16 decompensated cirrhosis 349 delivery phase defects 179b Delormes procedure 215 dentures, and glossodynia 31 dermatitis herpetiformis 182f descending perineum syndrome 155–156

396

Index

diabetes and abdominal pain 93 and anal sepsis 150 and constipation 139 and dyspepsia 76 and glossodynia 31 diarrhoea acute See acute diarrhoea and abnormal intestinal mobility 159 and incontinence 211–212 and normal physiology 158 chronic See chronic diarrhoea definition 158 exudative 159 osmotic 158–159 pathophysiology 158–159 secretory 159 travellers 164–165 diet diary 243 diet and halitosis 35 in acute diarrhoea 162 cirrhosis and 10005#s0100 in Crohn's disease 203 elimination 243 dietary fibre, and IBS 97–98 difficulty swallowing See dysphagia diffuse oesophageal spasm 13 diverticular disease 49, 63–64, 90 complications 64 diverticulitis, acute 64 diverticulosis 125 diverticulum Meckel's 62–63 perforated 42 droperidol in gastrointestinal endoscopy 388 drug-induced oesophageal ulceration 16 drugs and the liver 340, 341t–342t as cause of dyspepsia 76 as cause of vomiting 111 Dukes' classification of colorectal cancer 287 duodenal obstruction 302 duodenal ulcer 80, 121–122 D-xylose urine test 181 dynamic proctography 134 dyspepsia and gastric cancer 75 causes 76 clinical assessment 74–75 definition 73 differential diagnosis 75 functional (non-ulcer) 76, 81–84 management 76–78, 77f organic 75 overlap with other syndromes 74 subtypes 74 dysphagia 3, 16–26 approach to 17–21 associated with heartburn and regurgitation 12 causes 16–17, 17b–18b, 21 diagnostic and therapeutic algorithm 23 high-grade 11–12

investigation 22–24 oesophageal 19–21, 18b, 23–26 oral-pharyngeal 16–17, 19, 22–23, 26 physical examination 21–22 site of bolus hold-up 19 treatment 24–26 Echinococcus granulosus 60 Echinococcus multilocularis 60 ectopic pregnancy, ruptured 43 electromyography 211, 212f empyema of the gall bladder 57 encysted hydrocoele of the cord 273–274 end-stage liver disease 346–353 endoanal ultrasound 211 endocrine diseases 188 endocrine tumours of the pancreas 363t endometriosis 90–91 endoscopic retrograde cholangiopancreatography (ERCP) 52, 55f, 85, 182, 300, 382–383 endoscopy, gastrointestinal for H. pylori 68–69 for jaundice 299–300 of pancreas 370 endoscopy, gastrointestinal, anaesthesia for 385–389 airway management problems 386b ASA classification of risk 386t blood pressure monitoring 387 clinical states of sedation 386t logistics of administering sedation 385–386 medications in sedation 387–388 benzodiazepines and opiates 387 droperidol 388 intravenous cannulas and supplemental oxygen 388 pharyngeal anaesthesia 388 propofol 387–388 unsedated endoscopy 387 oversedation management 388–389 specific situations 389 staffing 388–389 patient assessment 385 patient monitoring 386–387 pulse oximetry 386 capnography 386–387 patient who should be sedated by anaesthetist 385 endoscopy, gastrointestinal, patient preparation 382–385, 384f antibiotic prophyaxis 383, 383b bowel preparation for colonoscopy 382 disease-specific issues 383–385 endoscopic retrograde cholangiopancreatography 382–383 informed consent 382 enlarged abdominal organs 256–261 enlarged lymph nodes 259, 275 management 277 Entamoeba histolytica 59, 170–171 enteral feeding 228–230 enteric-release budesonide 201–202 enteric-release corticosteroids 201 enteroaggregative E. coli (EAEC) 169–170 enterocytes 176–179

Index enterohaemorrhagic E. coli (EHEC) 169–170 enteroinvasive E. coli (EIEC) 169–170 enteropathogenic E. coli (EPEC) 169–170 enteropathy-associated T-cell lymphoma (EATL) 186 enterotoxigenic E. coli (ETEC) 169–170 eosinophilic gastroenteritis 186–187 epigastric pain acute 50–51 chronic 73–87 differential diagnosis 75t underlying mechanisms 73–74 erosive oesophagitis 3–4, 4f erythropoiesis, ineffective 297 Escherichia coli infection acute bloody diarrhoea 169–170 travellers' diarrhoea 164 excess gas causes 100 composition 103 history 100 investigations 100–102 laboratory tests 102–103 physiology of gas 103 physical examination 100 symptoms 103–105 external prolapse at the anus, causes 208b extraadrenal endocrine tumours 371–372 extrahepatic biliary obstruction 297 extrahepatic obstructive jaundice 297–298 extrasphincteric fistula 147, 149f exudative diarrhoea 159 faecal antigen test 68 faecal fat excretion 180 faecal impaction of the colon 264, 267 faecal incontinence 206–219 causes with a normal sphincter 207b, 211–213 with an abnormal sphincter 207b, 213–218 examination 207–208 history 207 physiological anorectal examination 208–211 simplified Wexner scoring system 207t See also neurogenic incontinence faeces, in abdominal distension 264, 267 familial adenomatous polyposis (FAP) 283–284, 284f familial Mediterranean fever 93 fat assimilation 179 fat, and abdominal distension 264, 267 fatty liver disease acute, of pregnancy 343–344 non-alcoholic 332–333 fatty stools 174–189 femoral artery aneurysm 272 femoral hernias 271, 274–275 management 276–277 femoral region anatomy 274–275 lumps in 274–276 physical examination 275 uncertain diagnosis 275–276 fetus, and abdominal distension 264, 267

397

fibronodular hyperplasia 367 fissure-in-ano See anal fissure flatus 100, 103 excessive 104–105 in abdominal distension 263–266 odour of 103 fluid, and abdominal distension 263–264, 266–267 focal nodular hyperplasia 60 food allergens, identification 249 food allergy 238–245 history and physical examination 238–239 incidence 240 investigations 241 morbidity and mortality 240 pharmacological management 241–242 physical examination 240 food intolerance 242–243 food poisoning bacterial 163 non-bacterial 164 food reactions acute management 241 pathophysiology 240 pharmacologically related 243 food regurgitation 2 food-borne illnesses, causes of 162–164 foods, adverse reactions to 246 fulminant hepatic failure 316–318 assessment and management 316–318 history 316 infection 317 Kings College Criteria for 316t prognosis 317–318 functional (non-ulcer) dyspepsia 76, 81–84 clinical features 84b pathophysiology 81–83 treatment 83–84 functional abdominal bloating 94 functional abdominal pain syndrome 94 'functional' bowel disorders 93–94 clinical features 94b See also irritable bowel syndrome functional vomiting 113 fundoplication 9–10, 9f gallbladder enlargement 258 polyps 358–359 gallstones 56–58 and jaundice 298, 302–303 asymptomatic 358 complications 57b management 58 gamma-glutamyl transpeptidase (GGT) 310 gangrenous cholecystitis 57 Gardener's syndrome 284 gas See excess gas gas bloat 265–266 gaseous distension of the bowel 263–266 gastric carcinoid 235 gastric carcinoma 76, 234–235 aetiology 234 clinical features 234

398

Index

gastric carcinoma (Continued) diagnosis 234–235 pathology 234 prognosis 235 risk factors 235b treatment 235 gastric dilatation, acute 265 gastric electrical stimulation 113 gastric enlargement 258 gastric erosions 122 gastric histology 69–70 gastric obstruction, and vomiting 110 gastric outlet obstruction 50 gastric stasis, and functional dyspepsia 82 gastric ulcer See peptic ulcer gastrinoma See Zollinger-Ellison syndrome gastroduodenal sensitivity, and functional ­dyspepsia 82 gastrointestinal gas composition 103 mechanisms influencing rate of accumulation 104f gastrointestinal haemorrhage, in portal ­hypertension 320–322 gastrointestinal sensorimotor dysfunction 96–97 gastrointestinal stromal tumours (GIST) 235 gastro-oesophageal reflux disease 1 and glossodynia 31–32 anti-reflux surgery 8–10 as cause of odynophagia 16 failure of proton pump inhibitor therapy 8 pathophysiology 3–4 pH monitoring 5 symptoms 74 upper gastrointestinal endoscopy 5 upper gastrointestinal radiology 5 gastroparesis 113 generalised acute abdominal pain 40–46 causes and clinical features 41t investigations 43t specific management of conditions causing 41–46 See also abdominal catastrophe giant migrating contractions 96 Giardia lamblia acute watery diarrhoea 165–166 chronic diarrhoea 176 food poisoning 164 Gilbert's disease 296 gingivitis 34 glossodynia/glossopyrosis (burning mouth ­syndrome) 31–33 aetiology 31–32, 32b glue sniffing 316 gluten-sensitive enteropathy See coeliac disease Goodsall's rule 151f groin lump 271–278 causes 271b history 271–272 management 276–278, 276f enlarged lymph node 277 femoral and inguinal hernias 276–277 generalised lymphadenopathy 277–278 psoas abscess 278

saphena varix 278 painful lump 272 painless lump 271 physical examination anatomical localisation of the lump 272 lumps in femoral region 274–276 lumps in inguinal region 272–274 reducibility 272 guaiac test 127 haemangiomas 343, 367 haematemesis 115–129 causes 116b, 119–121 gastric or duodenal ulceration 121–122 oesophageal varices 119–121 management 116–119 active bleeding 117 airway 116 discharge from hospital 122 endoscopy 118–119 hypotension/shock 116–117 indications for blood transfusion 117, 117b source of bleed 117–118 risk factors 119b haemoccult test 127 haemochromatosis 310, 334–336, 336f clinical features 335f haemolysis acute intravascular 296–297 chronic 296–297 haemorrhoids 124, 142, 150 anatomy 150 clinical features bleeding 152 discomfort 152 incontinence 153 prolapse 152 pathophysiology 151–152 prolapsing 212–213, 153f thrombosed 142, 152 thrombosed external 153–154 treatment 153 Haggitt's level of carcinoma invasion 288, 288f 288t halitosis 33–35 and excess wind 103 approach to 34–35, 34b causes 33b pathogenesis 33–34 treatment 35 heartburn 1–2 and oesophagitis 4 clinical management 7 investigation 4–7 Helicobacter pylori 75, 78, 121, 234 gastritis 82 Helicobacter pylori testing advantages/disadvantages of 68t clinical practice 71 diagnostic tests 66–73 indications for diagnosis and treatment 67b initial 71 integration into clinical practice 71 management 67–71

Index non-invasive (non-endoscopic) tests 67–68 pathogenesis 66–67 post-theraoy 71 treatment 70 failure 71 side effects 71t HELLP syndrome 344 hepatic abscesses 59 hepatic adenoma and focal nodular hyperplasia 60 and hepatocellular carcinoma 367 hepatic cystadenocarcinoma 365 hepatic cystadenoma 365 hepatic cysts 343 hydatid 364–365 simple 364 hepatic encephalopathy 317, 349–350 and cirrhosis 324–325 factors precipitating 325b grades of severity 324t management 325 nomenclature 324b hepatic failure, fulminant 316–318 hepatic function tests 308–309 hepatic graft versus host disease (GVHD) 305 hepatic haemangiomas 367 hepatic incidentalomas 343, 364–370 benign 343 cystic 364 invasive diagnostic procedures 370 investigation of incidental, scan-detected lesions 366f radioactive pharmaceutical imaging 369–370 solid 365–369 hepatic ischaemia 342 hepatic jaundice 295 hepatic metastasis 59, 367–368 hepatitis A virus (HAV) 327 food poisoning 164 vaccination 327 hepatitis B virus (HBV) 327–330 active immunity 327 mutant varieties 330 passive immunity 328 phases of infection 329t transmission 328 hepatitis B, chronic 327–328 hepatitis C virus (HCV) 330–332 transmission 331 treatment 331 hepatitis D virus (HDV) 330 hepatitis E virus (HEV) 332 hepatitis G 332 hepatitis acute 315–316 alcoholic 315–316, 333 chronic, 313–314, 314t idiopathic, autoimmune chronic 337–338 viral 305, 312t hepatobiliary scintigraphy 300 hepatocellular carcinoma 60, 332, 342–343 cirrhosis and 348–349 hepatocellular disease

399

primary 295–296 versus cholestasis 310 hepatomegaly, causes 256b hepatorenal syndrome 352–353, 353b hepatosplenomegaly, causes 259b hereditary non-polyposis colorectal cancer (­HNPCC) 284, 290 hernias and types of pain 272 femoral 271, 274–275, 277 hiatus 3, 9–11, 9f incarcerated 272 inguinal 272–273, 276–277 herpes simplex oesophagitis 16 herpes simplex ulcers 31 hiatus hernia 10–11 rolling 10–11 sliding 9–11, 9f hiccup 27–31 aetiology 28 and achalasia 28 and reflux 28 approach to 28–30 intractable 27–30 pathophysiology 27–28 physical examination 29–30 sequential approach to suppression of 30–31 treatment 30 hidradenitis suppurativa 146 Hirschsprung's disease 134–135, 137 HIV, and jaundice 304–305 hunger 220 hydatid cyst 60 hydatid disease 364–365, 365f 366t hydration for travellers' diarrhoea 165 in acute diarrhoea 162 hydrogen breath test 181 hydrophilic bulk-forming agents 135–136 hyperbilirubinaemia 293–296 hypertensive lower oesophageal sphincter 13 hypoglycaemia 317 hypoproteinaemia 267 hypotension 317 hypovolaemia 352 idiopathic perianal and perineal pain 156 idiopathic slow-transit constipation 138 idiopathic, autoimmune chronic hepatitis (IACH) 337–338 IgE immunoassays 241 ileitis, terminal 62 immunocompromised patient, jaundice in, 304–305 immunosuppression, and anal infections 148 impaired delivery of bilirubin to the liver 297 impaired fundic relaxation, and functional ­dyspepsia 82 incarcerated hernias 272 incidentaloma 356–374 biliary 358–361 diagnosis and management 356–358 hepatic 343, 364–370

400

Index

incidentaloma (Continued) investigation plan 357–358, 357b pancreatic 361–363 incontinence algorithm 218f faecal 206–219 neurogenic 207–208, 210–211, 217–218 indigestion 1–3, 73–87 definition 73 infected pancreatic necrosis 53 inflammation intraperitoneal 38–39 non-intraperitoneal 39 inflammatory bowel disease 125, 147–148, 190–205 common symptoms 191b Crohn's disease 63, 91–92, 147–148, 192, 198–204 extraintestinal manifestation 192t health maintenance in 203–204 in pregnancy 203 ulcerative colitis 191–198 infliximab 195–196 informed consent for gastrointestinal endoscopy 382 infranuclear lesions, and faecal incontinence 214 inguinal hernias 272–273 direct and indirect 273–274 management 276–277 reducible or irreducible 273–274 inguinal region, anatomy 274–275 international normalised ratio (INR) 309 intersphincteric abscess 146 intersphincteric fistula 146, 148f intestinal angina 76 intestinal ischaemia, and dyspepsia 76 intestinal lymphoma 186 intestinal mobility, abnormal 159 intestinal obstruction, and vomiting 110 intestinal pseudo-obstruction 265 chronic 92, 92b intraabdominal masses 249–255 clinical clues 251t features that need to be defined 252b mobility 252 movement with respiration 250–252 organ of origin 250t relation to the costal margin and the brim of the pelvis 252 shape, edge and consistency 252 single or multiple 252 site 249–250 intractable hiccups 27 approach to 28–30, 29b causes 28, 29b treatment 30b intrahepatic cholestasis 297–298 benign, of pregnancy 344 intraperitoneal inflammation 38–39 intravenous cholangiogram 300–301 iron-containing stools 123 iron deficiency anaemia 126–127 irritable bowel syndrome (IBS) 93–98, 265 gastrointestinal sensorimotor dysfunction 96–97 behavioural factors 96 dietary factors 96–97

pathophysiology 95 treatment 97–98 diet and role of fibre 97–98 if there is no improvement 98 medications 98 when to review the diagnosis 98 ischaemia 39 hepatic 342 intestinal 76 small bowel 44–45 ischaemic colitis 45–46, 64, 125, 125f jaundice 293–306 and acute right upper quadrant pain 58–59 cholestatic 295–296 clinical syndromes 296–298 diagnostic tests laboratory evaluation 298–299 organ imaging 299–301, 299t hepatic 295 in cirrhosis 349 immunocompromised patient 304–305 liver function tests 295t obstructive 295–296, 301–303 physiology 293–294 postsurgical 303–304 prehepatic 295–297 sick patient with 315–316 kidney enlargement 259–260 kidney injury in cirrhotics 352f L-ornithine L-aspartate 349–350 labelled red cell scan 369 lactase deficiency 90, 242 lactate dehydrogenase (LDH) 310 lactose breath hydrogen test 101 lactose intolerance 101, 242–243 lamivudine 330 laparoscopic adjustable gastric band (LGB) 377, 377f large bowel obstruction 48–50 lead poisoning 93 leakage of stool See faecal incontinence left iliac fossa pain 63–64 constipation 64 diverticular disease 63–64 gastrointestinal causes 63b ischaemic colitis 64 sigmoid colon cancer 64 leucopenia 148 levator ani syndrome 156 lipolytic phase defects 179b lipoma of the cord 274 liver biopsy 300, 310–311, 370 liver disease alcoholic 333–334, 333t and drugs 340, 341t–342t approach to patient with 307 drug-induced 305 in pregnancy 325–326, 326t symptoms and signs 308b See also chronic liver disease liver enlargement 256–258

Index liver failure, fulminant/acute 316–318 liver function test interpretation 308–309 alpha-fetoprotein 310 autoantibodies 310 autoimmune liver disease 311t bilirubin 308 cholestasis versus hepatocellular disease 310 hepatic function tests 308–309 liver injury tests 309–311 metabolic disorders 311t viral hepatitis 312t liver function test results, patients with abnormal 312–315 liver injury tests 309–311 liver transplantation 353–354 for alcoholic liver disease 334 for chronic hepatitis B 330 for hepatitis C 332 liver, vascular and perfusion disorders 340–342 liver/spleen scan 369 loss of appetite See anorexia loss of weight See weight loss lower abdominal pain, chronic 88–99 lump in the groin See groin lump lymph node enlargement 259 lymph node masses 371 lymph nodes, inflamed 272 lymphadenitis 277 lymphadenopathy, generalised 277–278 'lymphatic look' (femoral region) 275 magnetic resonance cholangiopancreatography, 300, 357 magnetic resonance imaging, for jaundice 300 magnetic resonance pancreatogram 182 malabsorption 176–179 causes 181–188, 181b classification 179b clinical approach 180–183 confirming 180–181 history 181 investigations 181–183 physiology 176–179 suspecting 180 typical test results 180t maldescended testis 273 malignant ascites 266, 269 Mallory-Weiss tear 122 MALT lymphoma 71 mass movements 96 massive rectal bleeding 125–126 mechanical obstruction of the bowel (small or large) 264 Meckel's diverticulum 62–63 Meckel's scan 126 Mediterranean fever, familial 93 megacolon 138–139 melaena 122–123 melanosis coli 133f MELD (Model for End Stage Disease) score 318 6-mercaptopurine 196–197, 202 mesalamine 194–196, 195t, 201 mesenchymal tumours, benign 371

401

mesenteric adenitis 62 mesenteric angina 76 mesenteric cysts 373 mesenteric ischaemia, chronic 92–93 mesenteric lymph node masses and neoplasms 373 mesenteric masses 373 metabolic disorders affecting the liver, tests for 311t and vomiting 111 methotrexate 202 micellar phase defects 179b microscopic colitis 199 microvascular angina 12 migrating motor complexes 95–96 mineral deficiencies, clinical findings 226t Minnesota tube 120 Model for End Strage Liver Disease (MELD) 346, 352–353 morning sickness 111 motion sickness 112 mucinous cystadenoma 362–363 mucocoele of the gall bladder 57 mucosal disease 187 mucosal phase defects 179b multiple endocrine neoplasia (MEN) 372b Murphy's sign 56 muscle-layer disease 187 musculoskeletal conditions, and chest pain 12 mushroom poisoning 316 natalizumab 202 nausea common causes 107b consequences of 110 definition 106 diagnostic algorithm 109f diseases causing 110–112 history 107–108 investigation 108–110 medical therapy 112–113 physical examination 108 principles of treatment 112–113 nerve conduction studies, anal mucosa 208 neurogenic incontinence 210–211, 217–218 aetiology 217 clinical features 217 treatment 217–218 neurological conditions, in faecal incontinence 214 neuromuscular agents, for constipation 136 non-alcoholic fatty liver disease 332–333 non-alcoholic steatohepatitis 332–333 non-bacterial food-borne illnesses 164 non-cardiac chest pain 12–14 non-steroidal anti-inflammatory drugs See NSAIDs non-typhoidal salmonellosis 168 normal sphincter 207b, 211–213 norovirus 167 Norwalk virus 166–167 NSAIDs and chronic peptic ulcer 75, 79–80, 121–122 and dyspepsia 76 as cause of nausea and vomiting 111 H. pylori testing and 71

402

Index

nutcracker oesophagus 13 nutritional assessment 181, 225 obesity and abdominal distension 264, 267 cirrhosis and 347 medical management 375–376 surgical management 376–378 laparoscopic adjustable gastric band (LGB) 377, 377f outcomes 377–378 pros and cons 378 roux-en-Y gastric bypass (GBP) 376–377, 377f sleeve gastrectomy 377, 377f obstruction bile duct 301–303 bowel (small or large) 39, 46–50, 264 duodenum 302 gastrointestinal tract 39 portal vein 340 obstructive jaundice 295–296 extrahepatic 297–298 management 301–303 occult blood test, positive faecal 127–128 odynophagia 3, 15–16 causes 15b drug-induced oesophageal ulceration 16 gastro-oesophageal reflux disease 16 oesophageal candidiasis 16 oesophageal achalasia 19, 21, 23f, 24–25, 27–28 oesophageal biopsy at upper gastrointestinal ­endoscopy 5 oesophageal cancers 233–234 oesophageal candidiasis 16 oesophageal conditions, and chest pain 13–14 oesophageal dysphagia causes 18b endoscopy 23 oesophageal manometry 24, 24f radiology 23–24 treatment 24–26 oesophageal manometry 7, 24 oesophageal motility disorders 13t oesophageal rings and webs 24–25 oesophageal strictures 24–25 oesophageal varices 119–121, 320 cirrhosis and 347 haemorrhage 350 oesophagitis and heartburn 4 cytomegalovirus 16 herpetic 16 peptic 3 reflux 16 ulcerative 122 Ogilvie's syndrome 47–48 omentum enlargement 260 opiates in gastrointestinal endoscopy 387 oral care, for halitosis 35 oral mouthwashes 35 oral ulceration 31 oral-pharyngeal dysphagia 21

causes 16–17, 17b investigation 22–23 treatment 24–26 organ transplantation, and jaundice 305 'organic' bowel disorders 90 organic dyspepsia 75 organomegaly 256–261 and abdominal distension 264, 267 orthotopic liver transplantation 353–354 osmotic diarrhoea 158–159 osmotic laxatives 136 osteoporosis, cirrhosis and 347 ovarian enlargement 261 pain on swallowing See odynophagia palpable abdominal masses 247 pancreatic abscess 54 pancreatic adenocarcinoma 363 pancreatic ascites 263, 267–268, 270 pancreatic cancer 76, 231–233, 258–259, 362–363, 363t and bile duct obstruction 301 and jaundice 298 clinical features 231–232 diagnosis 232 pathogenesis 231 treatment 232–233 pancreatic cysts 362 pancreatic enlargement 258–259 pancreatic incidentalomas 361–363 pancreatic necrosis 52–54, 54f pancreatic pseudocyst 53–54, 55f pancreatitis acute 39, 51–55 and malabsorption 182 autoimmune 362 chronic 76, 84–86, 298 focal 362 severe 52 panic attacks, and chest pain 12–13 paracetamol overdose 316 paralytic ileus 264–265 pelvic floor repair 137 pelvic inflammatory disease 91 peptic oesophagitis 4 peptic ulcer bleeding 121–122 chronic 75–76 perforated 41–42 surgery, complications 82b per rectum evacuants 136 percutaneous transhepatic cholangiography (PTC) 300 perforated appendicitis 42 perforated peptic ulcer 41–42 perforated sigmoid diverticulum 42 perfusion disorders of the liver 340–342 perianal abscess 143, 150f perianal mass causes 279b history 279 physical examination 280 sigmoidoscopy and proctoscopy 280–281

Index See also anal canal cancer; colorectal cancer; familial adenomatous polyposis perianal pain 141–157 causes 142b anal fissuren 143–145 anal sepsis 145–150 coccygodynia 155 descending perineum syndrome 155–156 haemorrhoids 150–154 idiopathic perianal and perineal pain 156 levator ani syndrome 156 proctalgia fugax 155 pruritis ani 154–155 examination inspection 142–143 palpation 143 proctoscopy 143 rigid sigmoidoscopy 143 history 142 management 156 referred 156 perianal sepsis 213 perineal neuralgia 156 perineal rectosigmoidectomy 215 periodontal disease 34 peristaltic reflex 95–96 peritoneal masses 373 peritoneal pain 38–39 peritonitis, spontaneous bacterial 268, 323–324 pH monitoring, gastro-oesophageal reflux 4 pharyngeal anaesthesia 388 pharyngeal dysphasia See oral-pharyngeal ­dysphasia pigment stones 56 pilonidal sinus 146 plain abdominal X-ray examination abdominal distension 267, 267f–268f abdominal masses 255 polycystic liver disease 364 portal hypertension 319–322 and acute upper gastrointestinal haemorrhage 320–322 classification of causes 320b portal systemic shunts 297, 321f positive faecal occult blood test 127–128 postoperative jaundice, distinguishing features 304t pouchitis 198 pre-eclampsia, and liver disease 344 pregnancy acute fatty liver 343–344 and abdominal distension 264, 267 and nausea/vomiting 111 benign intrahepatic cholestasis of 344 liver disease in 325–326, 326t prehepatic jaundice 295–297 primary biliary cirrhosis 338–339 primary sclerosing cholangitis 339–340 proctalgia fugax 155 proctitis, ulcerative 125 proctography 211, 214f proctoscopy 143, 208, 280–281, 281f prognostic nutritional index (PNI) 225 prokinetic agents 112–113 prolapse of anal cushions, classification 152

prolapsing haemorrhoids 212–213 propofol in gastrointestinal endoscopy 387–388 protein assimilation 179 protein-losing enteropathy 188 prothrombin time 309 pruritis ani 142–143, 154–155 aetiology 154 instructions to patients 155b management 154–155 pruritis 303 pseudoaneurysm (femoral artery aneurysm) 272 pseudocysts 362 psoas abscess 278 psychiatric disease, and vomiting 111 psychosocial factors, and functional dyspepsia 82–83 puborectalis muscle 208, 209f pudendal motor latency 210–211, 211f pulse oximetry 386 pyogenic liver abscess 59 aetiology 60t radiation enteritis 188 rapid urease test 78 rectal balloons 134 rectal biopsy 134–135 rectal bleeding 123–126, 142 causes 123b, 124–125 examination 123–124 massive 125–126 rectal cancer See colorectal cancer rectal mass 279–281 causes 279b history 279–280 physical examination inspection 280 palpation 280 sigomoidoscopy and proctoscopy 280–281 See also anal canal cancer; colorectal cancer; familial adenomatous polyposis rectal polyps 124 rectal prolapse 208, 214–215, 215f aetiology 214 clinical features 214–215 treatment 214 recto-sphincteric reflex 134 referred abdominal pain 38, 76, 93 referred epigastric pain 73–74 reflux oesophagitis, classification 4t refractory ascites 350–351 regurgitation See acid regurgitation renal failure 317, 352–353 retroperitoneal masses 249, 371–373 right heart failure 60 right iliac fossa pain 61–63 differential diagnosis 61b specific management 62–63 right upper quadrant pain 55–61 after previous cholecystectomy 60–61 and jaundice 58–59 causes 56b other than gallstones 59t gallstones 56–58

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Index

rolling hiatus hernia 10–11 rotavirus, as cause of watery diarrhoea 167 roux-en-Y gastric bypass (GBP) 376–377, 377f rumination 106 ruptured abdominal aortic aneurysm 42–43 ruptured ectopic pregnancy 43 ruptured pathological organ 44 Salmonella choleraesuis 168 Salmonella enterica 168 Salmonella enteritidis 168 Salmonella infections 168 Salmonella paratyphi 168 Salmonella typhi 168–169 saphena varix 271–272, 275 Schilling's test 183 scintigraphy, hepatobiliary 300 secretory diarrhoea 159 Sengstaken-Blakemore tube 120, 120f sequential therapy 70 serous cystadenoma 362–363 serum albumin 308–309 serum bilirubin 308 measurement 294–295 serum transaminase 309, 315 serum-ascites albumin gradient (SAAG) 268 severe pancreatitis 52 Shigella infections 167 short bowel syndrome 187 sigmoid colon cancer 64 sigmoid volvulus 49, 49f sigmoidoscopy 143, 162, 176, 193–194, 200, 208, 280–281, 281f simplified Wexner scoring system for faecal ­incontinence 207t singultus See hiccups skin-prick tests 241 sleeve gastrectomy 377, 377f sliding hiatus hernia 9–11, 9f small bowel biopsy 183–184, 184b small bowel disease, and malabsorption 182 small bowel ischaemia 44–45 small bowel masses, causes 260, 260t small bowel motility 134 small bowel obstruction 43–44, 44f, 46 small bowel, normal, and colonic motility 95–96 small intestinal bacterial overgrowth 187–188 solid hepatic incidentalomas 365–369 somatic pain 73–74 sore mouth 31–33 sphincter division 137 sphincter of Oddi dysfunction 61 sphincter trauma 215–216 aetiology 215–216 clinical features 216 treatment 216 sphincterotomy 145 spinal cord lesions, and constipation 139 spinal disease 93 splenomegaly, causes 259, 259b spontaneous bacterial peritonitis 268, 323–324, 351 Staphylococcus aureus food poisoning 163 steatohepatitis, non-alcoholic 332–333

steatorrhoea 188 stimulant laxatives 136 stoma 137 stomach enlargement 258 stool biomarkers 193, 199 stool consistency, and continence 209 stool examination, for acute diarrhoea 162 stool leakage See faecal incontinence stool-softening agents 136 stools black See melaena buoyancy of 104 fatty 174–189 iron-containing 123 strangulated bowel 43–44 subcutaneous fistula 147 subjective global assessment (SGA) 225 subserosal disease 187 sulfasalazine, side effects 194b supralevator extension 151f supranuclear lesions, and faecal incontinence 214 suprasphincteric fistula 147, 149f swallowing difficulty See dysphagia swallowing pain See odynophagia swallowing problems 3 tabes dorsalis 93 tension in a solid organ 39–40 terminal ileitis 62 thrombosed external haemorrhoids 153–154 thrombosed haemorrhoids 142, 152 TNF-alpha antibodies 202 TNM classification of colorectal cancer 287t Todani classification of choledochal cysts 361t total parenteral nutrition 230–231 complications 231, 231b indications 230, 230b transaminase levels 309, 315 transjugular intrahepatic portal systemic shunt 351t trans-sphincteric fistula 146–147, 148f travellers' diarrhoea 164–165 aetiology and transmission 164 clinical manifestations 164 investigations 165 prevention 164–165 treatment 165 Trichinella spiralis food poisoning 164 tricyclic antidepressants 113 triolein breath test 180–181 triple therapy 70 tropical sprue 185 tumour markers, causes of elevated 228b typhoid fever 168–169 ulcerative colitis 191–198 aetiology 191 clinical presentation 191 complications 197 diagnosis 192–193 differential diagnosis 192 disease extent and location 191–192 haematology and biochemistry 193 pathology 194

Index radiology 193 severity determination 192t sigmoidoscopy, colonoscopy and biopsy 193–194 stool biomarkers 193 stool studies 193 surgery 198, 198b treatment 194 ulcerative oesophagitis 122 ulcerative proctitis 125 ultrasound abdominal distension 267 abdominal masses 255–256 enlarged abdominal organs 256–261 obstructive jaundice 299 unconjugated (nonconjugated) bilirubin 294–295, 308 unconjugated hyperbilirubinaemia 295–296 mechanisms of development 297t upper gastrointestinal endoscopy 3 oesophageal biopsy 5 upper gastrointestinal haemorrhage, in portal ­hypertension 320–322 upper gastrointestinal radiology 5 urea breath testing 68 variceal haemorrhages 320 vascular disorders of the liver 340–342 vascular ectasia of the bowel 124–125 vascular mesenteric masses 373 veno-occlusive disease of the liver 305, 340 Vibrio cholerae 166 Vibrio parahaemolyticus food poisoning 163 videoradiographic swallow study 22 viral gastroenteritis 166–167 viral hepatitis 327–332 and jaundice 305 tests for 312t visceral pain 38–39, 73–74 and vomiting 111 visible abdominal masses 247 vitamin deficiencies, clinical findings 226t vomiting blood See haematemesis

clinical scenarios 113 common causes 107b consequences of 110 cyclical 113 definition 106 diagnostic algorithm 109f diseases causing 110–112 functional 113 history 107–108 investigation 108–110 medical therapy 112–113 physical examination 108 physiology 106–107 principles of treatment 112–113 waterbrash 2 watery diarrhoea, acute 161b, 165–167 weight loss 220–237 causes 222t clinical approach 222–226 definition 220–221 diseases associated with 231–237 history 222–223 investigations 223–226 diagnostic tests 225–226 nutritional assessment 225 management 226–227 enteral feeding 228–230 nutritional support 228–231 pathophysiology 221–222 physical examination 223 test yield 226 total parenteral nutrition 230–231 well patient with cirrhosis 319 Whipple's disease 185–186 Wilson's disease 310, 316, 336–337 wind See excess gas xerostomia 32, 35 Yersinia enterocolitica infection 62, 169 Zollinger-Ellison syndrome 75, 80–81

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