Davidson’s Principles and practice of medicine [23 ed.] 9780702070273

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Medicine

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Davidson’s Principles and Practice of

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This famous textbook was the brainchild of one of the great Professors of Medicine of the 20th century. Stanley Davidson was born in Sri Lanka and began his medical undergraduate training at Trinity College, Cambridge; this was interrupted by World War I and later resumed in Edinburgh. He was seriously wounded in battle, and the carnage and shocking waste of young life that he encountered at that time had a profound effect on his subsequent attitudes and values. In 1930 Stanley Davidson was appointed Professor of Medicine at the University of Aberdeen, one of the first full-time Chairs of Medicine anywhere and the first in Scotland. In 1938 he took up the Chair of Medicine at Edinburgh and was to remain in this post until retirement in 1959. He was a renowned educator and a particularly gifted teacher at the bedside, where he taught that everything had to be questioned and explained. He himself gave most of the systematic lectures in Medicine, which were made available as typewritten notes that emphasised the essentials and far surpassed any textbook available at the time. Principles and Practice of Medicine was conceived in the late 1940s with its origins in those lecture notes. The first edition, published in 1952, was a masterpiece of clarity and uniformity of style. It was of modest size and price, but sufficiently comprehensive and up to date to provide students with the main elements of sound medical practice. Although the format and presentation have seen many changes in 22 subsequent editions, Sir Stanley’s original vision and objectives remain. More than half a century after its first publication, his book continues to inform and educate students, doctors and health professionals all over the world.

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Sir Stanley Davidson (1894–1981)

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Edinburgh  London  New York  Oxford  Philadelphia  St Louis  Sydney  2018

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Illustrations by Robert Britton

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Consultant Microbiologist, Harrogate and District NHS Foundation Trust; Honorary Senior Lecturer, University of Leeds, UK

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Richard P Hobson LLM, PhD, MRCP(UK), FRCPath

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Consultant Endocrinologist, Metabolic Unit, Western General Hospital, Edinburgh; Honorary Professor, University of Edinburgh, UK

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Mark WJ Strachan BSc(Hons), MD, FRCPE

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Consultant Gastroenterologist, Royal Infirmary of Edinburgh; Honorary Senior Lecturer, University of Edinburgh, UK

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Arthritis Research UK Professor of Rheumatology, University of Edinburgh; Honorary Consultant Rheumatologist, Western General Hospital, Edinburgh, UK

Ian D Penman BSc(Hons), MD, FRCPE

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Stuart H Ralston MD, FRCP, FMedSci, FRSE, FFPM(Hon)

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Edited by

Medicine

23rd Edition

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Davidson’s Principles and Practice of

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Illustrations and boxes in Chapter 8 © Julian White.

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© 2018 Elsevier Ltd. All rights reserved.

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Content Strategist: Laurence Hunter Content Development Specialist: Wendy Lee Content Coordinator: Susan Jansons Project Manager: Louisa Talbott Designer: Miles Hitchen

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The publisher’s policy is to use paper manufactured from sustainable forests

Printed in China Last digit is the print number:  9  8  7  6  5  4  3  2  1

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Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

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ISBN  978-0-7020-7028-0 International ISBN  978-0-7020-7027-3

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Seventeenth edition 1995 Eighteenth edition 1999 Nineteenth edition 2002 Twentieth edition 2006 Twenty-first edition 2010 Twenty-second edition 2014 Twenty-third edition 2018

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Ninth edition 1968 Tenth edition 1971 Eleventh edition 1974 Twelfth edition 1977 Thirteenth edition 1981 Fourteenth edition 1984 Fifteenth edition 1987 Sixteenth edition 1991

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First edition 1952 Second edition 1954 Third edition 1956 Fourth edition 1958 Fifth edition 1960 Sixth edition 1962 Seventh edition 1964 Eighth edition 1966

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No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the publisher (other than as may be noted herein).

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8. Envenomation

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7. Poisoning

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EMERGENCY AND CRITICAL CARE MEDICINE

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PART 2

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JAT Sandoe, DH Dockrell

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6. Principles of infectious disease

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5. Population health and epidemiology H Campbell, DA McAllister

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SE Marshall, SL Johnston

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4. Clinical immunology

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3. Clinical genetics

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2. Clinical therapeutics and good prescribing

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FUNDAMENTALS OF MEDICINE

1. Clinical decision-making



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Introduction



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VR Tallentire, MJ MacMahon

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10. Acute medicine and critical illness

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9. Environmental medicine

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Acknowledgements



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Contributors

International Advisory Board



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Preface

PART 1

Contents

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L Mackillop, FEM Neuberger

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30. Maternal medicine

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29. Dermatology



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28. Medical psychiatry

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27. Medical ophthalmology J Olson

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26. Stroke medicine

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25. Neurology

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24. Rheumatology and bone disease

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HG Watson, DJ Culligan, LM Manson



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23. Haematology and transfusion medicine

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20. Diabetes mellitus

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19. Nutritional factors in disease

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B Conway, PJ Phelan, GD Stewart

16. Cardiology



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A Mather, L Burnett, DR Sullivan, P Stewart

15. Nephrology and urology

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14. Clinical biochemistry and metabolic medicine



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12. HIV infection and AIDS



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11. Infectious disease

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CLINICAL MEDICINE

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PART 3

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vi • Contents

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31. Adolescent and transition medicine

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34. Pain and palliative care

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33. Oncology

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32. Ageing and disease

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35. Laboratory reference ranges

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Index

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MD Witham

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SHR, IDP, MWJS, RPH Edinburgh 2018

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the core principles behind clinical decision-making and good prescribing. Subsequent chapters discuss medical emergencies in poisoning, envenomation and environmental medicine, while a new chapter explores common presentations in acute medicine, as well as the recognition and management of the critically ill. The disease-specific chapters that follow cover the major medical specialties, each one thoroughly revised and updated to ensure that readers have access to the ‘cutting edge’ of medical knowledge and practice. Two new chapters on maternal and adolescent/transition medicine now complement the one on ageing and disease, addressing particular problems encountered at key stages of patients’ lives. Medical ophthalmology is also now included as a direct response to readers’ requests. The innovations introduced in recent editions have been maintained and, in many cases, developed. The highly popular ‘Clinical Examination’ overviews have been extended to the biochemistry, nutrition and dermatology chapters. The ‘Presenting Problems’ sections continue to provide an invaluable overview of the most common presentations in each disease area. The ‘Emergency’ and ‘Practice Point’ boxes have been retained along with the ‘In Old Age’, ‘In Pregnancy’ and ‘In Adolescence’ boxes, which emphasise key practical points in the presentation and management of the elderly, women with medical disorders who are pregnant or planning pregnancy, and teenagers transitioning between paediatric and adult services. Education is achieved by assimilating information from many sources and readers of this book can enhance their learning experience by using several complementary resources. We are delighted to have a new self-testing companion book entitled Davidson’s Assessment in Medicine, containing over 1250 multiple choice questions specifically tailored to the contents of Davidson’s. The long-standing association of Davidson’s with its sister books, Macleod’s Clinical Examination (now in its 14th Edition) and Principles and Practice of Surgery (7th Edition), still holds good. Our ‘family’ has also expanded with the publication of Davidson’s Essentials of Medicine, a long-requested pocket-sized version of the main text; Davidson’s 100 Clinical Cases, which contains scenarios directly based on our ‘Presenting Problems’; and Macleod’s Clinical Diagnosis, which describes a systematic approach to the differential diagnosis of symptoms and signs. We congratulate the editors and authors of these books for continuing the tradition of easily digested and expertly illustrated texts. We all take immense pride in continuing the great tradition first established by Sir Stanley Davidson and in producing an outstanding book for the next generation of doctors.

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Well over two million copies of Davidson’s Principles and Practice of Medicine have been sold since it was first published in 1952. Now in its 23rd Edition, Davidson’s is regarded as a ‘must-have’ textbook for thousands of medical students, doctors and health professionals across the world, describing the pathophysiology and clinical features of the most important conditions encountered in the major specialties of adult medicine and explaining how to investigate, diagnose and manage them. The book is the winner of numerous prizes and awards and has been translated into many languages. Taking its origins from Sir Stanley Davidson’s much-admired lecture notes, the book has endured because it continues to keep pace with how modern medicine is taught and to provide a wealth of information in an easy-to-read, concise and beautifully illustrated format. Davidson’s strives to ensure that readers can not only recognise the clinical features of a disease but also understand the underlying causes. To achieve this, each chapter begins with a summary of the relevant pre-clinical science, linking pathophysiology with clinical presentation and treatment so that students can use the book from the outset of their medical studies right through to their final examinations and beyond. The regular introduction of new authors and editors is important for maintaining freshness. On this occasion, Professor Mark Strachan and Dr Richard Hobson have come on board as editors, and 26 new authors have joined our existing contributors to make up an outstanding team of authorities in their respective fields. As well as recruiting authors from around the globe, particularly for topics such as infectious diseases, HIV and envenomation, we welcome members from 17 countries on to our International Advisory Board. These leading experts provide detailed comments that are crucial to our revision of each new edition. A particularly important aspect in planning the revision is for the editors to meet students and faculty in medical schools in those countries where the book is most widely read, so that we can respond to the feedback of our global readership and their tutors. We use this feedback, along with the information we gather via detailed student reviews and surveys, to craft each edition. The authors, editors and publishing team aim to ensure that readers all over the world are best served by a book that integrates medical science with clinical medicine to convey key knowledge and practical advice in an accessible and readable format. The amount of detail is tailored to the needs of medical students working towards their final examinations, as well as candidates preparing for Membership of the Royal Colleges of Physicians (MRCP) or its equivalent. With this new edition we have introduced several changes in both structure and content. The opening six chapters provide an account of the principles of genetics, immunology, infectious diseases and population health, along with a discussion of

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Preface

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Marie Fallon MD, FRCP St Columba’s Hospice Chair of Palliative Medicine, University of Edinburgh, UK

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Neil R Grubb MD, FRCP Consultant in Cardiology, Royal Infirmary of Edinburgh; Honorary Senior Lecturer in Cardiovascular Sciences, University of Edinburgh, UK

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David R FitzPatrick MD, FMedSci Professor, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, UK

Sally H Ibbotson BSc(Hons), MD, FRCPE Professor of Photodermatology, University of Dundee; Honorary Consultant Dermatologist and Head of Photobiology Unit, Ninewells Hospital and Medical School, Dundee, UK

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Emad El-Omar BSc(Hons), MD(Hons), FRCPE, FRSE, FRACP Professor of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia

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Nicola Cooper FAcadMEd, FRCPE, FRACP Consultant Physician, Derby Teaching Hospitals NHS Foundation Trust, Derby; Honorary Clinical Associate Professor, Division of Medical Sciences and Graduate Entry Medicine, University of Nottingham, UK

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David H Dockrell MD, FRCPI, FRCPG, FACP Professor of Infection Medicine, Medical Research Council/ University of Edinburgh Centre for Inflammation Research, University of Edinburgh, UK

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Bryan Conway MB, MRCP, PhD Senior Lecturer, Centre for Cardiovascular Science, University of Edinburgh; Honorary Consultant Nephrologist, Royal Infirmary of Edinburgh, UK

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Richard J Davenport DM, FRCPE, BMedSci Consultant Neurologist, Royal Infirmary of Edinburgh and Western General Hospital, Edinburgh; Honorary Senior Lecturer, University of Edinburgh, UK

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Lesley A Colvin BSc, FRCA, PhD, FRCPE, FFPMRCA Consultant, Department of Anaesthesia, Critical Care and Pain Medicine, Western General Hospital, Edinburgh; Honorary Professor in Anaesthesia and Pain Medicine, University of Edinburgh, UK

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Graham G Dark FRCP, FHEA Senior Lecturer in Medical Oncology and Cancer Education, Newcastle University, Newcastle upon Tyne, UK

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Gavin PR Clunie BSc, MD, FRCP Consultant Rheumatologist and Metabolic Bone Physician, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK

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Harry Campbell MD, FRCPE, FFPH, FRSE Professor of Genetic Epidemiology and Public Health, Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, UK

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Dominic J Culligan BSc, MD, FRCP, FRCPath Consultant Haematologist, Aberdeen Royal Infirmary; Honorary Senior Lecturer, University of Aberdeen, UK

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Quentin M Anstee BSc(Hons), PhD, FRCP Professor of Experimental Hepatology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne; Honorary Consultant Hepatologist, Freeman Hospital, Newcastle upon Tyne, UK

Mark Byers OBE, FRCGP, FFSEM, FIMC, MRCEM Consultant in Pre-Hospital Emergency Medicine, Institute of Pre-Hospital Care, London, UK

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Alison L Cracknell FRCP Consultant, Medicine for Older People, Leeds Teaching Hospitals NHS Trust, Leeds; Honorary Clinical Associate Professor, University of Leeds, UK

Leslie Burnett MBBS, PhD, FRCPA, FHGSA Chief Medical Officer, Genome.One, Garvan Institute of Medical Research, Sydney; Conjoint Professor, St Vincent’s Clinical School, UNSW; Honorary Professor in Pathology and Genetic Medicine, Sydney Medical School, University of Sydney, Australia

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Brian J Angus BSc(Hons), DTM&H, FRCP, MD, FFTM(Glas) Associate Professor, Nuffield Department of Medicine, University of Oxford, UK

Contributors

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Michael J MacMahon FRCA, FICM, EDIC Consultant in Anaesthesia and Intensive Care, Victoria Hospital, Kirkcaldy, UK

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Peter T Reid MD, FRCPE Consultant Physician, Respiratory Medicine, Lothian University Hospitals, Edinburgh, UK

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Jonathan AT Sandoe PhD, FRCPath Associate Clinical Professor, University of Leeds; Consultant Microbiologist, Leeds Teaching Hospitals NHS Trust, UK

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Stuart H Ralston MD, FRCP, FMedSci, FRSE, FFPM(Hon) Arthritis Research UK Professor of Rheumatology, University of Edinburgh; Honorary Consultant Rheumatologist, Western General Hospital, Edinburgh, UK

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Amanda Mather MBBS, FRACP, PhD Consultant Nephrologist, Department of Renal Medicine, Royal North Shore Hospital, Sydney; Conjoint Senior Lecturer, Faculty of Medicine, University of Sydney, Australia

Paul J Phelan MD, FRCPE Consultant Nephrologist and Renal Transplant Physician, Royal Infirmary of Edinburgh; Honorary Senior Lecturer, University of Edinburgh, UK

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Sara E Marshall FRCP, FRCPath, PhD Professor of Clinical Immunology, Medical Research Institute, University of Dundee, UK

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Lynn M Manson MD, FRCPE, FRCPath Consultant Haematologist, Scottish National Blood Transfusion Service, Department of Transfusion Medicine, Royal Infirmary of Edinburgh, UK

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John Olson MD, FRPCE, FRCOphth Consultant Ophthalmic Physician, Aberdeen Royal Infirmary; Honorary Reader, University of Aberdeen, UK Ewan R Pearson MA, PhD, FRCPE Professor of Diabetic Medicine, University of Dundee, UK

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Rebecca Mann BMedSci, MRCP, FRCPCh Consultant Paediatrician, Taunton and Somerset NHS Foundation Trust, Taunton, UK

John DC Newell-Price MA, PhD, FRCP Professor of Endocrinology and Consultant Endocrinologist, Department of Oncology and Metabolism, University of Sheffield, UK

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Lucy Mackillop MA(Oxon), FRCP Consultant Obstetric Physician, Oxford University Hospitals NHS Foundation Trust, Oxford; Honorary Senior Clinical Lecturer, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, UK

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David E Newby BA, BSc(Hons), PhD, BM DM DSc, FMedSci, FRSE, FESC, FACC British Heart Foundation John Wheatley Professor of Cardiology, British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, UK

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Gary Maartens MBChB, FCP(SA), MMed Professor of Clinical Pharmacology, University of Cape Town, South Africa

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Francesca EM Neuberger MRCP(UK) Consultant Physician in Acute Medicine and Obstetric Medicine, Southmead Hospital, Bristol, UK

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Stephen M Lawrie MD(Hons), FRCPsych, FRCPE(Hon) Professor of Psychiatry, University of Edinburgh, UK John Paul Leach MD, FRCPG, FRCPE Consultant Neurologist, Institute of Neuroscience, Queen Elizabeth University Hospital, Glasgow; Head of Undergraduate Medicine and Honorary Associate Clinical Professor, University of Glasgow, UK

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Mairi H McLean BSc(Hons), MRCP, PhD Senior Clinical Lecturer in Gastroenterology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen; Honorary Consultant Gastroenterologist, Aberdeen Royal Infirmary, UK

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Rory J McCrimmon MD, FRCPE Professor of Experimental Diabetes and Metabolism, University of Dundee, UK

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David EJ Jones MA, BM, PhD, FRCP Professor of Liver Immunology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne; Consultant Hepatologist, Freeman Hospital, Newcastle upon Tyne, UK

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Sarah L Johnston FCRP, FRCPath Consultant Immunologist, Department of Immunology and Immunogenetics, North Bristol NHS Trust, Bristol, UK

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David A McAllister MSc, MD, MRCP, MFPH Wellcome Trust Intermediate Clinical Fellow and Beit Fellow, Senior Clinical Lecturer in Epidemiology, and Honorary Consultant in Public Health Medicine, University of Glasgow, UK

Peter Langhorne PhD, FRCPG, FRCPI Professor of Stroke Care, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK

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Sara J Jenks BSc(Hons), MRCP, FRCPath Consultant in Metabolic Medicine, Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, UK

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Simon RJ Maxwell BSc, MD, PhD, FRCP, FRCPE, FBPhS, FHEA Professor of Student Learning – Clinical Pharmacology and Prescribing, and Medical Director, UK Prescribing Safety Assessment, Clinical Pharmacology Unit, University of Edinburgh, UK

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J Alastair Innes BSc, PhD, FRCPE Consultant, Respiratory Unit, Western General Hospital, Edinburgh; Honorary Reader in Respiratory Medicine, University of Edinburgh, UK

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xii • Contributors

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Miles D Witham PhD, FRCPE Clinical Reader in Ageing and Health, University of Dundee, UK

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John PH Wilding DM, FRCP Professor of Medicine, Obesity and Endocrinology, University of Liverpool, UK

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Julian White MB, BS, MD, FACTM Head of Toxinology, Women’s and Children’s Hospital, North Adelaide; Professor, University of Adelaide, Australia

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David R Sullivan MBBS, FRACP, FRCPA, FCSANZ Clinical Associate Professor, Faculty of Medicine, University of Sydney; Physician and Chemical Pathologist, Department of Chemical Pathology, Royal Prince Alfred Hospital, Sydney, Australia

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Henry G Watson MD, FRCPE, FRCPath Consultant Haematologist, Aberdeen Royal Infirmary; Honorary Professor of Medicine, University of Aberdeen, UK

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Mark WJ Strachan BSc(Hons), MD, FRCPE Consultant Endocrinologist, Metabolic Unit, Western General Hospital, Edinburgh; Honorary Professor, University of Edinburgh, UK

Simon HL Thomas MD, FRCP, FRCPE Professor of Clinical Pharmacology and Therapeutics, Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, UK

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Peter Stewart MBBS, FRACP, FRCPA, MBA Associate Professor in Chemical Pathology, University of Sydney; Area Director of Clinical Biochemistry and Head of the Biochemistry Department, Royal Prince Alfred and Liverpool Hospitals, Sydney, Australia

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Katrina Tatton-Brown BA, MD, FRCP Consultant in Clinical Genetics, South West Thames Regional Genetics Service, St George’s Universities NHS Foundation Trust, London; Reader in Clinical Genetics and Genomic Education, St George’s University, London, UK

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Grant D Stewart BSc(Hons), FRCSEd(Urol), PhD University Lecturer in Urological Surgery, Academic Urology Group, University of Cambridge; Honorary Consultant Urological Surgeon, Department of Urology, Addenbrooke’s Hospital, Cambridge; Honorary Senior Clinical Lecturer, University of Edinburgh, UK

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Robby M Steel MA, MD, FRCPsych Consultant Liaison Psychiatrist, Department of Psychological Medicine, Royal Infirmary of Edinburgh; Honorary (Clinical) Senior Lecturer, Department of Psychiatry, University of Edinburgh, UK

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Shyam Sundar MD, FRCP(London), FAMS, FNASc, FASc, FNA Professor of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India Victoria R Tallentire BSc(Hons), MD, FRCPE Consultant Physician, Western General Hospital, Edinburgh; Honorary Clinical Senior Lecturer, University of Edinburgh, UK

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Alan G Shand MD, FRCPE Consultant Gastroenterologist, Western General Hospital, Edinburgh, UK

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Gordon R Scott BSc, FRCP Consultant in Genitourinary Medicine, Chalmers Sexual Health Centre, Edinburgh, UK

Contributors • xiii

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Piotr Kuna Professor of Medicine; Chairman, 2nd Department of Medicine; Head of Division of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Poland

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Vasantha Kamath Senior Professor, Department of Internal Medicine, MVJ Medical College and Research Hospital, Bengaluru, Karnataka, India

Pravin Manga Emeritus Professor of Medicine, Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa

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AL Kakrani Professor and Head, Department of Medicine, Dr DY Patil Medical College, Hospital and Research Centre; Dean, Faculty of Medicine, Dr DY Patil Vidyapeeth Deemed University, Pimpri, Pune, India

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Tarun Kumar Dutta Professor of Medicine and Clinical Hematology, Mahatma Gandhi Medical College and Research Institute, Puducherry, India

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Saroj Jayasinghe Chair Professor of Medicine, Faculty of Medicine, University of Colombo; Honorary Consultant Physician, National Hospital of Sri Lanka, Colombo, Sri Lanka

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Sydney C D’Souza Professor of Medicine, AJ Institute of Medical Science, Mangalore; Former Head, Department of Medicine, Kasturba Medical College Mangalore, Manipal University, India

M Abul Faiz Professor of Medicine (Retired), Sir Salimullah Medical College, Mitford, Dhaka, Bangladesh

Rajiva Gupta Director and Head, Rheumatology and Clinical Immunology, Medanta – The Medicity, Gurgaon, India

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D Dalus Professor and Head, Department of Internal Medicine, Medical College and Hospital, Trivandrum, India

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MK Daga Director Professor of Medicine, and In-Charge Intensive Care Unit and Center for Occupational and Environment Medicine, Maulana Azad Medical College, New Delhi, India

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Arnold Cohen Clinical Professor of Medicine, Elson S. Floyd College of Medicine at Washington State University, Spokane, Washington; Associate Clinical Professor, University of Washington School of Medicine; Gastroenterologist, Spokane Digestive Disease Center, Washington, USA

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Hadi A Goubran Haematologist, Saskatoon Cancer Centre and Adjunct Professor, College of Medicine, University of Saskatchewan, Canada; Professor of Medicine and Haematology (Sabbatical), Cairo University, Egypt

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Matthew A Brown Professor and Director of Genomics, Queensland University of Technology, Brisbane, Australia

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Sujoy Ghosh Associate Professor, Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, India

Khalid I Bzeizi Senior Consultant and Head of Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

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AG Frauman Professor of Clinical Pharmacology and Therapeutics, University of Melbourne, Australia

Ragavendra Bhat Professor of Internal Medicine, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates

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Amitesh Aggarwal Associate Professor, Department of Medicine, University College of Medical Sciences and GTB Hospital, Delhi, India

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International Advisory Board

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Josanne Vassallo Professor of Medicine, Faculty of Medicine and Surgery, University of Malta; Consultant Endocrinologist, Division of Endocrinology, Mater Dei Hospital, Msida, Malta

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SG Siva Chidambaram Professor of Medicine, Dean/SPL Officer, Perambalur Government Medical College and GHQ, Perambalur, India

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Ian J Simpson Emeritus Professor of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand

Arvind K Vaish Professor and Head, Department of Medicine, Hind Institute of Medical Sciences, Lucknow; Ex-Professor and Head of Medicine, KG Medical University, Lucknow, India

NR Rau Consultant Physician, Anugraha Medical Centre and Adarsha Hospital, Udupi, Karnataka; Former Professor and Head, Department of Medicine, Kasturba Medical College, Manipal University, Karnataka, India

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Ami Prakashvir Parikh Consultant Physician, Sheth VS General Hospital, Ellisbridge, Ahmedabad; Professor of Medicine and Head of Department of Medicine, NHL Municipal Medical College, Ahmedabad, India Medha Y Rao Professor of Internal Medicine, Principal and Dean, MS Ramaiah Medical College, Bangalore, India

Ibrahim Sherif Emeritus Professor of Medicine, Tripoli University; Consultant Endocrinologist, Alafia Clinic, Tripoli, Libya

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Tommy Olsson Professor of Medicine, Department of Medicine, Umeå University Hospital, Sweden

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Surendra K Sharma Adjunct Professor, Department of Molecular Medicine, Jamia Hamdard Institute of Molecular Medicine, Hamdard University, Delhi; Director of Research and Adjunct Professor, Departments of General Medicine and Pulmonary Medicine, JNMC, Datta Meghe Institute of Medical Sciences, Sawangi (M), Wardha Maharashtra, India

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Matthew Ng Honorary Clinical Professor, University of Hong Kong, Tung Wah Hospital, Hong Kong

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KR Sethuraman Vice-Chancellor, Sri Balaji Vidyapeeth University, Pondicherry, India

Moffat Nyirenda Professor of Medicine (Global Non-Communicable Diseases), London School of Hygiene and Tropical Medicine, UK; Honorary Professor of Research, College of Medicine, University of Malawi

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Milind Nadkar Professor of Medicine and Chief of Rheumatology and Emergency Medicine, Seth GS Medical College and KEM Hospital, Mumbai, India

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Nirmalendu Sarkar Professor and Head (Retired), Department of Medicine, Institute of Post Graduate Medical Education and Research and SSKM Hospital, Kolkata, India

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Ammar F Mubaidin Professor of Neurology, Jordan University Hospital, Khalidi Medical Center, Amman, Jordan

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xvi • International Advisory Board

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Avin Aggarwal, Dorothy Agrapidis, Sakir Ahmed, Iman Akhtar, Muhammad Faizan Ali, Syeda A Rfa Ali, M Amogh, Ramprasath Anbazhagan, Anju George C, Vamseedhar Annam, Muhammad Ehtisham Ansar, David C Antoney, Hina Arif, Sriharsha Athota, Muhammed Ali Azher, Bilal Al Azzawi, Janak Bahirwani, Devyani Bahl, Mohammed Naseem Baig, Deepak Kumar Bandari, Sagnik Banerjee, Tapastanu Banerjee, Kieran Bannerman, Emily Bart, Suranjana Basak, Saravana Bavan, Mark Beeston, Andrew Beverstock, Jeetendra Bhandari, Navin Bhatt, Soumyadeep Bhaumik, Rajrsh Bhawani, Kriti Bhayana, Praveen Bhugra, Amit Bisht, Rahul Bisht, Rudradeep Biswas, Tamoghna Biswas, Moira Bradfield, S Charles Bronson, Rosie Jane Campbell, Anup Chalise, Subhankar Chatterjee, Chiranjivi Chaudhari, Lok Bandhu Chaudhary, Muhammad Hamid Chaudhary, Umar Iftikhar Chaudhry, Himshree Gaurang Chhaya, Smitha Chirayil, Alexandra Choa, Rahul Choudhary, Guy Conlon, Gabriel MetcalfCuenca, Jack Cuningham, Gopal Dabade, Saraswata Das, Rahul Dev, Muinul Islam Dewan, Sree Divya, Muhammad Dizayee, Lucy Drummond, Simon Dryden, Fiona Drysdale, Kaitlin Duell, Gemma Dwyer, Md Khader Faheem N, Mahedi Hasan Faisal, Ali Mokhtari Farivar, Mohammed Omar Farooq, Ten Fu Fatt, Muhammad Zubair Fazal, Rebecca Ferris, Rebecca Fisher, Kartik Nimish Gandhi, Vibhav Gandhi, James Gao, Ella Gardner, Ankit Kumar Garg, Vibhuti Garg, Vishal Garg, Rakesh Garlapati, Partha Sarathi Ghosh, Prattay Ghosh, Muhammad Umer Gill, Madelaine Gimzewska, Nikolaos D Giotis, Evan Goh, Iain Gow, Bharatiram Guduri, Aantriksha Gupta, Shiwam Kumar Gupta, Michael Hagarty, Md Rashid Haider, Iqra Haq, Abdalla A Hassan, Fatima Hemani, Bianca Honnekeri, Prerana Huddar, Sandip Hulke, Mohammed Laique Hussain, Syahir Ibrahim, Victor Ilubaera, Sushrut Ingawale, Aroobah Iqbal, Tooba Irshad, Nagib Ul-Islam, Sehra Jabeen, Jeevan Jacob, Samreen Jaffar, Ankita Jain, Anukriti Jain, Ghazfa Jamil, Karan Jatwani, Surani Dilhani Jayawickrema, Per-Kristian Jensen, Love Kapil, Ishwor Karki, Ewan D Kennedy, Amit Keshri, Haider Ali Khalid, Ali Khaliq, Hina Khan, Md Taha Ali Khan, Raazia Khan, Priya Khetarpal, Robert Kimmitt, Navneet Kishore, Narendranath Reddy Konda, Kirsten Kramers, Ajay Kumar, Gaurav Kumar, Karun Kumar, Mudit Kumar, Sathish Kumar A, Sonu Kumar, Ramasamy Shakthi Kumaran, Joachim Langhans, Keith Leung, Ang Li, Lai Nai Lim (Jeremiah), Marlene Da Vitoria Lobo, Bo Løfgren, Sham Kumar Lulla, Apurva Lunia, Arslan Luqman, Faizan Luqman, Mithilesh Chandra Malviya, Sudhir Mane, Sachin Mangal, G. Manju, Adupa Manupranay, Ussama Maqbool, Zahid Marwat, Ronny John Mathew, Ross Mclaren, Lucy Mcnally, Varshil Mehta, Kamran Younis Memon, Nisha Menon, Varun Menon P, Jessica Mills, Asim Abid Minhas,

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Following the publication of the 22nd edition of Davidson’s, Professor Brian Walker and Dr Nicki Colledge retired as editors. We would like to express our gratitude for the immense contribution they both made to the continuing success of this textbook. The current editors would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new edition would not have been possible. In particular we are indebted to those former authors who step down with the arrival of this new edition. They include Assistant Professor Albiruni Ryan Abdul-Razak, Professor Andrew Bradbury, Dr Jenny Craig, Professor Allan Cumming, Dr Robert Dawe, Emeritus Professor Michael Field, Dr Jane Goddard, Professor Philip Hanlon, Dr Charlie Lees, Dr Helen Macdonald, Professor Iain McInnes, Dr Graham Nimmo, Dr Simon Noble, Dr David Oxenham, Professor Jonathan Seckl, Professor Michael Sharpe, Professor Neil Turner, Dr Simon Walker and Professor Timothy Walsh. We are grateful to members of the International Advisory Board, all of whom provided detailed suggestions that have improved the book. Several members have now retired from the Board and we are grateful for their support during the preparation of previous editions. They include Professor OC Abraham, Professor Tofayel Ahmed, Professor Samar Banerjee, Professor Tapas Das, Professor Tsuguya Fukui, Professor Saman Gunatilake, Professor Wasim Jafri, Professor Saraladevi Naicker, Professor Nardeep Naithani, Professor Prem Pais, Professor A Ramachandran, the late Professor (Mrs) Harsha R Salkar and Professor Subhash Varma. Detailed chapter reviews were commissioned to help plan this new edition and we are grateful to all those who assisted, including Professor Rustam Al-Shahi, Dr David Enoch, Dr Colin Forfar, Dr Richard Herriot and Dr Robert Lindsay. The Editors and Publisher would like to thank all those who have provided valuable feedback on this textbook and whose comments have helped shape this new edition. We would particularly like to extend our thanks to the many readers who contact us with suggestions for improvements. This input has been invaluable and is much appreciated; we regret the names are too numerous to mention individually. As part of the Publisher’s review, 360 readers from over 200 universities and colleges around the world supplied many innovative ideas on how to enhance the book. We are deeply indebted to the following for their enthusiastic support and we trust we have listed all those who contributed; we apologise if any names have been accidentally omitted. Rabab Hasan Abbasi, Ayesha Abdul Aziz, Ahmed Al Abdullah, Osama Abuzagaia, Humaira Achakzai, Sajan Acharya, Anurag Adhikari, Esha Agarwal,

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Acknowledgements

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SHR, IDP, MWJS, RPH Edinburgh 2018

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Prince Singh, Rajshree Singh, Shruti Singh, Vikas Singh, Yogita Singh, Ayush Keshav Singhal, Dattatreya Sitaram, Brooke Smith, Yeshwanth Sonnathi, Soundarya Soundararajan, Nicola Stuber, Maleeha Subhan, Udayasree Sagar Surampally, Monika Surana, Jason Suresh, Salman Ali Syed, Mohammad Hasnain Tahir, Syeda Sara Tamkanath, Areeba Tariq, Saipriya Tatineni, Ghias Un Nabi Tayyab, Arul Qubert Thaya, Jolley Thomas, Stephanie Tristram, Neelanchal Trivedi, Vaibhav Trivedi, Kriti Upadhyay, Sanjaya Kumar Upadhyaya, Rukhsar Vankani, Rajkumar Krishnan Vasanthi, D Vijayaraju, R Vinayak, Neelakantan Viswanathan, Joarder Wakil, Syed Hamza Bin Waqar, Waiz A Wasey, William Wasif, Kiran Wasti, Donald Waters, Katherine Weir, Clinton White, Aalok Yadav, Loong Yee Yew, Shahwar Yousuf, Amal Yusof and Hassam Zulfiqar. The authors of Chapter 20 would like to thank Dr Drew Henderson, who reviewed the ‘Diabetic nephropathy’ section. Two short sections in Chapter 3 on array comparative genomic hybridisation and single-molecule sequencing are adapted from Dr K Tatton-Brown’s Massive Open Online Course for FutureLearn. We would like to thank the Open University and St George’s, University of London, for permission to use this material. We are especially grateful to all those working for Elsevier, in particular Laurence Hunter, Wendy Lee and Robert Britton, for their endless support and expertise in the shaping, collation and illustration of this edition.

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Mohd Nasir Mohiuddin, Matshidiso Mokgwathi, Kristin Monk, Joseph Raja Mony, Sudeb Mukherjee, Sadaf Nadeem, Huda Naim, B Abhilash Nair, Ramya Narasimhan, Rahul Navani, Ayesha Nazir, Prakhar Nigam, Sripriya Nopany, Prakash Raj Oli, Chieh Yin Ooi, Muhammad Osama, Kate O’Sullivan, Hajer Oun, Ashwin Pachat, Akshay Pachyala, Kannan Padma, Gregory Page, Vishal Krishna Pai, Dhiman Pal, Vidit Panchal, Madhav Pandey, Ambikapathi Panneerselvam, Rakesh Singh Panwar, Prakash Parida, Ashwin Singh Parihar, Kunal Parwani, Riya Patel, Himanshu Pathak, Prathamesh Pathrikar, Samanvith Patlori, Gary Paul, Harris Penman, Lydia B Peters, Kausthubha Puttalingaiah, Muneeb Qureshi, Sidra Qureshi, Varun Venkat Raghavan MS, Raghavendra MS, Abdur Rahaman, Ajmal Rahman Km, SM Tajdit Rahman, Ankit Raj, Solai Raj, Namita Raja, Revathi Rajagopal, Aswathy Raju B, Nagarajan Raju, Al-Amin Hossain Rakib, Abhiraj Ramchandani, Varun Ramchandani, Viviktha Ramesh, Jai Ranjan, Ganga Raghava Rao, Gomathi Ravula, Aneeqa Abdul Rehman, Neeha Abdul Rehman, Varun Bhaktarahalli Renukappa, Rosalind Revans, Madina Riaz, Lachlan Rodd, Jan Ross, Pritam Roy, Jazeel Sa, Iqra Saeed, Israel Safiriyu, Partha Saha, Mohammed Sulaiman Sait J, Ribha Salman, Souvik Samaddar, Juliane Rf Sanner, Abhinav Sathe, Smarter Sawant, Jeff Schwartz, Somanshi Sehgal, Arbind Shah, Basit Shah, Rakesh Kumar Shah, Mohith Shamdas, Abhishek Sharma, Anmol Sharma, Deepak Sharma, Pawan Kumar Sharma, Nisha Sharoff, Alsba Sheikh, Haris Sheikh, Nujood Al Shirawi, William Shomali, Pratima Shrestha, Suhana Shrestha, Ajay Shukla, Prithiv Siddharth, Arpit Sikri, Ankita Singh, Avinash Singh, Deepali Singh, Jeevika Singh,

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xviii • Acknowledgements

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There are many practical skills that students and doctors must master. These vary from inserting a nasogastric tube to reading an ECG or X-ray, or interpreting investigations such as arterial blood gases or thyroid function tests. ‘Practice Point’ boxes provide straightforward guidance on how these and many other skills can be acquired and applied.

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In many countries, older people comprise 20% of the population and are the chief users of health care. While they contract the same diseases as those who are younger, there are often important differences in the way they present and how they are best managed. Chapter 32, ‘Ageing and disease’, concentrates on the principles of managing the frailest group who suffer from multiple comorbidity and disability, and who tend to present with non-specific problems such as falls or delirium. Many older people, though, also suffer from specific single-organ pathology. ‘In Old Age’ boxes are thus included in each chapter and describe common presentations, implications of physiological changes of ageing, effects of age on investigations, problems of

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These boxes describe the management of many of the most common emergencies in medicine.

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These include causes, clinical features, investigations, treatments and other useful information.

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Medical students and junior doctors must not only assimilate a great many facts about various disorders but also develop an analytical approach to formulating a differential diagnosis

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Boxes are a popular way of presenting information and are particularly useful for revision. They are classified by the type of information they contain, using specific symbols.

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Presenting problems

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Boxes

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The value of good clinical skills is highlighted by a two-page overview of the important elements of the clinical examination at the beginning of most chapters. The left-hand page includes a mannikin to illustrate key steps in examination of the relevant system, beginning with simple observations and progressing in a logical sequence around the body. The right-hand page expands on selected themes and includes tips on examination technique and interpretation of physical signs. These overviews are intended to act as an aide-mémoire and not as a replacement for a detailed text on clinical examination, as provided in our sister title, Macleod’s Clinical Examination.

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and a plan of investigation for patients who present with particular symptoms or signs. In Davidson’s this is addressed by incorporating a ‘Presenting Problems’ section into all relevant chapters. Nearly 250 presentations are included, which represent the most common reasons for referral to each medical specialty.

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The opening six chapters of the book, making up Part 1 on ‘Fundamentals of Medicine’, provide an account of the principles of genetics, immunology, infectious diseases and population health, along with a discussion of the core principles behind clinical decision-making and good prescribing. Subsequent chapters in Part 2, ‘Emergency and Critical Care Medicine’, discuss medical emergencies in poisoning, envenomation and environmental medicine, while a new chapter explores common presentations in acute medicine, as well as the recognition and management of the critically ill. The third part, ‘Clinical Medicine’, is devoted to the major medical specialties. Each chapter has been written by experts in the field to provide the level of detail expected of trainees in their discipline. To maintain the book’s virtue of being concise, care has been taken to avoid unnecessary duplication between chapters. The system-based chapters in Part 3 follow a standard format, beginning with an overview of the relevant aspects of clinical examination, followed by an account of functional anatomy, physiology and investigations, then the common presentations of disease, and details of the individual diseases and treatments relevant to that system. In chapters that describe the immunological, cellular and molecular basis of disease, this problem-based approach brings the close links between modern medical science and clinical practice into sharp focus. The methods used to present information are described below.

Clinical examination overviews

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The Editors and Publisher hope that you will find this edition of Davidson’s informative and easy to use. We would be delighted to hear from you if you have any comments or suggestions to make for future editions of the book. Please contact us by e-mail at: davidson. [email protected]. All comments received will be much appreciated and will be considered by the editorial team.

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Giving us your feedback

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The recommended International Non-proprietary Names (INNs) are used for all drugs, with the exception of adrenaline and

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A contents list is given on the opening page of each chapter. In addition, the book contains numerous cross-references to help readers find their way around, along with an extensive index. A list of up-to-date reviews and useful websites with links to management guidelines appears at the end of each chapter.

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Finding what you are looking for

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Terminology

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The International System of Units (SI units) is the recommended means of presentation for laboratory data and has been used throughout Davidson’s. We recognise, though, that many laboratories around the world continue to provide data in non-SI units, so these have been included in the text for the commonly measured analytes. Both SI and non-SI units are also given in Chapter 35, which describes the reference ranges used in Edinburgh’s laboratories. It is important to appreciate that these reference ranges may vary from those used in other laboratories.

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Although paediatric medicine is not covered in Davidson’s, many chronic disorders begin in childhood and adult physicians often contribute to multidisciplinary teams that manage young patients ‘in transition’ between paediatric and adult health-care services. This group of patients often presents a particular challenge, due to the physiological and psychological changes that occur in adolescence and which can have a major impact on the disease and its management. Adolescents can be encouraged to take over responsibility from their parents/carers in managing their disease, but are naturally rebellious and often struggle to adhere to the impositions of chronic treatment. To highlight these issues, we have introduced a new chapter on adolescent and transition medicine to accompany the ‘In Adolescence’ boxes that appear in relevant chapters.

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Units of measurement

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Many conditions are different in the context of pregnancy, while some arise only during or shortly after pregnancy. Particular care must be taken with investigations (for example, to avoid radiation exposure to the fetus) and treatment (to avoid the use of drugs that harm the fetus). These issues are highlighted by ‘In Pregnancy’ boxes distributed throughout the book, which complement the new chapter on maternal medicine.

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noradrenaline. British spellings have been retained for drug classes and groups (e.g. amphetamines not amfetamines).

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treatment in old age, and the benefits and risks of intervention in older people.

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xx • Introduction

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Answers to problems 12

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Clinical decision-making: putting it all together 10

Dealing with uncertainty 5

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Patient-centred evidence-based medicine and shared decision-making 10

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Use and interpretation of diagnostic tests 3 Normal values 3 Factors other than disease that influence test results 4 Operating characteristics 4 Sensitivity and specificity 4 Prevalence of disease 5

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Reducing errors in clinical decision-making 9 Cognitive debiasing strategies 9 Using clinical prediction rules and other decision aids 10 Effective team communication 10

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Cognitive biases 6 Type 1 and type 2 thinking 7 Common cognitive biases in medicine 7 Human factors 9

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The problem of diagnostic error 2

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Clinical decision-making

Introduction 2

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N Cooper AL Cracknell

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Understanding cognitive biases and human factors

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medicine)

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Accepting a diagnosis handed over to you without question (the ‘framing effect’) instead of asking yourself ‘What is the evidence that supports this diagnosis?’

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Cognitive biases

Deciding a patient has not had a stroke because his brain scan is normal – computed tomography and even magnetic resonance imaging, especially when performed early, may not identify an infarct

Using and interpreting diagnostic tests

Clinical reasoning

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Telling a patient she cannot have biliary colic because she has had her gallbladder removed – gallstones can form in the bile ducts in patients who have had a cholecystectomy

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1.2  Reasons for errors in clinical reasoning

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Clinical skills (history and physical examination)

Adapted from Graber M, Gordon R, Franklin N. Reducing diagnostic errors in medicine: what’s the goal? Acad Med 2002; 77:981–992.

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Inadequate data-gathering Errors in reasoning

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Inadequate diagnostic support Results not available Error-prone processes Poor supervision of inexperienced staff Poor team communication

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‘Clinical reasoning’ describes the thinking and decision-making processes associated with clinical practice. It is a clinician’s ability to make decisions (often with others) based on all the available clinical information, starting with the history and physical examination. Our understanding of clinical reasoning derives from the fields of education, cognitive psychology and studies of expertise. Figure 1.1 shows the different elements involved in clinical reasoning. Good clinical skills are fundamental, followed by understanding how to use and interpret diagnostic tests. Other essential elements include an understanding of cognitive biases and human factors, and the ability to think about one’s own thinking (which is explained in more detail later). Other key elements of clinical reasoning include patient-centred evidencebased medicine (EBM) and shared decision-making with patients and/or carers.

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1.1  Root causes of diagnostic error in studies

Clinical reasoning: definitions

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It is estimated that diagnosis is wrong 10–15% of the time in specialties such as emergency medicine, internal medicine and general practice. Diagnostic error is associated with greater morbidity than other types of medical error, and the majority is considered to be preventable. For every diagnostic error there are a number of root causes. Studies of misdiagnosis assign three main categories, shown in Box 1.1; however, errors in clinical reasoning play a significant role in the majority of diagnostic adverse events.

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The problem of diagnostic error

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Examples of errors in these three categories are shown in Box 1.2. Clearly, clinical knowledge is required for sound clinical reasoning, and an incomplete knowledge base or inadequate experience can lead to diagnostic error. However, this chapter focuses on other elements of clinical reasoning: namely, the interpretation of diagnostic tests, cognitive biases and human factors.

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A great deal of knowledge and skill is required to practise as a doctor. Physicians in the 21st century need to have a comprehensive knowledge of basic and clinical sciences, have good communication skills, be able to perform procedures, work effectively in a team and demonstrate professional and ethical behaviour. But how doctors think, reason and make decisions is arguably their most critical skill. Knowledge is necessary, but not sufficient on its own for good performance and safe care. This chapter describes the principles of clinical decision-making, or clinical reasoning.

Diagnostic error has been defined as ‘a situation in which the clinician has all the information necessary to make the diagnosis but then makes the wrong diagnosis’. Why does this happen? Studies reveal three main reasons: • knowledge gaps • misinterpretation of diagnostic tests • cognitive biases.

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2 • Clinical decision-making

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probability of finding in patients with disease probability of finding in patients without disease

LRs are also used for diagnostic tests; here a physical examination finding can be considered a diagnostic test. Data from Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis 2002; 35:46–52.

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nuchal rigidity in the clinical diagnosis of meningitis.

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Most tests provide quantitative results (i.e. a value on a continuous numerical scale). In order to classify quantitative results as normal or abnormal, it is necessary to define a cut-off point. Many quantitative measurements in populations have a Gaussian or ‘normal’ distribution. By convention, the normal range is defined as those values that encompass 95% of the population, or 2 standard deviations above and below the mean. This means that 2.5% of the normal population will have values above, and 2.5% will have values below the normal range. For this reason, it is more appropriate to talk about the ‘reference range’ rather than the ‘normal range’ (Fig. 1.3). Test results in abnormal populations also have a Gaussian distribution, with a different mean and standard deviation. In some diseases there is no overlap between results from the abnormal and normal population. However, in many diseases there is overlap; in these circumstances, the greater the difference between the test result and the limits of the reference range, the higher the chance that the person has a disease. However, there are also situations in medicine when ‘normal’ is abnormal and ‘abnormal’ is normal. For example, a normal PaCO2 in the context of a severe asthma attack is abnormal and means the patient has life-threatening asthma. A low ferritin in a young menstruating woman is not considered to be a disease at all. Normal, to some extent, is therefore arbitrary.

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Fig. 1.2  Likelihood ratio (LR) of Kernig’s sign, Brudzinski’s sign and LR =

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There is no such thing as a perfect diagnostic test. Test results give us test probabilities, not real probabilities. Test results have to be interpreted because they are affected by the following: • how ‘normal’ is defined • factors other than disease • operating characteristics • sensitivity and specificity • prevalence of disease in the population.

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value, the greater the probability). Similarly, an LR of less than 1 decreases the probability of disease. LRs are developed against a diagnostic standard (e.g. in the case of meningitis, lumbar puncture results), so do not exist for all clinical findings. LRs illustrate how an individual clinical finding changes the probability of a disease. For example, in a person presenting with headache and fever, the clinical finding of nuchal rigidity (neck stiffness) may carry little weight in deciding whether to perform a lumbar puncture because LRs do not determine the prior probability of disease; they reflect only how a single clinical finding changes it. Clinicians have to take all the available information from the history and physical examination into account. If the overall clinical probability is high to begin with, a clinical finding with an LR of around 1 does not change this. ‘Evidence-based history and examination’ is a term used to describe how clinicians incorporate knowledge about the prevalence and diagnostic weight of clinical findings into their history and physical examination. This is important because an estimate of clinical probability is vital in decision-making and the interpretation of diagnostic tests.

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However, the frequency with which patients present with certain features and the diagnostic weight of each feature are important in clinical reasoning. For example, many patients with meningitis do not have classical signs of meningeal irritation (Kernig’s sign, Brudzinski’s sign and nuchal rigidity). In one prospective study, they had likelihood ratios of around 1, meaning they carried little diagnostic weight (Fig. 1.2). Likelihood ratios (LR) are clinical diagnostic weights. An LR of greater than 1 increases the probability of disease (the higher the

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Even with major advances in medical technology, the history remains the most important part of the clinical decision-making process. Studies show that physicians make a diagnosis in 70–90% of cases from the history alone. It is important to remember that a good history is gathered not only from the patient but also, if necessary (and with consent if required), from all available sources: for example, paramedic and emergency department notes, eye-witnesses, relatives and/or carers. Clinicians need to be aware of the diagnostic usefulness of clinical features in the history and examination. For example, students are taught that meningitis presents with the following features: • headache • fever • meningism (photophobia, nuchal rigidity).

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Clinical skills and decision-making

Use and interpretation of diagnostic tests

Examples

Age

Creatinine is lower in old age (due to relatively lower muscle mass) – an older person can have a significantly reduced eGFR rate with a ‘normal’ creatinine

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Diagnostic tests have characteristics termed ‘sensitivity’ and ‘specificity’. Sensitivity is the ability to detect true positives; specificity is the ability to detect true negatives. Even a very good test, with 95% sensitivity, will miss 1 in 20 people with the disease. Every test therefore has ‘false positives’ and ‘false negatives’ (Box 1.4). A very sensitive test will detect most disease but generate abnormal findings in healthy people. A negative result will therefore reliably exclude disease but a positive result does not mean the disease is present – it means further evaluation is required. On the other hand, a very specific test may miss significant pathology but is likely to establish the diagnosis beyond doubt when the result is positive. All tests differ in their sensitivity and specificity, and clinicians require a working knowledge of the tests they use in this respect. In choosing how a test is used to guide decision-making there is a trade-off between sensitivity versus specificity. For example, defining an exercise electrocardiogram (p. 449) as abnormal if there is at least 0.5 mm of ST depression would ensure that very few cases of coronary artery disease are missed but would generate many false-positive results (high sensitivity, low specificity). On the other hand, a cut-off point of 2.0 mm of ST depression would detect most cases of important coronary artery disease with far fewer false positives. This trade-off is illustrated by the receiver operating characteristic curve of the test (Fig. 1.4). An extremely important concept is this: the probability that a person has a disease depends on the pre-test probability, and the sensitivity and specificity of the test. For example, imagine that an elderly lady has fallen and hurt her left hip. On examination,

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Tests are also subject to operating characteristics. This refers to the way the test is performed. Patients need to be able to comply fully with some tests, such as spirometry (p. 569), and if they cannot, then the test result will be affected. Some tests are very dependent on the skill of the operator and are also affected by the patient’s body habitus and clinical state; ultrasound of the heart and abdomen are examples. A common mistake is when doctors refer to a test result as ‘no abnormality detected’ when, in fact, the report describes a technically difficult and incomplete scan that should more accurately be described as ‘non-diagnostic’. Some conditions are paroxysmal. For example, around half of patients with epilepsy have a normal standard electroencephalogram (EEG). A normal EEG therefore does not exclude epilepsy. On the other hand, around 10% of patients who do not have epilepsy have epileptiform discharges on their EEG. This is referred to as an ‘incidental finding’. Incidental findings are common in medicine, and are increasing in incidence with the greater availability of more sensitive tests. Test results should always be interpreted in the light of the patient’s history and physical examination.

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A spurious high potassium is seen in haemolysis and in thrombocytosis (‘pseudohyperkalaemia’)

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Box 1.3 gives some examples.

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A number of factors other than disease influence test results: • age • ethnicity • pregnancy • sex • spurious (in vitro) results.

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(ECG = electrocardiogram; eGFR = estimated glomerular filtration rate, a better estimate of renal function than creatinine)

Factors other than disease that influence test results

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the frequency distribution of results in the normal healthy population (red line) is a symmetrical bell-shaped curve. The mean ± 2 standard deviations (SD) encompasses 95% of the normal population and usually defines the ‘reference range’; 2.5% of the normal population have values above, and 2.5% below, this range (shaded areas). For some diseases (blue line), test results overlap with the normal population or even with the reference range. For other diseases (green line), tests may be more reliable because there is no overlap between the normal and abnormal population.

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Fig. 1.3  Normal distribution and reference range. For many tests,

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‘Reference range’

Several tests are affected by late pregnancy, due to the effects of a growing fetus, including: Reduced urea and creatinine (haemodilution) Iron deficiency anaemia (increased demand) Increased alkaline phosphatase (produced by the placenta) Raised D-dimer (physiological changes in the coagulation system) Mild respiratory alkalosis (physiological maternal hyperventilation) ECG changes (tachycardia, left axis deviation)

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Healthy people of African ancestry have lower white cell counts

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Abnormal populations

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Clinical findings are imperfect and diagnostic tests are imperfect. It is important to recognise that clinicians frequently deal with uncertainty. By expressing uncertainty as probability, new information from diagnostic tests can be incorporated more accurately. However, subjective estimates of probability can sometimes be unreliable. As the section on cognitive biases will demonstrate (see below), intuition can be a source of error.

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Positive predictive value = A/(A+B) × 100 Negative predictive value = D/(D+C) × 100

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1.5  Predictive values: ‘What is the probability that a person with a positive test actually has the disease?’

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the hip is extremely painful to move and she cannot stand. However, her hip X-rays are normal. Does she have a fracture? The sensitivity of plain X-rays of the hip performed in the emergency department for suspected hip fracture is around 95%. A small percentage of fractures are therefore missed. If our patient has (or is at risk of) osteoporosis, has severe pain on hip movement and cannot bear weight on the affected side, then the clinical probability of hip fracture is high. If, on the other hand, she is unlikely to have osteoporosis, has no pain on hip movement and is able to bear weight, then the clinical probability of hip fracture is low. Doctors are continually making judgements about whether something is true, given that something else is true. This is known as ‘conditional probability’. Bayes’ Theorem (named after English clergyman Thomas Bayes, 1702–1761) is a mathematical way to describe the post-test probability of a disease by combining pre-test probability, sensitivity and specificity. In clinical practice, doctors are not able to make complex mathematical calculations for every decision they make. In practical terms, the answer to the question of whether there is a fracture is that in a high-probability patient a normal test result does not exclude the condition, but in a low-probability patient it makes it very unlikely. This principle is illustrated in Figure 1.5. Sox and colleagues (see ‘Further information’) state a fundamental assertion, which they describe as a profound and subtle principle of clinical medicine: the interpretation of

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trade-off between sensitivity and specificity for a given test. The curve is generated by ‘adjusting’ the cut-off values defining normal and abnormal results, calculating the effect on sensitivity and specificity and then plotting these against each other. The closer the curve lies to the top left-hand corner, the more useful the test. The red line illustrates a test with useful discriminant value and the green line illustrates a less useful, poorly discriminant test.

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Consider this problem that was posed to a group of Harvard doctors: if a test to detect a disease whose prevalence is 1 : 1000 has a false-positive rate of 5%, what is the chance that a person found to have a positive result actually has the disease, assuming you know nothing about the person’s symptoms and signs? Take a moment to work this out. In this problem, we have removed clinical probability and are only considering prevalence. The answer is at the end of the chapter. Predictive values combine sensitivity, specificity and prevalence. Sensitivity and specificity are characteristics of the test; the population does not change this. However, as doctors, we are interested in the question, ‘What is the probability that a person with a positive test actually has the disease?’ This is illustrated in Box 1.5. Post-test probability and predictive values are different. Posttest probability is the probability of a disease after taking into account new information from a test result. Bayes’ Theorem can be used to calculate post-test probability for a patient in any population. The pre-test probability of disease is decided by the doctor; it is a judgement based on information gathered prior to ordering the test. Predictive value is the proportion of patients with a test result who have the disease (or no disease) and is calculated from a table of results in a specific population (see Box 1.5). It is not possible to transfer this value to a different population. This is important to realise because published information about the performance of diagnostic tests may not apply to different populations. In deciding the pre-test probability of disease, clinicians often neglect to take prevalence into account and this distorts their estimate of probability. To estimate the probability of disease in a patient more accurately, clinicians should anchor on the prevalence of disease in the subgroup to which the patient belongs and then adjust to take the individual factors into account.

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new information depends on what you believed beforehand. In other words, the interpretation of a test result depends on the probability of disease before the test.

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Dealing with uncertainty • 5

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6 • Clinical decision-making

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Advances in cognitive psychology in recent decades have demonstrated that human thinking and decision-making are prone to error. Cognitive biases are subconscious errors that lead to inaccurate judgement and illogical interpretation of information. They are prevalent in everyday life; as the famous saying goes, ‘to err is human.’ Take a few moments to look at this simple puzzle. Do not try to solve it mathematically but listen to your intuition: A bat and ball cost £1.10. The bat costs £1 more than the ball. How much does the ball cost? The answer is at the end of the chapter. Most people get the answer to this puzzle wrong. Two things are going on: one is that humans have two distinct types of processes when it comes to thinking and decision-making – termed ‘type 1’ and ‘type 2’ thinking. The other is that the human brain is wired to jump to conclusions sometimes or to miss things that are obvious. British psychologist and patient safety pioneer James

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an understanding of the prevalence of disease in the particular care setting or the population to which the patient belongs.

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Knowing the patient’s true state is often unnecessary in clinical decision-making. Sox and colleagues (see ‘Further information’) argue that there is a difference between knowing that a disease is present and acting as if it were present. The requirement for diagnostic certainty depends on the penalty for being wrong. Different situations require different levels of certainty before starting treatment. How we communicate uncertainty to patients will be discussed later in this chapter (p. 10). The treatment threshold combines factors such as the risks of the test, and the risks versus benefits of treatment. The point at which the factors are all evenly weighed is the threshold. If a test or treatment for a disease is effective and low-risk (e.g. giving antibiotics for a suspected urinary tract infection), then there is a lower threshold for going ahead. On the other hand, if a test or treatment is less effective or high-risk (e.g. starting chemotherapy for a malignant brain tumour), then greater confidence is required in the clinical diagnosis and potential benefits of treatment first. In principle, if a diagnostic test will not change the management of the patient, then careful consideration should be given to whether it is necessary to do the test at all. In summary, test results shift our thinking, but rarely give a ‘yes’ or a ‘no’ answer in terms of a diagnosis. Sometimes tests shift the probability of disease by less than we realise. Pre-test probability is key, and this is derived from the history and physical examination, combined with a sound knowledge of medicine and

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being carried out has a sensitivity of 95% and a specificity of 85%. Patient A has very characteristic clinical findings, which make the pre-test probability of the condition for which the test is being used very high – estimated as 90%. Patient B has more equivocal findings, such that the pre-test probability is estimated as only 50%. If the result in Patient A is negative, there is still a significant chance that he has the condition for which he is being tested; in Patient B, however, a negative result makes the diagnosis very unlikely.

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Fig. 1.5  The interpretation of a test result depends on the probability of the disease before the test is carried out. In the example shown, the test

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was found beside her at home. Her observations show she has a Glasgow Coma Scale score of 10/15, heart rate 100 beats/ min, blood pressure 100/60 mmHg, respiratory rate 14 breaths/ min, oxygen saturations 98% on air and temperature 37.5°C. Already your mind has reached a working diagnosis. It fits a pattern (type 1 thinking). You think she has taken an overdose. At this point you can stop to think about your thinking (rational override in Fig. 1.6): ‘What is the evidence for this diagnosis? What else could it be?’ On the other hand, imagine being asked to assess a patient who has been admitted with syncope. There are several different causes of syncope and a systematic approach is required to reach a diagnosis (type 2 thinking). However, you recently heard about a case of syncope due to a leaking abdominal aortic aneurysm. At the end of your assessment, following evidence-based guidelines, it is clear the patient can be discharged. Despite this, you decide to observe the patient overnight ‘just in case’ (irrational override in Fig. 1.6). In this example, your intuition is actually availability bias (when things are at the forefront of your mind), which has significantly distorted your estimate of probability.

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Common cognitive biases in medicine

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Figure 1.7 illustrates the common cognitive biases prevalent in medical practice. Biases often work together; for example, in

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type 2 thinking in the diagnostic process. Adapted from Croskerry P. A universal model of diagnostic reasoning. Acad Med 2009; 84:1022–1028.

1.6  Type 1 and type 2 thinking

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Studies of cognitive psychology and functional magnetic resonance imaging demonstrate two distinct types of processes when it comes to decision-making: intuitive (type 1) and analytical (type 2). This has been termed ‘dual process theory’. Box 1.6 explains this in more detail. Psychologists estimate that we spend 95% of our daily lives engaged in type 1 thinking – the intuitive, fast, subconscious mode of decision-making. Imagine driving a car, for example; it would be impossible to function efficiently if every decision and movement were as deliberate, conscious, slow and effortful as in our first driving lesson. With experience, complex procedures become automatic, fast and effortless. The same applies to medical practice. There is evidence that expert decision-making is well served by intuitive thinking. The problem is that although intuitive processing is highly efficient in many circumstances, in others it is prone to error. Clinicians use both type 1 and type 2 thinking, and both types are important in clinical decision-making. When encountering a problem that is familiar, clinicians employ pattern recognition and reach a working diagnosis or differential diagnosis quickly (type 1 thinking). When encountering a problem that is more complicated, they use a slower, systematic approach (type 2 thinking). Both types of thinking interplay – they are not mutually exclusive in the diagnostic process. Figure 1.6 illustrates the interplay between type 1 and type 2 thinking in clinical practice. Errors can occur in both type 1 and type 2 thinking; for example, people can apply the wrong rules or make errors in their application while using type 2 thinking. However, it has been argued that the common cognitive biases encountered in medicine tend to occur when clinicians are engaged in type 1 thinking. For example, imagine being asked to see a young woman who is drowsy. She is handed over to you as a ‘probable overdose’ because she has a history of depression and a packet of painkillers

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Reason said that, ‘Our propensity for certain types of error is the price we pay for the brain’s remarkable ability to think and act intuitively – to sift quickly through the sensory information that constantly bombards us without wasting time trying to work through every situation anew.’ This property of human thinking is highly relevant to clinical decision-making.

Type 1 and type 2 thinking

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Cognitive biases • 7

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Unpacking principle Failure to ‘unpack’ all the available information may mean things are missed. For example, if a thorough history is not obtained from either the patient or carers (a common problem in geriatric medicine), diagnostic possibilities may be discounted

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Visceral bias The influence of either negative or positive feelings towards patients, which can affect our decisionmaking

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Posterior probability Our estimate of the likelihood of disease may be unduly influenced by what has gone on before for a particular patient. For example, a patient who has been extensively investigated for headaches presents with a severe headache, and serious causes are discounted

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Triage-cueing Triage ensures patients are sent to the right department. However, this leads to ‘geography is destiny’. For example, a diabetic ketoacidosis patient with abdominal pain and vomiting is sent to surgery. The wrong location (surgical ward) stops people thinking about medical causes of abdominal pain and vomiting

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Overconfidence bias The tendency to believe we know more than we actually do, placing too much faith in opinion instead of gathered evidence

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Fig. 1.7  Common cognitive biases in medicine. Adapted from Croskerry P. Achieving quality in clinical decision-making: cognitive strategies and

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detection of bias. Acad Emerg Med 2002; 9:1184–1204.

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Commission bias The tendency towards action rather than inaction, on the assumption that good can come only from doing something (rather than ‘watching and waiting’)

Confirmation bias The tendency to look for confirming evidence to support a theory rather than looking for disconfirming evidence to refute it, even if the latter is clearly present. Confirmation bias is common when a patient has been seen first by another doctor

Search satisficing We may stop searching because we have found something that fits or is convenient, instead of systematically looking for the best alternative, which involves more effort

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Omission bias The tendency towards inaction, rooted in the principle of ‘first do no harm.’ Events that occur through natural progression of disease are more acceptable than those that may be attributed directly to the action of the health-care team

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Base rate neglect The tendency to ignore the prevalence of a disease, which then distorts Bayesian reasoning. In some cases, clinicians do this deliberately in order to rule out an unlikely but worst-case scenario

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Hindsight bias Knowing the outcome may profoundly influence the perception of past events and decision-making, preventing a realistic appraisal of what actually occurred – a major problem in learning from diagnostic error

Psych-out error Psychiatric patients who present with medical problems are underassessed, under-examined and under-investigated because problems are presumed to be due to, or exacerbated by, their psychiatric condition

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Framing effect How a case is presented – for example, in handover – can generate bias in the listener. This can be mitigated by always having ‘healthy scepticism’ about other people’s diagnoses

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Availability bias Things may be at the forefront of your mind because you have seen several cases recently or have been studying that condition in particular. For example, when one of the authors worked in an epilepsy clinic, all blackouts were possible seizures

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Ascertainment bias We sometimes see what we expect to see (‘self-fulfilling prophecy’). For example, a frequent self-harmer attends the emergency department with drowsiness; everyone assumes he has taken another overdose and misses a brain injury

Premature closure The tendency to close the decisionmaking process prematurely and accept a diagnosis before it, and other possibilities, have been fully explored

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Anchoring The common human tendency to rely too heavily on the first piece of information offered (the ‘anchor’) when making decisions

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8 • Clinical decision-making

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Red flags and ROWS (‘rule out worst case scenario’)

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These are used frequently in medicine in order to reduce reliance on fallible human memory. ABCDE (airway, breathing, circulation, disability, exposure/examination) is probably the most successful checklist in medicine, used during the assessment and treatment of critically ill patients (ABCDE is sometimes prefixed with ‘C’ for ‘control of any obvious problem’; see p. 188). Checklists ensure that important issues have been considered and completed, especially under conditions of complexity, stress or fatigue.

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Fig. 1.8  Factors that affect our judgement and

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decision-making. Type 1 thinking = fast, intuitive, subconscious, low-effort.

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External factors Interruptions Cognitive overload Time pressure Ambient conditions Insufficient data Team factors Patient factors Poor feedback

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These are strategies that force doctors to consider serious diseases that can present with common symptoms. Red flags in back pain are listed in Box 24.19 (p. 996). Considering and investigating for possible pulmonary embolism in patients who

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Once all the available data from history, physical examination and (sometimes) initial test results are available, these need to be synthesised into a problem list. The ability to identify key clinical data and create a problem list is a key step in clinical reasoning. Some problems (e.g. low serum potassium) require action but not necessarily a differential diagnosis. Other problems (e.g. vomiting) require a differential diagnosis. The process of generating a problem list ensures nothing is missed. The process of generating a differential diagnosis works against anchoring on a particular diagnosis too early, thereby avoiding search satisficing and premature closure (see Fig. 1.7).

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Type 1 thinking/ conservation of cognitive effort Cognitive and affective biases

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Internal factors Knowledge Training Beliefs and values Emotions Sleep/fatigue Stress Physical illness Personality type

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Taking a history and performing a physical examination may seem obvious, but these are sometimes carried out inadequately. This is the ‘unpacking principle’: failure to unpack all the available information means things can be missed and lead to error.

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Knowledge and experience do not eliminate errors. Instead, there are a number of ways in which we can act to reduce errors in clinical decision-making. Examples are:

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There are some simple and established techniques that can be used to avoid cognitive biases and errors in clinical decision-making.

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An understanding of these interactions makes it easier for health-care professionals, who are committed to ‘first do no harm,’ to work in the safest way possible. For example, performance is adversely affected by factors such as poorly designed processes and equipment, frequent interruptions and fatigue. The areas of the brain required for type 2 processing are most affected by things like fatigue and cognitive overload, and the brain reverts to type 1 processing to conserve cognitive energy. Figure 1.8 illustrates some of the internal and external factors that affect human judgement and decision-making. Various experiments demonstrate that we focus our attention to filter out distractions. This is advantageous in many situations, but in focusing on what we are trying to see we may not notice the unexpected. In a team context, what is obvious to one person may be completely missed by someone else. Safe and effective team communication therefore requires us never to assume, and to verbalise things, even though they may seem obvious.

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‘Human factors’ is the science of the limitations of human performance, and how technology, the work environment and team communication can adapt for this to reduce diagnostic and other types of error. Analysis of serious adverse events in clinical practice shows that human factors and poor team communication play a significant role when things go wrong. Research shows that many errors are beyond an individual’s conscious control and are precipitated by many factors. The discipline of human factors seeks to understand interactions between: • people and tasks or technology • people and their work environment • people in a team.

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overconfidence bias (the tendency to believe we know more than we actually do), too much faith is placed in opinion instead of gathered evidence. This bias can be augmented by the availability bias and finally by commission bias (the tendency towards action rather than inaction) – sometimes with disastrous results. The mark of a well-calibrated thinker is the ability to recognise what mode of thinking is being employed and to anticipate and recognise situations in which cognitive biases and errors are more likely to occur.

Human factors

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Reducing errors in clinical decision-making • 9

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Please can you come and see her as soon as possible? I think she needs admission to Intensive Care.

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(NEWS = National Early Warning Score; a patient with normal vital signs scores 0) From Royal College of Physicians of London. National Early Warning Score: standardising the assessment of illness severity in the NHS. Report of a working party. RCP, July 2012; www.rcplondon.ac.uk/projects/outputs/national-earlywarning-score-news (accessed March 2016).

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with dual antiplatelet therapy and low-molecular-weight heparin as recommended in clinical guidelines? As this chapter has described, clinicians frequently deal with uncertainty/probability. Clinicians need to be able to explain risks and benefits of treatment in an accurate and understandable way. Providing the relevant statistics is seldom sufficient to guide decision-making because a patient’s perception of risk may be influenced by irrational factors as well as individual values. Research evidence provides statistics but these can be confusing. Terms such as ‘common’ and ‘rare’ are nebulous. Whenever possible, clinicians should quote numerical information using consistent denominators (e.g. ‘90 out of 100 patients who have this operation feel much better, 1 will die during the operation and 2 will suffer a stroke’). Visual aids can be used to present complex statistical information (Fig. 1.9). How uncertainty is conveyed to patients is important. Many studies demonstrate a correlation between effective clinician– patient communication and improved health outcomes. If patients feel they have been listened to and understand the problem and proposed treatment plan, they are more likely to follow the plan and less likely to re-attend.

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Clinical decision-making: putting it all together

The following is a practical example that brings together many of the concepts outlined in this chapter: A 25-year-old woman presents with right-sided pleuritic chest pain and breathlessness. She reports that she had an upper

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‘Patient-centred evidence-based medicine’ refers to the application of best-available research evidence while taking individual patient factors into account; these include both clinical and non-clinical factors (e.g. the patient’s social circumstances, values and wishes). For example, a 95-year-old man with dementia and a recent gastrointestinal bleed is admitted with an inferior myocardial infarction. He is clinically well. Should he be treated

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Her vital signs are: blood pressure 115/60 mmHg, heart rate 120 beats/min, temperature 38°C, respiratory rate 32 breaths/min, oxygen saturations 89% on 15 L via reservoir bag mask. An arterial blood gas shows pH 7.3 (H+ 50 nmol/L), PaCO2 4.0 kPa (30 mmHg), PaO2 7 kPa (52.5 mmHg), standard bicarbonate 14 mmol/L. Chest X-ray shows extensive right lower zone consolidation.

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Patient-centred evidence-based medicine and shared decision-making

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[Patient’s name], 30-year-old woman, no past medical history, was admitted last night with community-acquired pneumonia. Since then her oxygen requirements have been steadily increasing.

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Effective team communication and proper handovers are vital for safe clinical care. The SBAR system of communication has been recommended by the UK’s Patient Safety First campaign. It is a structured way to communicate about a patient with another health-care professional (e.g. during handover or when making a referral) and increases the amount of relevant information being communicated in a shorter time. It is illustrated in Box 1.7. In increasingly complex health-care systems, patients are looked after by a wide variety of professionals, each of whom has access to important information required to make clinical decisions. Strict hierarchies are hazardous to patient safety if certain members of the team are not able to speak up.

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I am [name] calling from [place] about a patient with a NEWS of 10.

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A clinical prediction rule is a statistical model of the diagnostic process. When clinical prediction rules are matched against the opinion of experts, the model usually outperforms the experts, because it is applied consistently in each case. However, it is important that clinical prediction rules are used correctly – that is, applied to the patient population that was used to create the rule. Clinical prediction rules force a scientific assessment of the patient’s symptoms, signs and other data to develop a numerical probability of a disease or an outcome. They help clinicians to estimate probability more accurately. A good example of a clinical prediction rule to estimate pre-test probability is the Wells score in suspected deep vein thrombosis (see Box 10.15, p. 187). Other commonly used clinical prediction rules predict outcomes and therefore guide the management plan. These include the GRACE score in acute coronary syndromes (see Fig. 16.62, p. 494) and the CURB-65 score in communityacquired pneumonia (see Fig. 17.32, p. 583).

Effective team communication

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Newer strategies to avoid cognitive biases and errors in decisionmaking are emerging. These involve explicit training in clinical reasoning and human factors. In theory, if doctors are aware of the science of human thinking and decision-making, then they are more able to think about their thinking, understand situations in which their decision-making may be affected, and take steps to mitigate this.

1.7  The SBAR system of communicating

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present with pleuritic chest pain and breathlessness is a common example of ruling out a worst-case scenario, as pulmonary embolism can be fatal if missed. Red flags and ROWS help to avoid cognitive biases such as the ‘framing effect’ and ‘premature closure’.

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Fig. 1.9  Visual portrayal of benefits and risks. The image refers to an

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The diagnosis of pulmonary embolism can be difficult. Clinical prediction rules (e.g. modified Wells score), guidelines (e.g. from the UK’s National Institute for Health and Care Excellence, or NICE) and decision aids (e.g. simplified pulmonary embolism severity index, or PESI) are frequently used in combination with the doctor’s opinion, derived from information gathered in the history and physical examination.

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Imagine the patient went on to have a normal chest X-ray and blood results, apart from a raised D-dimer of 900 (normal

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Imagine that, after you have seen the patient, a nurse hands you some blood forms and asks you what tests you would like to request on ‘this lady’. You request blood tests including a D-dimer on the wrong patient. Luckily, this error is intercepted.

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The prevalence of pulmonary embolism in 25-year-old women is low. We anchor on this prevalence and then adjust for individual patient factors. This patient has no major risk factors for pulmonary embolism. To assist our estimate of pre-test probability, we could use a clinical prediction rule: in this case, the modified Wells score for pulmonary embolism, which would give a score of 3 (low probability – answering yes only to the criterion ‘PE is the number one diagnosis, an alternative is less likely’).

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Imagine during this case that the patient had been handed over to you as ‘nothing wrong – probably a pulled muscle’. Cognitive biases (subconscious tendencies to respond in a certain way) would come into play, such as the ‘framing effect’, ‘confirmation bias’ and ‘search satisficing’. The normal clinical examination might confirm the diagnosis of musculoskeletal pain in your mind, despite the examination being entirely consistent with pulmonary embolism and despite the lack of history and examination findings (e.g. chest wall tenderness) to support the diagnosis of musculoskeletal chest pain.

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Deciding pre-test probability

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Information from the history and physical examination is vital in deciding whether this could be a pulmonary embolism. Pleurisy and breathlessness are common presenting features of this disease but are also common presenting features in other diseases. There is nothing in the history to suggest an alternative diagnosis (e.g. high fever, productive cough, recent chest trauma). The patient’s vital signs are normal, as is the physical examination. However, the only feature in the history and examination that has a negative likelihood ratio in the diagnosis of pulmonary embolism is a heart rate of less than 90 beats/min. In other words, the normal physical examination findings (including normal oxygen saturations) carry very little diagnostic weight.

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The patient’s scan result is subsequently reported as ‘no pulmonary embolism’. Combined with the low pre-test probability, this scan result reliably excludes pulmonary embolism.

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Post-test probability

Evidence-based history and examination

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The treatment threshold combines factors such as the risks of the test, and the risks versus benefits of treatment. A CT pulmonary angiogram (CTPA) could be requested for this patient, although in some circumstances ventilation–perfusion single-photon emission computed tomography (V̇ /Q̇ SPECT, p. 620) may be a more suitable alternative. However, what if the scan cannot be performed until the next day? Because pulmonary embolism is potentially fatal and the risks of treatment in this case are low, the patient should be started on treatment while awaiting the scan.

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Treatment threshold

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respiratory tract infection a week ago and was almost back to normal when the symptoms started. The patient has no past medical history and no family history, and her only medication is the combined oral contraceptive pill. On examination, her vital signs are normal (respiratory rate 19 breaths/min, oxygen saturations 98% on air, blood pressure 115/60 mmHg, heart rate 90 beats/min, temperature 37.5°C) and the physical examination is also normal. You have been asked to assess her for the possibility of a pulmonary embolism. (More information on pulmonary embolism can be found on page 619.)

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operation that is expected to relieve symptoms in 90% of patients, but cause stroke in 2% and death in 1%. From Edwards A, Elwyn G, Mulley A. Explaining risks: turning numerical data into meaningful pictures. BMJ 2002; 324:827–830, reproduced with permission from the BMJ Publishing Group.

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 45 mL/min/1.73 m2 unless there is also proteinuria • eGFR is not valid in under-18s or during pregnancy • Ethnicity is not taken into account in routine laboratory reporting; the laboratory eGFR value should therefore be multiplied by 1.21 for black people • Few patients will understand eGFR in terms of mL/min/1.73 m2; it may therefore be helpful to assume that a GFR of 100 mL/ min/1.73 m2 is approximately normal and to discuss eGFR values in terms of a percentage of normal, e.g. 25 mL/min/1.73 m2 = 25% of normal kidney function

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105

15.2  Limitations of estimated glomerular filtration rate (eGFR)

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Investigation of renal and urinary tract disease • 387

Prevalence4

Clinical presentation5

Kidney damage with normal or high GFR (> 90)

Normal function

3.5%

Asymptomatic

2

Kidney damage and GFR 60–89

Mild CKD

3.9%

Asymptomatic

3A 3B

GFR 45–59 GFR 30–44

Mild to moderate CKD Moderate to severe CKD

7.6% (3A and 3B combined)

Usually asymptomatic Anaemia in some patients at 3B Most are non-progressive or progress very slowly

4

GFR 15–29

Severe CKD

0.4%

5

GFR 70 mg/mmol

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In healthy individuals, there is virtually no urinary excretion of large-molecular-weight serum proteins, such as albumin, in contrast to modest urinary excretion of tubule-derived proteins. The presence of even moderate amounts of albuminuria (previously referred to as microalbuminuria) is therefore abnormal, and may indicate early glomerular pathology, at a time when the standard dipstick test remains negative (Box 15.9). Screening for moderately elevated albuminuria should be performed regularly in patients with diabetes, as persistently elevated levels warrant therapy with inhibitors of the renin–angiotensin–aldosterone system, even in normotensive individuals, to reduce the rate of loss of renal function (see Box 20.39, p. 758). Persistent moderately increased albuminuria has also been associated with cardiovascular mortality in patients with and without diabetes, but an explanation for this association has not yet been established.

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Quantify

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Moderately elevated albuminuria (microalbuminuria)

Overt (dipstick-positive) proteinuria

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Repeated proteinuria on dipstick

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tract infection. Patients should be assessed for the presence of these conditions and urine testing repeated once the potential trigger has been treated or resolved. Testing for proteinuria is best done on an early morning sample, as some individuals exhibit orthostatic proteinuria. In these patients, typically less than 1 g/24 hrs of protein is excreted only in association with an upright posture, the first morning sample being negative. Orthostatic proteinuria is regarded as a benign disorder that does not require treatment.

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1 Urinary albumin (mg/L)/urine creatinine (mmol/L). 2Urine protein (mg/L)/urine creatinine (mmol/L). (If urine creatinine is measured in mg/dL, reference values for PCR and ACR can be derived by dividing by 11.31.) 3Dipstick results are affected by urine concentration and are occasionally weakly positive on normal samples.

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Management

Secondary hyperaldosteronism Additional poorly characterised intrarenal mechanisms

Oedema

Diuretics and a low-sodium diet*

Hypercholesterolaemia

Non-specific increase in lipoprotein synthesis by liver in response to low oncotic pressure

High rate of atherosclerosis

Statins, ezetimibe

Hypercoagulability

Relative loss of inhibitors of coagulation (antithrombin III, protein C and S) and increase in liver synthesis of procoagulant factors

Venous thromboembolism

Consideration of prophylaxis in chronic or severe nephrotic syndrome

Infection

Hypogammaglobulinaemia due to urinary loss of immunoglobulins

Pneumococcal and meningococcal infection

Consideration of vaccination

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Avid sodium retention

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Treatment of underlying cause

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Reduced oncotic pressure Oedema

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Consequence

Urinary protein losses exceed synthetic capacity of liver

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*Severe nephrotic syndrome may need very large doses of combinations of diuretics acting on different parts of the nephron (e.g. loop diuretic plus thiazide plus amiloride). In occasional patients with hypovolaemia, intravenous salt-poor albumin infusions may help to establish a diuresis, although efficacy is controversial. Over-diuresis risks secondary impairment of renal function through hypovolaemia.

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Mechanism

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Dependent areas, such as the ankles and lower legs, are typically affected first but oedema can be restricted to the sacrum in bed-bound patients. With increasing severity, oedema spreads to affect the upper parts of the legs, the genitalia and abdomen. Ascites is common and often an earlier feature in children or young adults, and in liver disease. Pleural effusions are common but frank pulmonary oedema is rare. Facial oedema on waking is common. Features of intravascular volume depletion (tachycardia, postural hypotension) may occur when oedema is due to decreased

15.11  Consequences of the nephrotic syndrome and their management Hypoalbuminaemia

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Clinical assessment

(ANA = antinuclear antibody; dsDNA = double-stranded DNA; HIV = human immunodeficiency virus; PPE = plasma protein electrophoresis)

Feature

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Hepatitis B, C + HIV serology, ANA, dsDNA Immunoglobulins, PPE, Bence Jones protein, serum free light chains

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None specific

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Gradual progression Diabetic Any age, but rarely nephropathy  3.5 g/24 hrs), hypoalbuminaemia and oedema (see below). Blood volume may be normal, reduced or increased. Renal sodium retention is an early and universal feature; the mechanisms of this are shown in Figure 14.5 (p. 354). The diseases that cause nephrotic syndrome all affect the glomerulus (see Fig. 15.9), either directly, by damaging podocytes, or indirectly, by causing

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scarring or deposition of exogenous material such as amyloid into the glomerulus. Investigation of nephrotic syndrome usually involves renal biopsy, although non-invasive tests may also be helpful in suggesting the underlying cause (Box 15.10). In children, minimal change disease is by far the most common cause of nephrotic syndrome and therefore renal biopsy is not usually required unless the patient fails to respond to high-dose glucocorticoid therapy. Similarly, most patients with diabetes presenting with nephrotic syndrome will have diabetic nephropathy, and so renal biopsy is usually not performed unless the course of the disease is atypical (rapidly increasing proteinuria or rapid decline in renal function; p. 757). Management of nephrotic syndrome should be directed at the underlying cause. In addition, nephrotic syndrome is associated with a number of complications (Box 15.11), which may require supportive management unless the nephrosis is expected to resolve rapidly, such as in glucocorticoid-responsive minimal change disease.

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Nephrotic syndrome

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dipstick tests. Hence, electrophoresis of the urine and specific immunodetection methods are required to detect immunoglobulin light chains, known as ‘Bence Jones protein’. This may occur in AL amyloidosis (p. 81) and in B-cell dyscrasias but is particularly important as a marker for myeloma (p. 966).

Cause

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Presenting problems in renal and urinary tract disease • 395

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Excess fluid intake Osmotic diuresis: hyperglycaemia, hypercalcaemia Cranial diabetes insipidus Nephrogenic diabetes insipidus: Rare inherited mutations in vasopressin receptor or aquaporin 2 genes Lithium Diuretics Interstitial nephritis Hypokalaemia Hypercalcaemia

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• • • •

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15.13  Causes of polyuria

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Polyuria is defined as a urine volume in excess of 3 L/24 hrs. Various underlying conditions, both renal and extrarenal, may be responsible, as outlined in Box 15.13. Investigation of polyuria includes measurement of urea, creatinine and electrolytes, glucose, calcium and albumin. A 24-hour urine collection may be helpful to confirm the severity of polyuria. The presence of nocturnal polyuria suggests a

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Hypertension is a very common feature of renal disease. Additionally, the presence of hypertension identifies a population

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Polyuria

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Mild oedema usually responds to elevation of the legs, compression stockings, or a thiazide or a low dose of a loop diuretic, such as furosemide or bumetanide. In nephrotic syndrome, renal failure and severe cardiac failure, very large doses of diuretics, sometimes in combination, may be required to achieve a negative sodium and fluid balance. Restriction of sodium intake and fluid intake may be required. Diuretics are not helpful in the treatment of oedema caused by venous or lymphatic obstruction or by increased capillary permeability. Specific causes of oedema, such as venous thrombosis, should be treated.

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Frequency describes daytime micturition more often than a patient would expect. It may be a consequence of polyuria, when urine volume is normal or high, but is also found in patients with dysuria and prostatic diseases, when the urine volume is normal.

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Management

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Frequency

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Oedema may be due to a number of causes (Box 15.12), which are usually apparent from the history and examination of the cardiovascular system and abdomen. Blood should be taken for measurement of urea and electrolytes, liver function and serum albumin, and the urine tested for protein. Further imaging of the liver, heart or kidneys may be indicated, based on history and clinical examination. Where ascites or pleural effusions occur in isolation, aspiration of fluid with measurement of protein and glucose, and microscopy for cells, will usually help to clarify the diagnosis in differentiating a transudate (typical of oedema) from an exudate (more suggestive of local pathology, p. 564).

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Investigations

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Dysuria refers to painful urination, often described as burning, scalding or stinging, and commonly accompanied by suprapubic pain. It is often associated with frequency of micturition and a feeling of incomplete emptying of the bladder. By far the most common cause is urinary tract infection, as described on page 426. Other diagnoses that need to be considered in patients with dysuria include sexually transmitted infections (p. 329) and bladder stones (p. 431).

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oncotic pressure or increased capillary permeability. If oedema is localised – for example, to one ankle but not the other – then venous thrombosis, inflammation or lymphatic disease should be suspected.

Hypertension

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Dysuria

Infection: filariasis, lymphogranuloma venereum (pp. 290 and 341) Malignancy Radiation injury Congenital abnormality

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• Leakage of proteins into the interstitium, reducing the osmotic pressure gradient that draws fluid into the lymphatics and blood • Infection/inflammation • Severe sepsis • Calcium channel blockers

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Increased capillary permeability

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• Nephrotic syndrome • Liver failure • Malnutrition/malabsorption

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Loin pain is often caused by musculoskeletal disease but can be a manifestation of renal tract disease; in the latter case, it may arise from renal stones, ureteric stones, renal tumours, acute pyelonephritis and urinary tract obstruction. Acute loin pain radiating anteriorly and often to the groin is termed renal colic. When combined with haematuria, this is typical of ureteric obstruction due to calculi (p. 431). Precipitation of loin pain by a large fluid intake (Dietl’s crisis) suggests upper urinary tract obstruction caused by a congenital abnormality of the pelvi-ureteric junction (p. 433).

Low plasma oncotic pressure/serum albumin

• • • •

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Loin pain

• Deep venous thrombosis or venous insufficiency • Pregnancy • Pelvic tumour

Lymphatic obstruction

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High local venous pressure

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Increased total extracellular fluid

at risk of developing CKD and current recommendations are that hypertensive patients should have renal function checked annually. Control of hypertension is very important in patients with renal impairment because of its close relationship with further decline of renal function (p. 420) and because of the exaggerated cardiovascular risk associated with CKD. Pathophysiology and management are discussed on pages 509 and 510.

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15.12  Causes of oedema • Congestive heart failure • Renal failure • Liver disease

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396 • Nephrology and urology

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Planted antigens SLE – ANA, anti-dsDNA (serum) Post-infectious glomerulonephritis

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Antibodies and antigen–antibody (immune) complexes may target or be deposited in specific components of the glomerulus, resulting in different patterns of histological injury and clinical presentation. Testing for antibody deposition in the glomerulus by immunofluorescence (IF) on renal biopsy tissue or for antibodies in the serum may aid diagnosis. Diagnostic tests are shown in italics. (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; dsDNA = double-stranded DNA; GBM = glomerular basement membrane; IgA = immunoglobulin A; SLE = systemic lupus erythematosus)

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Male sex Hypertension Persistent and severe proteinuria Elevated creatinine at time of presentation Rapid rate of decline in renal function Tubulo-interstitial fibrosis observed on renal biopsy

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Podocyte Membranous nephropathy Anti-phosphilipase A2 receptor 1 (serum + IF on biopsy; experimental at present; see Fig.15.12F)

Fig. 15.11  Glomerulonephritis associated with antibody production.

15.14  Poor prognostic indicators in glomerular disease

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GBM Goodpasture's disease Anti-GBM antibody (serum + IF on biopsy; see Fig.15.12H) Mesangium IgA nephropathy (polyclonal rise in serum IgA in 50% patients; IF on biopsy; see Fig.15.12G)

While glomerulonephritis literally means ‘inflammation of glomeruli’, the term is often used more broadly to describe all types of glomerular disease, even though some of these (e.g. minimal change nephropathy) are not associated with inflammation.

• • • • • •

Endothelium (indirectly) Small-vessel vasculitis ANCA (serum)

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Glomerulonephritis

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Glomerular diseases account for a significant proportion of acute and chronic kidney disease. Most patients with glomerular disease do not present acutely and are asymptomatic until abnormalities are detected on routine screening of blood or urine samples. There are many causes of glomerular damage, including immunological injury, inherited diseases such as Alport’s syndrome (p. 403), metabolic diseases such as diabetes mellitus (p. 757), and deposition of abnormal proteins such as amyloid in the glomeruli (p. 81). The glomerular cell types that may be the target of injury are shown in Figure 15.11. Proteinuria is the hallmark of glomerular disease; however, the response of the glomerulus to injury and hence the predominant clinical features vary according to the nature of the insult, ranging from fulminant nephrotic syndrome to rapidly progressive glomerulonephritis (see Fig. 15.9). Several prognostic indicators are common to all causes of glomerulonephritis (Box 15.14) and may be helpful in assessing the need for immunosuppressive therapy.

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Circulating immune complexes Cryoglobulinaemia (Cryoglobulins in serum) Serum sickness Endocarditis

Glomerular diseases

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Urinary incontinence is defined as any involuntary leakage of urine. It may occur in patients with a normal urinary tract, as the result of dementia or poor mobility, or transiently during an acute illness or hospitalisation, especially in older people (see Box 15.54, p. 436). The pathophysiology, investigation and management of urinary incontinence are discussed in detail later in the chapter (p. 436).

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Urinary incontinence

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Nocturia is defined as waking up at night to void urine. It may be a consequence of polyuria but may also result from increased fluid intake or diuretic use in the late evening (including caffeine). Nocturia also occurs in CKD, and in prostatic enlargement when it is associated with poor stream, hesitancy, incomplete bladder emptying, terminal dribbling and urinary frequency due to partial urethral obstruction (p. 437). Nocturia may also occur due to sleep disturbance without any functional abnormalities of the urinary tract.

Most types of glomerulonephritis are immunologically mediated and several respond to immunosuppressive drugs. Deposition of antibody occurs in many types of glomerulonephritis and testing for circulating or glomerular deposition of antibodies may aid diagnosis (see Fig. 15.11 and Boxes 15.8 and 15.10). In small-vessel vasculitis, no glomerular antibody deposition is observed (pauci-immune), but the antibodies may be indirectly pathogenic by activating neutrophils to promote endothelial injury (Fig. 15.11). Glomerulonephritis is generally classified in terms of the histopathological appearances, as summarised in Box 15.15 and Figure 15.12. Many non-specialists find the terminology used in describing glomerulonephritis to be confusing; some definitions are provided in Box 15.16. It is important to stress that the histological appearance rarely confirms a specific renal disease but rather suggests a limited range of diagnoses, which may be confirmed by further investigation. Conversely, some diseases, such as lupus, are associated with more than one histological pattern of injury. The most common histological subtypes may be categorised according to their typical clinical presentation, as discussed below. Genetic disorders associated with glomerular disease are described later (p. 403).

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Nocturia

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pathological cause. Investigation and management of suspected diabetes insipidus are described on page 688.

Glomerular diseases • 397

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Minimal change disease occurs at all ages but accounts for most cases of nephrotic syndrome (see Box 15.15) in children and about one-quarter of adult cases. It is caused by reversible dysfunction of podocytes. On light microscopy, the glomeruli appear normal (Fig. 15.12A), but fusion of podocyte foot processes is observed on electron microscopy. The presentation is with nephrotic syndrome, which typically is severe; it remits

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Minimal change nephropathy

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In these diseases, the injury is focused on the podocyte and there is little histological evidence of inflammation or cell proliferation in the glomerulus (non-proliferative, Fig. 15.12). Minimal change and primary focal segmental glomerulosclerosis (FSGS) typically present with fulminant nephrotic syndrome, whereas in membranous nephropathy and secondary FSGS, the nephrosis tends to be more indolent in nature. Other causes of nephrotic syndrome due to systemic disease are

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discussed elsewhere, including diabetic nephropathy (p. 757) and amyloid (p. 81).

Diseases typically presenting with nephrotic syndrome

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398 • Nephrology and urology

Primary FSGS presents as idiopathic nephrotic syndrome but is less responsive to treatment than minimal change; may progress to renal impairment, and can recur after transplantation Secondary FSGS presents with variable proteinuria and outcome

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Common disease with range of presentations, usually including haematuria and hypertension Henoch–Schönlein purpura is an acute IgA variant common in children

Complement gene mutations C3 nephritic factor and partial lipodystrophy

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Continued

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Complement abnormalities, inherited or acquired Dense deposit disease is associated with abnormal activation of alternative complement pathway

Most common pattern found in association with subacute bacterial infection, but also with cryoglobulinaemia ± hepatitis C virus, and others In dense deposit disease, intramembranous deposits No proven treatments

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Infections, autoimmunity or monoclonal gammopathies

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Deposition of circulating immune complexes or ‘planted’ antigens

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Usually idiopathic, flares triggered by upper respiratory infection Liver disease Coeliac disease

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Common cause of adult idiopathic nephrotic syndrome One-third progress, one-third spontaneously remit and one-third remain stable; may respond to glucocorticoids and immunosuppressants

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HLA-DQA1 (for idiopathic) Drugs: Penicillamine, NSAIDs, heavy metals Hepatitis B virus Malignancy Lupus1

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Antibodies to a podocyte surface antigen (commonly phospholipase A2 receptor 1), with complementdependent podocyte injury

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Complement components

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APOL1 variant in people of West African descent Causes of secondary FSGS include: Healing of previous local glomerular injury HIV infection Heroin misuse Morbid obesity Chronic hypertension

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m Complement type

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Unknown; circulating factors may increase glomerular permeability Injury to podocytes may be common feature Some cases are genetic (p. 403)

Unknown Mucosal infections (e.g. helminths) may be involved

Mesangiocapillary glomerulonephritis Immunoglobulin type Immunoglobulins

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Acute and often severe nephrotic syndrome Good response to glucocorticoids Dominant cause of idiopathic nephrotic syndrome in childhood

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Atopy Drugs, most commonly NSAIDs Haematological malignancies

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Mild glomerulonephritic presentation IgA nephropathy Mesangial IgA Increased mesangial (and C3) matrix and cells Focal segmental nephritis in acute disease

Comments

Unknown; probable circulating factor promoting podocyte injury Some cases are genetic (p. 403)

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Membranous nephropathy Granular Thickening of GBM subepithelial IgG Progressing to increased matrix deposition and glomerulosclerosis

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Associations

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Pathogenesis

Nephrotic presentation Minimal change None Normal, except on electron microscopy, where fusion of podocyte foot processes is observed (non-specific finding) Focal segmental glomerulosclerosis (FSGS) Non-specific Segmental scars in trapping in focal some glomeruli scars No acute inflammation Podocyte foot process fusion seen in primary FSGS

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Histology

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15.15  Glomerulonephritis categorised by clinical presentation and histological classification

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Glomerular diseases • 399

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Presents with severe sodium and fluid retention, hypertension, haematuria, oliguria Usually resolves spontaneously

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Post-streptococcal Concurrent infection with staphylococci, endocarditis

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Associated with lung haemorrhage but renal or lung disease may occur alone Treat with glucocorticoids, cyclophosphamide and plasma exchange

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HLA-DR15 (previously known as DR2)

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ks Often occurs in systemic disease Responds to treatment with glucocorticoids and immunosuppressants

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Primary or secondary small-vessel vasculitis

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Rapidly progressive glomerulonephritis presentation Focal necrotising glomerulonephritis Small-vessel vasculitis, Variable according Segmental inflammation often ANCA-mediated to cause but and/or necrosis in some typically negative glomeruli ± crescent (or ‘pauciformation immune’) Diffuse proliferative glomerulonephritis 2 Infection-related diffuse proliferative glomerulonephritis 3 Subendothelial and Immune complex-mediated Diffuse proliferation subepithelial (e.g. to streptococcal of endothelial and infection with presumed mesangial cells cross-reactive epitopes) Infiltration by neutrophils and macrophages ± crescent formation Anti-glomerular basement membrane disease Usually crescentic Linear IgG along Autoantibodies to α3 nephritis GBM chain of type IV collagen in GBM

Comments

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Associations

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Pathogenesis

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Immune deposits

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Histology

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15.15  Glomerulonephritis categorised by clinical presentation and histological classification – continued

Systemic lupus erythematosus can cause almost any histological injury pattern, most commonly membranous nephropathy or diffuse proliferative glomerulonephritis. In addition to the association with infection and anti-GBM disease, a diffuse proliferative glomerulonephritis picture may also be seen with lupus and occasionally IgA nephropathy. 3Infection may also present with mesangioproliferative glomerulonephritis and membranous nephropathy (HIV). (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; APOL1 = apolipoprotein L1; GBM = glomerular basement membrane; HLA = human leucocyte antigen; IgA = immunoglobulin A; NSAIDs = non-steroidal anti-inflammatory drugs)

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G IgA nephropathy

Anti-GBM disease

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Fig. 15.12  Histopathology of glomerular disease. ( A – E Light microscopy) A A normal glomerulus. Note the open capillary loops and thinness of

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their walls. B Focal segmental glomerulosclerosis (GS). The portion of the glomerulus arrowed shows loss of capillary loops and cells, which are replaced by matrix. C Focal necrotising glomerulonephritis (GN). A portion of the glomerulus (N = focal necrotising lesion) is replaced by bright pink material with some ‘nuclear dust’. Neutrophils may be seen elsewhere in the glomerulus. There is surrounding interstitial inflammation (I). This is most commonly associated with small-vessel vasculitis and may progress to crescentic nephritis (see E ). D Membranous glomerulonephritis. The capillary loops (C) are thickened (compare with the normal glomerulus) and there is expansion of the mesangial regions by matrix deposition (M). However, there is no gross cellular proliferation or excess of inflammatory cells. E Crescentic glomerulonephritis. The lower part of Bowman’s space is occupied by a semicircular formation (‘crescent’, Cr) of large pale cells, compressing the glomerular tuft. This is seen in aggressive inflammatory glomerulonephritis. Antibody deposition in the glomerulus. ( F – H Direct immunofluorescence) F Granular deposits of IgG along the basement membrane in a subepithelial pattern, typical of membranous GN. G Immunoglobulin A (IgA) deposits in the mesangium, as seen in IgA nephropathy. H Ribbon-like linear deposits of anti-GBM antibodies along the glomerular basement membrane in Goodpasture’s disease. The glomerular structure is well preserved in all of these examples. (A, C, D, E) Courtesy of Dr J.G. Simpson, Aberdeen Royal Infirmary. (F, G, H) Courtesy of Dr R. Herriot.

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Membranous GN

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C Focal necrotising GN

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B Focal segmental GS

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A Normal glomerulus

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Focal: affecting some but not all glomeruli Diffuse: affecting > 50% of glomeruli Segmental: affecting a portion of a glomerulus Global: affecting all of the glomerulus Necrotising: severe injury leading to an area of necrosis, usually associated with vasculitis • Crescentic: a crescent-shaped area of inflammatory cells responding to severe glomerular injury

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This is one of the most common types of glomerulonephritis and can present in many ways. Haematuria is the earliest sign and non-visible haematuria is almost universal, while hypertension is also very common. These are often detected during routine screening: for example, at occupational medical examinations. Proteinuria can also occur but is usually a later feature. In many cases, there is slowly progressive loss of renal function leading to end-stage renal disease (ESRD). A particular hallmark of IgA nephropathy in young adults is the occurrence of acute self-limiting exacerbations, often with visible haematuria, in association with minor respiratory infections. This may be so acute as to resemble acute post-infectious glomerulonephritis, with fluid retention, hypertension and oliguria with dark or red urine. Characteristically, the latency from clinical infection to nephritis is short: a few days or less. Asymptomatic presentations dominate in older adults, with non-visible haematuria, hypertension and reduction in GFR. Occasionally, IgA nephropathy progresses rapidly in association with crescent formation on biopsy. Management is largely directed towards the control of blood pressure, with renin–angiotensin system inhibitors preferable in those with proteinuria. There is some evidence for additional benefit from several months of high-dose glucocorticoid treatment in those at high-risk of progressive disease (see Box 15.14), but no strong evidence for other immunosuppressive agents. A role for other therapies, such as fish oil, remains uncertain.

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IgA nephropathy

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Patients with mild glomerulonephritis typically present with nonvisible haematuria and modest proteinuria, and their renal disease tends to follow a slowly progressive course. IgA nephropathy and mesangiocapillary glomerulonephritis (MCGN) typically fall in this category. Their presentation is highly variable, however; IgA nephropathy occasionally presents with rapidly progressive glomerulonephritis while MCGN may present with nephrotic syndrome. Other diseases that present with haematuria, modest proteinuria and slow progression include Alport’s syndrome (p. 403).

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Primary focal segmental glomerulosclerosis (FSGS) (Fig. 15.12B) can occur in all age groups but is particularly common in people of West African descent, who, compared with other ethnicities, have a much higher carriage rate of an apolipoprotein L1 (APOL1) gene variant that is associated with increased risk of FSGS. Histological analysis shows sclerosis initially limited to segments of the glomeruli, which may also show positive staining for deposits of C3 and IgM on immunofluorescence. Since FSGS is a focal process, abnormal glomeruli may not be seen on renal biopsy if only a few are sampled, leading to an initial diagnosis of minimal change nephropathy. In most cases the underlying cause is unknown (primary FSGS) and these patients typically present with abrupt onset of severe nephrotic syndrome. Primary FSGS may respond to high-dose glucocorticoid therapy (0.5–2.0 mg/ kg/day) but the response is rarely as rapid or complete as for minimal change disease. Immunosuppressive drugs, such as ciclosporin, cyclophosphamide and mycophenolate mofetil, have also been used but their efficacy is uncertain. Progression to CKD is common in patients who do not respond to glucocorticoids and the disease frequently recurs after renal transplantation. FSGS may also be secondary to other diseases such as human immunodeficiency virus (HIV) renal disease (particularly in African Americans), morbid obesity or chronic hypertension. In addition, it may reflect scarring from previous focal glomerular injury resulting from HUS, cholesterol embolism or vasculitis. Patients with secondary FSGS typically present with more modest proteinuria than those with primary disease and

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Diseases typically presenting with mild nephritic syndrome

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Focal segmental glomerulosclerosis

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with high-dose glucocorticoid therapy (1 mg/kg prednisolone for 6 weeks), though the response to therapy is often less satisfactory in older patients. Some patients who respond incompletely (glucocorticoid-resistant) or relapse frequently need maintenance glucocorticoids (glucocorticoid dependence), cytotoxic therapy or other agents. Glucocorticoid resistance in children warrants a biopsy to exclude an alternative diagnosis, but if minimal change is confirmed, a genetic cause should be considered (p. 403). Minimal change disease typically does not progress to CKD but can present with problems related to the nephrotic syndrome (see Box 15.11) and complications of treatment.

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(GBM = glomerular basement membrane)

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• Subendothelial immune deposits: found between the endothelial cell and the GBM – often found in nephritic presentations • Intramembranous immune deposits: found within the GBM – found in the dense deposit variant of mesangiocapillary glomerulonephritis • Subepithelial immune deposits: found between the epithelial cell and the GBM – often found in nephrotic presentations, including membranous presentation of lupus

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Electron microscopy

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Membranous nephropathy is the most common cause of nephrotic syndrome in Caucasian adults. It is caused by antibodies (usually autoantibodies) directed at antigen(s) expressed on the surface of podocytes, including the M-type phospholipase A2 receptor 1. While most cases are idiopathic, a proportion are associated with other causes, such as heavy metal poisoning, drugs, infections, lupus and tumours (see Box 15.15 and Fig. 15.12D and F). Approximately one-third of patients with idiopathic membranous nephropathy undergo spontaneous remission, one-third remain in a nephrotic state, and one-third develop progressive CKD. High doses of glucocorticoids and cyclophosphamide may improve both the nephrotic syndrome and the long-term prognosis. However, because of the toxicity of these regimens, many nephrologists reserve such treatment for those with severe nephrotic syndrome or deteriorating renal function. Treatment of secondary membranous nephropathy is directed at the underlying cause.

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• • • • •

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Light microscopy

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rarely exhibit full-blown nephrotic syndrome. Management of secondary FSGS is focused on treating the underlying cause and reducing proteinuria by inhibiting the renin–angiotensin system (p. 417).

15.16  Terminology used in glomerulonephritis

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400 • Nephrology and urology

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Tubulo-interstitial diseases

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These diseases primarily affect the renal tubules and interstitial components of the renal parenchyma. They are characterised

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RPGN may occur either during or following an infection. In both cases, circulating immune complexes are present and activation of the complement system promotes consumption of complement factors, resulting in low serum C3 and C4 concentration, as observed in many causes of glomerulonephritis (Box 15.17). Post-infectious glomerulonephritis is observed most commonly in children and young adults, and typically presents 10 days after a streptococcal throat infection or longer after a skin infection. The clinical presentation ranges from mild abnormalities on urinalysis to RPGN with severe AKI. The anti-streptolysin (ASO) test is positive in up to 95% of patients with streptococcal throat infections. Treatment is supportive, with control of blood pressure and fluid overload with salt restriction, diuretics and dialysis if required. Antibiotic therapy is rarely needed, as the renal disease occurs after the infection has subsided. The medium-term prognosis for children and most adults is good, with recovery of renal function typical even in those requiring dialysis therapy. Some patients may develop CKD 20–30 years after the original presentation, however. An immune complex-mediated disease may also be observed during an infection, typically a staphylococcal infection such as endocarditis, skin infection or pneumonia, but also with subacute endocarditis due to Streptococcus viridans. This occurs more commonly in older adults and the presentation tends not to be as fulminant as with post-streptococcal disease. In addition to supportive measures, antibiotic therapy is required, as infection is usually concurrent with renal disease.

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Infection-related glomerulonephritis

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Rapidly progressive glomerulonephritis (RPGN) is characterised by rapid loss of renal function over days to weeks, usually in association with hypertension and oedema. Non-visible haematuria is almost always present with variable amounts of proteinuria, while characteristic red cell casts and dysmorphic red cells may be observed on urine microscopy (see Fig. 15.3). Renal biopsy typically shows crescentic lesions (see Fig. 15.12E), often associated with necrotising lesions within the glomerulus (Fig. 15.12C), particularly in small-vessel vasculitides. This pattern of presentation is typical of post-infectious glomerulonephritis, anti-GBM disease and small-vessel vasculitides (p. 1040). It can also be observed in SLE (p. 1034) and occasionally in IgA and other nephropathies (see Fig. 15.9).

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Anti-GBM disease is a rare autoimmune disease in which antibodies develop against the α3 chain of type 4 collagen GBM. Expression of the α3 chain is largely restricted to the basement membranes of glomeruli and lungs, and hence the disease may present with rapidly progressive glomerulonephritis, lung haemorrhage, or disease of both organs, when it is known as Goodpasture’s disease. Goodpasture’s disease is more common in younger patients, while elderly patients often present with renal-limited disease. Patients with anti-GBM disease should be treated with plasma exchange combined with glucocorticoids and immunosuppressants, but early diagnosis is essential, as renal function is rarely recoverable in those requiring dialysis at presentation. The combination of glomerulonephritis and pulmonary haemorrhage (Goodpasture’s syndrome) may also be observed with small-vessel vasculitis (particularly granulomatosis with polyangiitis, previously known as Wegener’s granulomatosis) and lupus.

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Anti-glomerular basement membrane disease

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Mesangiocapillary glomerulonephritis (MCGN), also known as membranoproliferative glomerulonephritis, is a pattern of injury seen on renal biopsy that is characterised by an increase in mesangial cellularity with thickening of glomerular capillary walls. The typical presentation is with proteinuria and haematuria. Several underlying causes have been identified, as summarised in Box 15.15. It can be classified into two main subtypes. The first is characterised by deposition of immunoglobulins within the glomeruli. This subtype is associated with chronic infections, autoimmune diseases and monoclonal gammopathy. The second is characterised by deposition of complement in the glomeruli and is associated with inherited or acquired abnormalities in the complement pathway. This category comprises ‘dense deposit disease’, which is typified by electron-dense deposits within the GBM, and C3 glomerulonephritis that shows deposits similar to immunoglobulin-type MCGN. Treatment of MCGN associated with immunoglobulin deposits consists of the identification and treatment of the underlying disease, if possible, and the use of immunosuppressive drugs such as mycophenolate mofetil or cyclophosphamide. There are few specific treatments for MCGN associated with complement dysregulation, although eculizumab, the anti-C5 inhibitor that prevents formation of the membrane attack complex, has shown promise.

Diseases typically presenting with rapidly progressive glomerulonephritis

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Post-infectious glomerulonephritis Subacute bacterial infection, especially endocarditis Systemic lupus erythematosus Cryoglobulinaemia Mesangiocapillary glomerulonephritis, usually complement type

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Mesangiocapillary glomerulonephritis

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Renal biopsy shows mesangial IgA deposition and appearances that are indistinguishable from acute IgA nephropathy (Fig. 15.12G). Treatment is supportive in nature; in most patients, the prognosis is good, with spontaneous resolution, though relapses are common. Some patients, particularly adults and those with severe or persistent proteinuria, progress to develop ESRD.

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15.17  Causes of glomerulonephritis associated with low serum complement

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This condition most commonly occurs in children but can also be observed in adults. It is a systemic vasculitis that often arises in response to an infectious trigger. It presents with a tetrad of features: • a characteristic petechial rash typically affecting buttocks and lower legs • abdominal pain due to vasculitis involving the gastrointestinal tract • arthralgia • renal disease characterised by visible or non-visible haematuria, with or without proteinuria.

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Henoch–Schönlein purpura

Tubulo-interstitial diseases • 401

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tubular histology. The tubules are back to back. Brush borders can be seen on the luminal borders of cells in the proximal tubule. B Acute tubular necrosis. There are scattered breaks (B) in tubular basement membranes, swelling and vacuolation of tubular cells, and, in places, apoptosis and necrosis of tubular cells with shedding of cells into the lumen. During the regenerative phase, there is increased tubular mitotic activity. The interstitium (I) is oedematous and infiltrated by inflammatory cells. The glomeruli (not shown) are relatively normal, although there may be endothelial cell swelling and fibrin deposition. C Acute bacterial pyelonephritis. A widespread inflammatory infiltrate that includes many neutrophils is seen. Granulocyte casts (G) are forming within some dilated tubules (T). Other tubules are scarcely visible because of the extent of the inflammation and damage. D Acute (allergic) interstitial nephritis. In this patient who received a non-steroidal anti-inflammatory drug (NSAID), an extensive mononuclear cell infiltrate (no neutrophils) involving tubules (T) is seen. This inflammation does not involve the glomeruli (not shown). Sometimes eosinophils are prominent. Transplant rejection looks similar to this.

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Fig. 15.13  Tubular histopathology. A Normal

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B Acute tubular necrosis

C Acute pyelonephritis

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A Normal tubular histology

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• Mushrooms (Cortinarius)

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• Myeloma light chains

Chronic interstitial nephritis

Chronic interstitial nephritis (CIN) is characterised by renal dysfunction with fibrosis and infiltration of the renal parenchyma by lymphocytes, plasma cells and macrophages, in association with tubular damage.

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Toxic

• Transplant rejection • Tuberculosis • Hantavirus

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Some patients with drug-induced AIN recover following withdrawal of the drug alone, but high-dose glucocorticoids (prednisolone 1 mg/kg/day) may accelerate recovery and prevent long-term scarring. Other specific causes (see Box 15.18) should be treated, if possible.

• Proton pump inhibitors • Mesalazine (delayed)

Immune

• Acute bacterial pyelonephritis • Leptospirosis

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Management

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Infections

Renal biopsy is usually required to confirm the diagnosis (Fig. 15.13D). This typically shows evidence of intense inflammation, with infiltration of the tubules and interstitium by polymorphonuclear leucocytes and lymphocytes. Eosinophils may also be observed, especially in drug-induced AIN. Often granulomas may be evident, especially in drug-induced AIN or sarcoidosis (p. 608). The degree of chronic inflammation in a biopsy is a useful predictor of long-term renal function. Eosinophiluria may be present but is not a good discriminator for AIN.

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15.18  Causes of acute interstitial nephritis

• Autoimmune nephritis ± uveitis

Investigations

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The clinical presentation is typically with renal impairment but, in some patients with drug-induced AIN, there may be

Many drugs but particularly: • Penicillins • Non-steroidal antiinflammatory drugs (NSAIDs)

signs of a generalised drug hypersensitivity reaction with fever, rash and eosinophilia. Proteinuria is generally modest (PCR  70 mg/ mmol), unless known to be due to diabetes and patient is already on appropriate medications • ACR > 30 mg/mmol with non-visible haematuria • Hypertension that remains poorly controlled despite at least four antihypertensive medications • Suspicion of renal involvement in multisystem disease

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patients with proteinuria (PCR > 50 mg/mmol or ACR > 30 mg/ mmol) through a reduction in glomerular perfusion pressure. In addition, ACE inhibitors have been shown to reduce the risk of cardiovascular events and all-cause mortality in CKD. Accordingly, ACE inhibitors and/or ARBs should be prescribed to all patients with diabetic nephropathy and patients with CKD and proteinuria, irrespective of whether or not hypertension is present. While ACE inhibitors and ARBs are excellent drugs for patients with diabetes or CKD and proteinuria, they need to be prescribed with care in certain circumstances. Initiation of treatment with ACE inhibitors and ARBs may be accompanied by an immediate reduction in GFR; patients should therefore have their renal function checked within 7–10 days of initiating or increasing the dose of an ACE inhibitor or ARB. Treatment can be continued so long as the reduction in GFR is not greater than 25% and is not progressive. Angiotensin II is critical for autoregulation of GFR in the context of low renal perfusion (see Fig. 15.1D, p. 385), and so ACE inhibitors or ARBs may exacerbate pre-renal failure (see Fig. 15.19). Patients on ACE inhibitors/ARBs should therefore be warned to stop taking the medication if they become unwell, such as with fever, vomiting or diarrhoea, restarting once they are better. This also applies to other common medications used in patients with CKD, such as diuretics, metformin and NSAIDs, and this advice may be reinforced by providing written information such as ‘sick-day rule’ cards (Box 15.31). ACE inhibitors and ARBs increase serum potassium and should not be commenced in patients with baseline potassium > 5.5 mmol/L. In patients with serum potassium > 6.0 mmol/L, the dose of ACE inhibitors or ARBs should be reduced or discontinued entirely, but only after all other measures to reduce potassium have been considered (see below). Combination therapy with ACE inhibitors and ARBs or direct renin inhibitors has not been shown to reduce progression of kidney disease but is associated with higher rates of hyperkalaemia and AKI, and is therefore to be avoided.

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15.30  Criteria for referral of chronic kidney disease patients to a nephrologist

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of monitoring (blue arrow), this patient entered an aggressive treatment programme aimed at optimising blood pressure (BP) and glycaemic control. The reduction in BP was accompanied by a fall in proteinuria (protein:creatinine ratio, PCR; shown in mg/mmol). At the previous rate of decline in renal function (dashed line), he was likely to reach the level of renal function at which dialysis therapy is typically required (eGFR = 10 mL/min/1.73 m2) within 18 months; however, the relative stabilisation in his renal function (dotted line) means that this has been deferred, potentially for several years.

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Fig. 15.23  Plot of estimated glomerular filtration rate (eGFR) against time in a patient with type 1 diabetes mellitus. After approximately 6 years

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BP 207/101 PCR 367

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BP 177/104 PCR 397

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eGFR mL/min/1.73 m2

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BP 162/88 PCR 284

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Chronic kidney disease • 417

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Maintenance of fluid and electrolyte balance  The kidneys excrete waste and regulate many electrolytes, and so patients with CKD may accumulate waste products and develop electrolyte abnormalities. Urea is a key product of protein degradation and accumulates with progressive CKD. All patients with stages 4 and 5 CKD should be given dietetic advice aimed at preventing excessive consumption of protein. Severe protein restriction is not recommended, however; there is no evidence that this reduces the rate of decline in renal function but may lead to malnutrition. Potassium often accumulates in patients with advanced CKD, who should be provided with dietary advice to reduce daily potassium intake to below 70 mmol (Box 15.32). Potassiumbinding compounds limit absorption of potassium from the gut and may be a useful adjunctive therapy. Calcium resonium is not recommended other than as a very short-term measure, as it can be associated with bowel necrosis; however, newer agents, such as zirconium cyclosilicate and patiromer, appear promising for chronic use. Other measures that may help regulate potassium include diuretic therapy and control of acidosis with sodium bicarbonate (see below). Consideration should be given to stopping or reducing drugs that elevate potassium, such as potassium-sparing diuretics and ACE inhibitors/ARBs; however, this has to be balanced against the potential benefit that such drugs may have on retarding progression of renal and cardiovascular disease, and hence withdrawal should be reserved for when other measures have failed.

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Renal bone disease  Disturbances of calcium and phosphate metabolism are almost universal in advanced CKD (Fig. 15.24). The sequence of events that leads to renal bone disease is complex, but two primary factors are impaired excretion of phosphate and failure of the renal tubular cells to convert 25-hydroxyvitamin D to its active metabolite, 1,25-dihydroxyvitamin D. A rise in serum phosphate levels promotes production of the hormone fibroblast growth factor 23 (FGF23) from osteocytes (Fig. 24.3, p. 986) and stimulates parathyroid hormone (PTH) release and hyperplasia of the parathyroid glands. The FGF23 and PTH promote tubular phosphate excretion, thereby partly compensating for the reduced glomerular filtration of phosphate. The reduced 1,25-dihydroxyvitamin D levels impair intestinal absorption of calcium. In addition, raised levels of serum phosphate complex with calcium in the extracellular space, leading to calcium phosphate deposition. Both the reduced absorption and increased deposition of calcium cause hypocalcaemia, which also stimulates PTH production by the parathyroid glands. Hence in many patients with CKD, compensatory responses initially maintain phosphate and calcium levels at the upper and lower ends of their respective normal ranges, at the expense of an elevated PTH level (secondary hyperparathyroidism). This is associated with a gradual transfer of calcium and phosphate from the bone to other tissues, leading to bone resorption (osteitis fibrosa cystica), and in severe cases this may result in bony pain and increased risk of fractures. Conversely there is increased deposition of calcium phosphate in many tissues, most notably blood vessels and heart valves, which may contribute to the increased risk of cardiovascular disease in patients with CKD (p. 420). In some cases, tertiary hyperparathyroidism supervenes, due to autonomous production of PTH by the enlarged parathyroid glands; this presents with hypercalcaemia. Additional problems in bone metabolism include low bone turnover (adynamic bone disease) in patients who have been over-treated with vitamin D metabolites, osteomalacia with over-treatment of

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The kidneys have many functions in addition to excretion of waste (p. 384). Treatments that substitute for all of the normal roles of the kidneys must therefore be instigated to maintain normal body homeostasis and prevent complications.

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Treatment of complications

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patients with CKD may lead to an anion-gap metabolic acidosis. In addition, in patients with tubulo-interstitial disease or diabetic nephropathy, there may be specific defects in acid–base regulation within the kidney, causing a non-anion-gap renal tubular acidosis (p. 365). Although acidosis is usually asymptomatic, it may be associated with increased tissue catabolism and decreased protein synthesis, and may exacerbate bone disease and the rate of decline in renal function. Hence, plasma bicarbonate concentrations should be maintained above 22 mmol/L by prescribing sodium bicarbonate supplements (starting dose of 1 g 8-hourly, increasing as required). There is some evidence that correcting acidosis may reduce the rate of decline in renal function.

• Fruit: bananas, avocados, figs, rhubarb • Vegetables: tomatoes, spinach, parsnips, courgettes, sprouts, potatoes (including baked, fries, wedges; boiling vegetables reduces potassium content) • Sweets/snacks: crisps, chocolate, toffee, nuts (including peanut butter) • Drinks: beer, cider, wine (spirits contain less potassium), hot chocolate, fruit juice, milk, yoghurt • Salt substitutes, such as Lo-Salt: sodium chloride is substituted with potassium chloride

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Acid–base balance  Reduced ability to excrete organic acids in

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15.32  Foods high in potassium

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Restart when you are well again (after 24–48 hours of eating and drinking normally).

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When you are unwell with vomiting, diarrhoea or fever, stop taking the following medications: • ACE inhibitors: medicines ending in ‘-pril’, e.g. lisinopril, ramipril • Angiotensin receptor blockers: medicines ending in ‘-sartan’, e.g. irbesartan, losartan, candesartan • Non-steroidal anti-inflammatory painkillers: e.g. ibuprofen (Brufen), diclofenac (Voltarol) • Diuretics: e.g. furosemide, bendroflumethiazide, indapamide, spironolactone • Metformin: a medicine for diabetes.

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The inability of the failing kidney to excrete sodium and water loads commonly leads to their accumulation, which may manifest as oedema and may drive hypertension. Patients with evidence of volume expansion should be instructed to consume a low-sodium diet ( 120/min)

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Consider Ectopic beats Atrial fibrillation

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Is the heart beat regular?

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456 • Cardiology

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The first indication of heart disease may be the discovery of an abnormal sound on auscultation (Box 16.8). This may be incidental – for example, during a routine childhood examination – or may be prompted by symptoms of heart disease.

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Clinical assessment

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The aims of clinical assessment are, firstly, to determine if the abnormal sound is cardiac; secondly, to determine if it is pathological; and thirdly, to try to determine its cause.

Is the sound cardiac?

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Additional heart sounds and murmurs demonstrate a consistent relationship to a specific part of the cardiac cycle, whereas extracardiac sounds, such as a pleural rub or venous hum,

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Abnormal heart sounds

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Advanced life support (ALS) (Fig. 16.20) aims to restore normal cardiac rhythm by defibrillation when the cause of cardiac arrest is a tachyarrhythmia, or to restore cardiac output by correcting other reversible causes of cardiac arrest. The initial priority is to assess the patient’s cardiac rhythm by attaching a defibrillator or monitor. Once that this has been done, treatment should be instituted based on the clinical findings. Ventricular fibrillation or pulseless ventricular tachycardia should be treated with immediate defibrillation. Defibrillation is more likely to be effective if a biphasic shock defibrillator is used, where the polarity of the shock is reversed midway through its delivery. Defibrillation is usually administered using a 150-joule biphasic shock, and CPR resumed immediately for 2 minutes without attempting to confirm restoration of a pulse because restoration of mechanical cardiac output rarely occurs immediately after successful defibrillation. If, after 2 minutes, a pulse is not restored, a further biphasic shock of 150–200 joules should be given. Thereafter, additional biphasic shocks of 150–200 joules are given every 2 minutes after each cycle of CPR. During resuscitation, adrenaline (epinephrine, 1 mg IV) should be given every 3–5 minutes and consideration given to the use

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Advanced life support

Patients who survive a cardiac arrest caused by acute MI need no specific treatment beyond that given to those recovering from an uncomplicated infarct, since their prognosis is similar (p. 498). Those with reversible causes, such as exercise-induced ischaemia or aortic stenosis, should have the underlying cause treated if possible. Survivors of ventricular tachycardia or ventricular fibrillation arrest in whom no reversible cause can be identified may be at risk of another episode, and should be considered for an implantable cardiac defibrillator (p. 483) and anti-arrhythmic drug therapy. In these patients, the risk is reduced by treatment of heart failure with β-adrenoceptor antagonists (β-blockers) and angiotensin-converting enzyme (ACE) inhibitors, and by coronary revascularisation.

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encompasses manœuvres that aim to maintain a low level of circulation until more definitive treatment with advanced life support can be given. Chest compression-only (‘hands-only’) cardiopulmonary resuscitation (CPR) is easier for members of the public to learn and administer, and is now advocated in public education campaigns.

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Survivors of cardiac arrest

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information, see www.resus.org.uk. (CPR = cardiopulmonary resuscitation) From Resuscitation Council (UK) guidelines: https://www.resus.org.uk/ resuscitation-guidelines/in-hospital-resuscitation/.

eb

This term refers to the sequence of events that is necessary to maximise the chances of a cardiac arrest victim surviving (Fig. 16.21). Survival is most likely if all links in the chain are strong: that is, if the arrest is witnessed, help is called immediately, basic life support is administered by a trained individual, the emergency medical services respond promptly, and defibrillation is achieved within a few minutes. Good training in both basic and advanced life support is essential and should be maintained by regular refresher courses. In recent years, public access defibrillation has been introduced in places of high population density, particularly where traffic congestion may impede the response of emergency services, such as railway stations, airports and sports stadia. Designated individuals can respond to a cardiac arrest using BLS and an automated external defibrillator.

oo

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Handover to resuscitation team

Fig. 16.19  Algorithm for adult basic life support. For further

m

fre e.

Call resuscitation team if appropriate

ks

fre

ks fre

The Chain of Survival

Apply pads/monitor Attempt defibrillation if appropriate

m

co m

e. co m

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CPR 30:2 with oxygen and airway adjuncts

Advanced life support when resuscitation team arrives

m

m

Assess ABCDE Recognise and treat Oxygen, monitoring, IV access

Call resuscitation team

oo

oo

YES

m

m

eb

eb o

eb

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Shout for HELP and assess patient

Signs of life?

of intravenous amiodarone, especially if ventricular fibrillation or ventricular tachycardia re-initiates after successful defibrillation. Ventricular fibrillation of low amplitude, or ‘fine VF’, may mimic asystole. If asystole cannot be confidently diagnosed, the patient should be treated for VF and defibrillated. If an electrical rhythm is observed that would be expected to produce a cardiac output, ‘pulseless electrical activity’ is present. Pulseless electrical activity should be treated by continuing CPR and adrenaline (epinephrine) administration while seeking such causes. Asystole should be treated similarly, with the additional support of atropine and sometimes external or transvenous pacing in an attempt to generate an electrical rhythm. There are many potentially reversible causes of cardiac arrest; the main ones can be easily remembered as a list of four Hs and four Ts (Fig. 16.20).

ks

ok s

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Collapsed / sick patient

• 457

fre

fre e. c

In-hospital resuscitation

NO

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Presenting problems in cardiovascular disease

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Advanced life support

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eb

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Call resuscitation team

CPR 30:2 Attach defibrillator/monitor Minimise interruptions

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Unresponsive and not breathing normally?

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458 • Cardiology

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ks

ks

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Consider • Ultrasound imaging • Mechanical chest compressions to facilitate transfer/treatment • Coronary angiography and percutaneous coronary intervention • Extracorporeal CPR

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Thrombosis – coronary or pulmonary Tension pneumothorax Tamponade – cardiac Toxins

eb

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Treat reversible causes Hypoxia Hypovolaemia Hypo-/hyperkalaemia/metabolic Hypothermia/hyperthermia

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Immediately resume CPR for 2 mins Minimise interruptions

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During CPR • Ensure high-quality chest compressions • Minimise interruptions to compressions • Give oxygen • Use waveform capnography • Perform continuous compressions when advanced airway in place • Gain vascular access (intravenous or interosseous) • Give adrenaline (epinephrine) every 3–5 min • Give amiodarone after 3 shocks

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eb

Immediate post-cardiac arrest treatment • Use ABCDE approach • Aim for SaO2 of 94 – 98% • Aim for normal PaCO2 • 12-lead ECG • Treat precipitating cause • Targeted temperature management

Immediately resume CPR for 2 mins Minimise interruptions

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e. co m Return of spontaneous circulation

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1 shock Minimise interruptions

Non-shockable (PEA/Asystole)

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Shockable (VF/Pulseless VT)

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Assess rhythm

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Early ALS

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to r estart heart

to stabilise

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to buy time

Fig. 16.21  The Chain of Survival in cardiac arrest. (ALS = advanced life support; CPR = cardiopulmonary resuscitation)

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fre N

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to get help

EFIBRILLAT IO

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ly D

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Early CPR

ly ACCESS

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PEA = pulseless electrical activity; VF = ventricular fibrillation; VT = ventricular tachycardia) From Resuscitation Council (UK) guidelines: https://www.resus.org.uk/resuscitation-guidelines/adult-advanced-life-support/.

m

m

co m

Fig. 16.20  Algorithm for adult advanced life support. For further information, see www.resus.org.uk. (CPR = cardiopulmonary resuscitation:

First heart sound (S1)

Onset of systole

Usually single or narrowly split

Closure of mitral and tricuspid valves

Loud: hyperdynamic circulation (anaemia, pregnancy, thyrotoxicosis); mitral stenosis Soft: heart failure; mitral regurgitation

Second heart sound (S2)

End of systole

Third heart sound (S3)

ks

From ventricular wall due to abrupt cessation of rapid filling

Physiological: young people, pregnancy Pathological: heart failure, mitral regurgitation

End of diastole, just before S1

Low pitch

Ventricular origin (stiff ventricle and augmented atrial contraction) related to atrial filling

Absent in atrial fibrillation A feature of severe left ventricular hypertrophy

Systolic clicks

Early or mid-systole

Brief, high-intensity sound

Valvular aortic stenosis Valvular pulmonary stenosis Floppy mitral valve Prosthetic heart sounds from opening and closing of normally functioning mechanical valves

Click may be lost when stenotic valve becomes thickened or calcified Prosthetic clicks lost when valve obstructed by thrombus or vegetations

Opening snap (OS)

Early in diastole

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Note: Diastolic murmurs are very rarely above grade 4

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Where is it heard best? (location)

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• Listen over the apex and base of the heart, including the aortic and pulmonary areas

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ok s

• Listen at the neck, axilla or back

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• Pitch is determined by flow (high pitch indicates high-velocity flow) • Is the intensity constant or variable?

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What does it sound like? (pitch and quality)

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the murmur, such as the ‘blowing’ murmur of mitral regurgitation or the ‘rasping’ murmur of aortic stenosis. The position of a murmur in relation to the cardiac cycle is crucial and should be assessed by timing it with the heart sounds, carotid pulse and apex beat (Figs 16.22 and 16.23).

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Systolic murmurs

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Ejection systolic murmurs are associated with ventricular outflow tract obstruction and occur in mid-systole with a

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Grade 1: very soft (audible only in ideal conditions) Grade 2: soft Grade 3: moderate Grade 4: loud with associated thrill Grade 5: very loud Grade 6: heard without stethoscope

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Timing, intensity, location, radiation and quality are all useful clues to the origin and nature of an additional sound or murmur (Box 16.10). Radiation of a murmur is determined by the direction of turbulent blood flow and is detectable only when there is a high-velocity jet, such as in mitral regurgitation (radiation from apex to axilla) or aortic stenosis (radiation from base to neck). Similarly, the pitch and quality of the sound can help to distinguish

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• Time the murmur using heart sounds, carotid pulse and the apex beat. Is it systolic or diastolic? • Does the murmur extend throughout systole or diastole or is it confined to a shorter part of the cardiac cycle?

Where does it radiate?

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What is the origin of the sound?

sf

16

16.10  How to assess a heart murmur

When does it occur?

• • • • • •

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Moves closer to S2 as mitral stenosis becomes more severe. May be absent in calcific mitral stenosis

How loud is it? (intensity)

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co m

Pathological sounds and murmurs are the product of turbulent blood flow or rapid ventricular filling due to abnormal loading conditions. Some added sounds are physiological but may also occur in pathological conditions; for example, a third sound is common in young people and in pregnancy but is also a feature of heart failure (Box 16.8). Similarly, a systolic murmur due to turbulence across the right ventricular outflow tract may occur in hyperdynamic states such as anaemia or pregnancy, but may also be due to pulmonary stenosis or an intracardiac shunt leading to volume overload of the RV, such as an atrial septal defect. Benign murmurs do not occur in diastole (Box 16.9), and systolic murmurs that radiate or are associated with a thrill are almost always pathological.

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eb

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• No radiation • No other cardiac abnormalities

do not. Pericardial friction produces a characteristic scratching noise termed a pericardial rub, which may have two components corresponding to atrial and ventricular systole, and may vary with posture and respiration.

Is the sound pathological?

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Opening of stenosed leaflets of mitral valve Prosthetic heart sounds

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High pitch, brief duration

Fixed wide splitting with atrial septal defect Wide but variable splitting with delayed right heart emptying (right bundle branch block) Reversed splitting due to delayed left heart emptying (left bundle branch block)

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Low pitch, often heard as ‘gallop’

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Early in diastole, just after S2

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Closure of aortic and pulmonary valve A2 first P2 second

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Split on inspiration Single on expiration (p. 447)

• Soft • Mid-systolic • Heard at left sternal edge

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Variable features

ks

Mechanisms

ok s

Characteristics

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Timing

16.9  Features of a benign or innocent heart murmur

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• 459

Sound

Fourth heart sound (S4)

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16.8  Normal and abnormal heart sounds

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Presenting problems in cardiovascular disease

Single second heart sound Ejection click (in young patients) Slow rising pulse Left ventricular hypertrophy (pressure overload)

Lower left sternal edge, radiating to whole precordium

m Left sternal edge, no radiation

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S2

eb

eb

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S1

Pansystolic murmur (mitral regurgitation, tricuspid regurgitation, ventricular septal defect)

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Aortic pressure

No other signs of heart disease

Ejection systolic murmur (aortic stenosis, pulmonary stenosis, aortic or pulmonary flow murmurs)

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ECG

Thrill Biventricular hypertrophy

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Soft

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Mid-systolic

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Benign

eb

Harsh

Soft first heart sound Third heart sound Left ventricular hypertrophy (volume overload)

m

Apex, radiating to axilla

m

Blowing

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Pansystolic

Base and left sternal edge, radiating to suprasternal notch and carotids

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Ventricular septal defect

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Pansystolic

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Mitral regurgitation

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Loud, rasping

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Mid-systolic

Associated features

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Aortic stenosis

Location and radiation

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Quality

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Timing and duration

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Condition

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16.11  Features of some common systolic murmurs

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460 • Cardiology

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ok s

These are due to accelerated or turbulent flow across the mitral or tricuspid valves. They are low-pitched noises that are often difficult to hear and should be evaluated with the bell of the stethoscope. A mid-diastolic murmur may be due to mitral stenosis (located at the apex and axilla), tricuspid stenosis (located at the left sternal edge), increased flow across the mitral valve (for example, the to-and-fro murmur of severe mitral regurgitation) or increased flow across the tricuspid valve (for example, a left-to-right shunt through a large atrial septal defect). Early diastolic murmurs have a soft, blowing quality with a decrescendo pattern and should be evaluated with the diaphragm of the stethoscope. They are due to regurgitation across the aortic or pulmonary valves and are best heard at the left sternal edge, with the patient sitting forwards in held expiration.

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ok s

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sf ok

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sf re

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sf

Diastolic murmurs

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crescendo–decrescendo pattern, reflecting the changing velocity of blood flow (Box 16.11). Pansystolic murmurs maintain a constant intensity and extend from the first heart sound throughout systole to the second heart sound, sometimes obscuring it. They occur when blood leaks from a ventricle into a low-pressure chamber at an even or constant velocity. Mitral regurgitation, tricuspid regurgitation and ventricular septal defect are the only causes of a pansystolic murmur. Late systolic murmurs are unusual but may

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ventricular pressure wave and the position of heart sounds.

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eb

Fig. 16.22  The relationship of the cardiac cycle to the ECG, the left

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occur in mitral valve prolapse, if the mitral regurgitation is confined to late systole, and hypertrophic obstructive cardiomyopathy, if dynamic obstruction occurs late in systole.

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3rd sound

1st 2nd sound sound

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Fig. 16.23  The timing and pattern of cardiac murmurs.

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Opening snap in mitral stenosis or mitral prosthesis

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DIASTOLE

Sounds

4th sound

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SYSTOLE Mid-systolic click

Opening snap

Mid-diastolic murmur (mitral stenosis, tricuspid stenosis, mitral or tricuspid flow murmurs)

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m DIASTOLE

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Early diastolic murmur (aortic or pulmonary regurgitation)

sf

fre

Left ventricular pressure

Left atrial pressure

Clicks Ejection click, or opening sound of aortic prosthesis

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Late systolic murmur (mitral valve prolapse)

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Click

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(D) heart failure. Ventricular performance is related to the degree of myocardial stretching. An increase in preload (end-diastolic volume, end-diastolic pressure, filling pressure or atrial pressure) will therefore enhance function; however, overstretching causes marked deterioration. In heart failure, the curve moves to the right and becomes flatter. An increase in myocardial contractility or a reduction in afterload will shift the curve upwards and to the left (green arrow).

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Ventricular dysfunction is the most common cause of heart failure. This can occur because of impaired systolic contraction due to myocardial disease, or diastolic dysfunction where there is abnormal ventricular relaxation due to a stiff, non-compliant ventricle. This is most commonly found in patients with left ventricular hypertrophy. Systolic dysfunction and diastolic dysfunction often coexist, particularly in patients with coronary artery disease. Ventricular dysfunction reduces cardiac output, which, in turn, activates the sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS). Under normal circumstances, activation of the SNS and RAAS supports cardiac function but, in the setting of impaired ventricular function, the consequences are negative and lead to an increase in both afterload and preload (Fig. 16.25). A vicious circle may then be

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fre

Ventricular dysfunction

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co

e.

ok s

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sf

ok

sf re

e.

Heart failure predominantly affects the elderly; the prevalence rises from 1% in those aged 50–59 years to over 10% in those

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Fig. 16.24  Starling’s Law. Normal (A), mild (B), moderate (C) and severe

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Epidemiology

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Preload

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m

m

In biventricular failure, both sides of the heart are affected. This may occur because the disease process, such as dilated cardiomyopathy or ischaemic heart disease, affects both ventricles or because disease of the left heart leads to chronic elevation of the left atrial pressure, pulmonary hypertension and right heart failure.

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Biventricular heart failure

16

C

co

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This is characterised by a reduction in right ventricular output and an increase in right atrial and systemic venous pressure. The most common causes are chronic lung disease, pulmonary embolism and pulmonary valvular stenosis. The term ‘cor pulmonale’ is used to describe right heart failure that is secondary to chronic lung disease.

ok

B

m

eb

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co m

Right heart failure

eb

A

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This is characterised by a reduction in left ventricular output and an increase in left atrial and pulmonary venous pressure. If left heart failure occurs suddenly – for example, as the result of an acute MI – the rapid increase in left atrial pressure causes pulmonary oedema. If the rise in atrial pressure is more gradual, as occurs with mitral stenosis, there is reflex pulmonary vasoconstriction, which protects the patient from pulmonary oedema. However, the resulting increase in pulmonary vascular resistance causes pulmonary hypertension, which in turn impairs right ventricular function.

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fre

fre

Left heart failure

Afterload Contractility

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Heart failure describes the clinical syndrome that develops when the heart cannot maintain adequate output, or can do so only at the expense of elevated ventricular filling pressure. In mild to moderate forms of heart failure, symptoms occur only when the metabolic demand increases during exercise or some other form of stress. In severe heart failure, symptoms may be present at rest. In clinical practice, heart failure may be diagnosed when a patient with significant heart disease develops the signs or symptoms of a low cardiac output, pulmonary congestion or systemic venous congestion at rest or on exercise. Three types of heart failure are recognised.

Heart failure occurs when cardiac output fails to meet the demands of the circulation. Cardiac output is determined by preload (the volume and pressure of blood in the ventricles at the end of diastole), afterload (the volume and pressure of blood in the ventricles during systole) and myocardial contractility, forming the basis of Starling’s Law (Fig. 16.24). The causes of heart failure are discussed below.

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Heart failure

Pathogenesis

Cardiac output or ventricular performance

fre

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Management of patients with additional cardiac sounds depends on the underlying cause. More details are provided in the sections on specific valve defects and congenital anomalies later in this chapter (pp. 514 and 531).

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eb

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Management

aged 80–89 years. In the UK, most patients admitted to hospital with heart failure are more than 70 years old; they typically remain hospitalised for a week or more and may be left with chronic disability. Although the outlook depends, to some extent, on the underlying cause of the problem, untreated heart failure generally carries a poor prognosis; approximately 50% of patients with severe heart failure due to left ventricular dysfunction will die within 2 years because of either pump failure or malignant ventricular arrhythmias. The most common causes are coronary artery disease and myocardial infarction but almost all forms of heart disease can lead to heart failure, as summarised in Box 16.12. An accurate diagnosis is important because treatment of the underlying cause may reverse heart failure or prevent its progression.

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eb o

If clinical evaluation suggests that the additional sound is cardiac and likely to be pathological, then echocardiography is indicated to determine the underlying cause.

m

m

eb

oo

ok s

ks f

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These result from a combination of systolic and diastolic flow, such as occurs with a persistent ductus arteriosus, and must be distinguished from extracardiac noises such as bruits from arterial shunts, venous hums (high rates of venous flow in children) and pericardial friction rubs.

• 461

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fre e. c

Continuous murmurs

Investigations

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Presenting problems in cardiovascular disease

Ventricular inflow obstruction

Mitral stenosis, tricuspid stenosis

Small, vigorous ventricle; dilated, hypertrophied atrium. Atrial fibrillation is common and often causes marked deterioration because ventricular filling depends heavily on atrial contraction

m

co m

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Dilatation and hypertrophy allow the ventricle to generate a high stroke volume and help to maintain a normal cardiac output. However, secondary changes in the myocardium lead to impaired contractility and worsening heart failure

Arrhythmia

Atrial fibrillation

Tachycardia does not allow for adequate filling of the heart, resulting in reduced cardiac output and back pressure Prolonged tachycardia causes myocardial fatigue Bradycardia limits cardiac output, even if stroke volume is normal

om

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ks

ks oo

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sf ok

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in heart failure. There is a vicious circle in progressive heart failure.

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fre

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Sodium and water retention

Fig. 16.25  Neurohumoral activation and compensatory mechanisms

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Sympathetic nervous system Renin – angiotensin system Vasopressin system Endothelin system

eb

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m e.

Reduced cardiac output

Neurohumoral activation

m

established because any additional fall in cardiac output causes further activation of the SNS and RAAS, and an additional increase in peripheral vascular resistance. Activation of the RAAS causes vasoconstriction and sodium and water retention. This is primarily mediated by angiotensin II, a potent constrictor of arterioles, in both the kidney and the systemic circulation (Fig. 16.25). Activation of the SNS also occurs and can initially sustain cardiac output through increased myocardial contractility and heart rate. Prolonged sympathetic stimulation has negative effects, however, causing cardiac myocyte apoptosis, cardiac hypertrophy and focal myocardial necrosis. Sympathetic stimulation also contributes to vasoconstriction and predisposes to arrhythmias. Sodium and water retention is further enhanced by the release of aldosterone, endothelin-1 (a potent vasoconstrictor peptide with marked effects on the renal vasculature) and, in severe heart failure, vasopressin (antidiuretic hormone, ADH). Natriuretic peptides are released from the atria in response to atrial dilatation and compensate to an extent for the sodium-conserving effect of aldosterone, but this mechanism is overwhelmed in heart failure. Pulmonary and peripheral oedema occurs because of high left and right atrial pressures, and is compounded by sodium and water retention, caused by impairment of renal perfusion and by secondary hyperaldosteronism. If the underlying cause is a myocardial infarction, cardiac contractility is impaired and SNS and RAAS activation causes hypertrophy of noninfarcted segments, with thinning, dilatation and expansion of the infarcted segment (see Fig. 16.64, p. 496). This leads to further deterioration in ventricular function and worsening heart failure.

co

Increased intravascular volume

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Heart failure

Vasoconstriction

Marked fluid retention and peripheral oedema, ascites, pleural effusions and elevated jugular veins Bi-atrial enlargement (restrictive filling pattern and high atrial pressures). Atrial fibrillation may cause deterioration Good systolic function but poor diastolic filling Hypotension, elevated jugular veins, pulsus paradoxus, poor urine output

oo k

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co m

Myocardial fibrosis

Increased afterload

m

m

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fre

ks

Increased blood pressure and cardiac work Myocyte loss

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Left ventricular hypertrophy and fibrosis Cardiac tamponade

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Restrictive cardiomyopathy

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Constrictive pericarditis

Increased blood pressure and cardiac work

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fre

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Tachycardia Complete heart block

Diastolic dysfunction

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Left ventricular volume overload (mitral or aortic regurgitation) Ventricular septal defect Right ventricular volume overload (atrial septal defect) Increased metabolic demand (high output)

ks fre

Ventricular volume overload

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Initially, concentric ventricular hypertrophy allows the ventricle to maintain a normal output by generating a high systolic pressure. Later, secondary changes in the myocardium and increasing obstruction lead to failure with ventricular dilatation and rapid clinical deterioration

m

Hypertension, aortic stenosis (left heart failure) Pulmonary hypertension, pulmonary valve stenosis (right heart failure)

ks

Myocarditis/cardiomyopathy (global dysfunction)

Ventricular outflow obstruction (pressure overload)

ks

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eb o

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In coronary artery disease, ‘akinetic’ or ‘dyskinetic’ segments contract poorly and may impede the function of normal segments by distorting their contraction and relaxation patterns Progressive ventricular dilatation

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Myocardial infarction (segmental dysfunction)

eb

Reduced ventricular contractility

Features

eb

Examples

ks f

Cause

fre

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16.12  Mechanisms of heart failure

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462 • Cardiology

fre

ks

eb

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fre e.

eb

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ks

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Right heart failure

e.

Left heart failure

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(JVP = jugular venous pressure)

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• Cardiac failure: right or combined left and right heart failure, pericardial constriction, cardiomyopathy • Chronic venous insufficiency: varicose veins • Hypoalbuminaemia: nephrotic syndrome, liver disease, proteinlosing enteropathy; often widespread, can affect arms and face • Drugs: Sodium retention: fludrocortisone, non-steroidal antiinflammatory drugs Increasing capillary permeability: nifedipine, amlodipine • Idiopathic: women > men • Chronic lymphatic obstruction

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16.14  Differential diagnosis of peripheral oedema

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Peripheral pitting oedema +++

Fig. 16.26  Clinical features of left and right heart failure.

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Ascites

Pitting oedema +/++

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Hepatomegaly

eb

eb

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Myocardial ischaemia or infarction Intercurrent illness Arrhythmia Inappropriate reduction of therapy Administration of a drug with negative inotropic (β-blocker) or fluid-retaining properties (non-steroidal anti-inflammatory drugs, glucocorticoids) • Pulmonary embolism • Conditions associated with increased metabolic demand (pregnancy, thyrotoxicosis, anaemia) • Intravenous fluid overload

16

Raised JVP +++

oo k

Pleural effusions

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Pulmonary oedema Cardiomegaly

16.13  Factors that may precipitate or aggravate heart failure in pre-existing heart disease

• • • • •

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fre

fre

Raised JVP +/++

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Acute left heart failure presents with a sudden onset of dyspnoea at rest that rapidly progresses to acute respiratory distress, orthopnoea and prostration. Often there is a clear precipitating factor, such as an acute MI, which may be apparent from the history. The patient appears agitated, pale and clammy. The peripheries are cool to the touch and the pulse is rapid, but in some cases there may be an inappropriate bradycardia that may contribute to the acute episode of heart failure. The BP is usually high because of SNS activation, but may be normal or low if the patient is in cardiogenic shock. The jugular venous pressure (JVP) is usually elevated, particularly with associated fluid overload or right heart failure. In acute heart failure, there has been no time for ventricular dilatation and the apex is not displaced. A ‘gallop’ rhythm, with a third heart sound, is heard quite early in the development of acute left-sided heart failure. A new systolic murmur may signify acute mitral regurgitation or ventricular septal rupture. Chest examination may reveal crepitations at the lung bases if there is pulmonary oedema, or crepitations throughout the lungs if this

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Patients with chronic heart failure commonly follow a relapsing and remitting course, with periods of stability and episodes of decompensation, leading to worsening symptoms that may necessitate hospitalisation. The clinical picture depends on the nature of the underlying heart disease, the type of heart failure that it has evoked, and the changes in the SNS and RAAS that have developed (see Box 16.12 and Fig. 16.26). Low cardiac output causes fatigue, listlessness and a poor effort tolerance; the peripheries are cold and the BP is low. To maintain perfusion of vital organs, blood flow is diverted away from skeletal muscle and this may contribute to fatigue and weakness. Poor renal perfusion leads to oliguria and uraemia. Pulmonary oedema due to left heart failure presents with dyspnoea and inspiratory crepitations over the lung bases. In contrast, right heart failure produces a high JVP with hepatic congestion and dependent peripheral oedema. In ambulant patients the oedema affects the ankles, whereas in bed-bound patients it collects around the thighs and sacrum. Ascites or pleural effusion may occur (Fig. 16.26). Heart failure is not the only cause of oedema (Box 16.14).

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Heart failure may develop suddenly, as in MI, or gradually, as in valvular heart disease. When there is gradual impairment of cardiac function, several compensatory changes take place. The term compensated heart failure is sometimes used to describe the condition of those with impaired cardiac function, in whom adaptive changes have prevented the development of overt heart failure. However, a minor event, such as an intercurrent infection or development of atrial fibrillation, may precipitate acute heart failure in these circumstances (Box 16.13). Similarly, acute heart failure sometimes supervenes as the result of a decompensating episode, on a background of chronic heart failure; this is called acute-on-chronic heart failure.

Acute left heart failure

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Clinical assessment

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Chronic heart failure

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Heart failure can also be caused by valvular disease in which there is impaired filling of the ventricles due to mitral or tricuspid stenosis; where there is obstruction to ventricular outflow, as occurs in aortic and tricuspid stenosis and hypertrophic cardiomyopathy; or as the result of ventricular overload secondary to valvular regurgitation.

is severe. There may be an expiratory wheeze. Patients with acute-on-chronic heart failure may have additional features of chronic heart failure (see below). Potential precipitants, such as an upper respiratory tract infection or inappropriate cessation of diuretic medication, may be identified on clinical examination or history-taking.

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Sometimes cardiac failure can occur in patients without heart disease due to a large arteriovenous shunt, or where there is an excessively high cardiac output due to beri-beri (p. 714), severe anaemia or thyrotoxicosis.

• 463

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High-output failure

Valvular disease

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Presenting problems in cardiovascular disease

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B’ lines). More advanced changes due to alveolar oedema cause a hazy opacification spreading from the hilar regions, and pleural effusions. Echocardiography is very useful and should be considered in all patients with heart failure in order to: • determine the aetiology • detect hitherto unsuspected valvular heart disease, such as occult mitral stenosis, and other conditions that may be amenable to specific remedies • identify patients who will benefit from long-term drug therapy.

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Management of acute heart failure

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Serum urea, creatinine and electrolytes, haemoglobin and thyroid function may help to establish the nature and severity of the underlying heart disease and detect any complications. BNP is elevated in heart failure and is a prognostic marker, as well as being useful in differentiating heart failure from other causes of breathlessness or peripheral oedema.

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Acute heart failure with pulmonary oedema is a medical emergency that should be treated urgently. The patient should initially be kept rested, with continuous monitoring of cardiac rhythm, BP and

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patient with pulmonary oedema. B Enlargement of lung base showing septal or ‘Kerley B’ lines (arrow).

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Fig. 16.27  Radiological features of heart failure. A Chest X-ray of a

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A chest X-ray should be performed in all cases. This may show abnormal distension of the upper lobe pulmonary veins with the patient in the erect position (Fig. 16.27). Vascularity of the lung fields becomes more prominent and the right and left pulmonary arteries dilate. Subsequently, interstitial oedema causes thickened interlobular septa and dilated lymphatics. These are evident as horizontal lines in the costophrenic angles (septal or ‘Kerley

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Enlarged cardiac silhouette; usually with coexisting chronic heart failure

Septal or ‘Kerley B’ lines

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Investigations

Enlarged hilar vessels

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Several complications may occur in advanced heart failure, as described below. • Renal failure is caused by poor renal perfusion due to low cardiac output and may be exacerbated by diuretic therapy, ACE inhibitors and angiotensin receptor blockers (ARBs). • Hypokalaemia may be the result of treatment with potassium-losing diuretics or hyperaldosteronism caused by activation of the renin–angiotensin system and impaired aldosterone metabolism due to hepatic congestion. Most of the body’s potassium is intracellular and there may be substantial depletion of potassium stores, even when the plasma concentration is in the reference range. • Hyperkalaemia may be due to the effects of drugs that promote renal resorption of potassium, in particular the combination of ACE inhibitors, ARBs and mineralocorticoid receptor antagonists. These effects are amplified if there is renal dysfunction due to low cardiac output or atherosclerotic renal vascular disease. • Hyponatraemia is a feature of severe heart failure and is a poor prognostic sign. It may be caused by diuretic therapy, inappropriate water retention due to high vasopressin secretion, or failure of the cell membrane ion pump. • Impaired liver function is caused by hepatic venous congestion and poor arterial perfusion, which frequently cause mild jaundice and abnormal liver function tests; reduced synthesis of clotting factors can make anticoagulant control difficult. • Thromboembolism. Deep vein thrombosis and pulmonary embolism may occur due to the effects of a low cardiac output and enforced immobility. Systemic emboli occur in patients with atrial fibrillation or flutter, or with intracardiac thrombus complicating conditions such as mitral stenosis, MI or left ventricular aneurysm. • Atrial and ventricular arrhythmias are very common and may be related to electrolyte changes such as hypokalaemia and hypomagnesaemia, the underlying cardiac disease, and the pro-arrhythmic effects of sympathetic activation. Atrial fibrillation occurs in approximately 20% of patients with heart failure and causes further impairment of cardiac function. Ventricular ectopic beats and runs of non-sustained ventricular tachycardia are common findings in patients with heart failure and are associated with an adverse prognosis. • Sudden death occurs in up to 50% of patients with heart failure and is most probably due to ventricular fibrillation.

Prominence of upper lobe blood vessels

Reticular shadowing of alveolar oedema

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Complications of heart failure

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Chronic heart failure is sometimes associated with marked weight loss (cardiac cachexia), caused by a combination of anorexia and impaired absorption due to gastrointestinal congestion, poor tissue perfusion due to a low cardiac output, and skeletal muscle atrophy due to immobility.

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464 • Cardiology

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• Explanation of nature of disease, treatment and self-help strategies

Corrects hypoxia

Diet

Reduces preload and pulmonary capillary hydraulic gradient

• Good general nutrition and weight reduction for the obese • Avoidance of high-salt foods and added salt, especially for patients with severe congestive heart failure

Administer nitrates:*   IV glyceryl trinitrate (10–200 µg/min)   Buccal glyceryl trinitrate 2–5 mg

Reduces preload and afterload

Alcohol

Administer a loop diuretic:   Furosemide (50–100 mg IV)

Combats fluid overload

Smoking

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Fig. 16.28  The effect of treatment on ventricular performance

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Backward failure Dyspnoea/oedema

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Preload

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curves in heart failure. Diuretics and venodilators (A), angiotensinconverting enzyme (ACE) inhibitors and mixed vasodilators (B), and positive inotropic agents (C).

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be a substantial and beneficial fall in filling pressure with either no change or an improvement in cardiac output (see Figs 16.24 and 16.28). Nevertheless, the dose of diuretics needs to be titrated carefully so as to avoid excessive volume depletion, which can cause a fall in cardiac output with hypotension, lethargy and renal failure. This is especially likely in patients with a marked diastolic component to their heart failure. Oedema may persist, despite oral loop diuretic therapy, in some patients with severe chronic heart failure, particularly if there is renal impairment. Under these circumstances an intravenous infusion of furosemide (5–10 mg/hr) may initiate a diuresis. Combining a loop diuretic with a thiazide diuretic such as bendroflumethiazide (5 mg daily) may also prove effective but care must be taken to avoid an excessive diuresis. Mineralocorticoid receptor antagonists, such as spironolactone and eplerenone, are potassium-sparing diuretics that are of particular benefit in patients with heart failure with severe left ventricular systolic dysfunction. They have been shown to improve long-term clinical outcome in individuals with severe heart failure or heart failure following acute MI but may cause hyperkalaemia, particularly when used with an ACE inhibitor.

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16 Heart failure

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leading to a reduction in blood plasma volume (p. 354), which in turn reduces preload and improves pulmonary and systemic venous congestion. They may also reduce afterload and ventricular volume, leading to a fall in ventricular wall tension and increased cardiac efficiency. Although a fall in preload (ventricular filling pressure) normally reduces cardiac output, patients with heart failure are beyond the apex of the Starling curve, so there may

C

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Diuretics  Diuretics promote urinary sodium and water excretion,

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A wide variety of drug treatments are now available for the treatment of heart failure. Drugs that reduce preload are appropriate in patients with high end-diastolic filling pressures and evidence of pulmonary or systemic venous congestion, whereas those that reduce afterload or increase myocardial contractility are more useful in patients with signs and symptoms of a low cardiac output.

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Normal

Forward failure Fatigue

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Drug treatment

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Cardiac output or ventricular performance

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Education of patients and their relatives about the causes and treatment of heart failure can improve adherence to a management plan (Box 16.16). Some patients may need to weigh themselves daily, as a measure of fluid load, and adjust their diuretic therapy accordingly.

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• Consideration of influenza and pneumococcal vaccination

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The aims of treatment in chronic heart failure are to improve cardiac function by increasing contractility, optimising preload or decreasing afterload, and controlling cardiac rate and rhythm (see Fig. 16.25). This can be achieved by a combination of drug treatment or non-drug treatments, as discussed below.

Education

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Vaccination

pulse oximetry. Intravenous opiates can be of value in distressed patients but must be used sparingly, as they may cause respiratory depression and exacerbation of hypoxaemia and hypercapnia. The key elements of management are summarised in Box 16.15. If these measures prove ineffective, inotropic agents such as dobutamine (2.5–10 µg/kg/min) may be required to augment cardiac output, particularly in hypotensive patients. Insertion of an intra-aortic balloon pump may be beneficial in patients with acute cardiogenic pulmonary oedema and shock. Following management of the acute episode, additional measures must be instituted to control heart failure in the longer term, as discussed below.

Management of chronic heart failure

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• Regular moderate aerobic exercise within limits of symptoms

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Exercise

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• Cessation

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• Moderation or elimination of alcohol consumption; alcohol-induced cardiomyopathy requires abstinence

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Ensure continuous positive airway pressure (CPAP) of 5–10 mmHg by tight-fitting mask

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Reduces preload

Give high-flow oxygen

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Sit the patient up

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Effect

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Education

Action

*The dose of nitrate should be titrated upwards every 10 mins until there is an improvement or systolic blood pressure is twice upper limit of reference range or transaminases > three times upper limit of reference range Abnormal renal function (creatinine > 200 µmol/L (2.26 mg/dL)

1 point

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B

AVNRT is a type of SVT caused by re-entry in a circuit involving the AV node and its two right atrial input pathways: a superior ‘fast’ pathway and an inferior ‘slow’ pathway (see Fig. 16.39A below). This produces a regular tachycardia with a rate of 120–240/ min. It tends to occur in the absence of structural heart disease and episodes may last from a few seconds to many hours. The patient is usually aware of a rapid, very forceful, regular heart beat and may experience chest discomfort, lightheadedness or breathlessness. Polyuria, mainly due to the release of ANP, is sometimes a feature. The ECG (Fig. 16.38) usually shows a tachycardia with normal QRS complexes but occasionally there may be rate-dependent bundle branch block.

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Hypertension; current systolic blood pressure > 160 mmHg

Stroke history

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Score

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From European Society of Cardiology Clinical practice guidelines: atrial fibrillation (management of) 2010 and focused update (2012). Eur Heart J 2012; 33:2719–2747.

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similar appearance on ECG. These are usually narrow-complex tachycardias and are characterised by a re-entry circuit or automatic focus involving the atria. The three principal types are atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular re-entrant tachycardia (AVRT) and atrial tachycardia. The term SVT is technically incorrect as, in many cases, the ventricles also form part of the re-entry circuit.

Atrioventricular nodal re-entrant tachycardia

16.24  HAS-BLED bleeding risk scoring system for patients receiving oral anticoagulation

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Vascular disease

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Previous stroke or transient ischemic attack (TIA)

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Parameter

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QRS complexes are normal.

Annual stroke risk 0 points = 0% (no prophylaxis required) 1 point = 1.3% (oral anticoagulant recommended in males only) 2+ points = > 2.2% (oral anticoagulant recommended)

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ks Fig. 16.38  Supraventricular tachycardia. The rate is 180/min and the

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Diabetes mellitus

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Age ≥ 75 years

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Hypertension history

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Congestive heart failure

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Parameter

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16.23  CHA2DS2-VASc stroke risk scoring system for non-valvular atrial fibrillation

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Cardiac arrhythmias • 473

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Management

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Treatment may not be necessary, unless the patient is highly symptomatic, in which case β-blockers or, in some situations,

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Ventricular premature beats (VPBs) are frequently found in healthy people and their prevalence increases with age. Ectopic beats in patients with otherwise normal hearts are more prominent at rest and disappear with exercise. Sometimes VPBs are a manifestation of subclinical coronary artery disease or cardiomyopathy but also may occur in patients with established heart disease following an MI. Most patients with VPBs are asymptomatic but some present with an irregular heart beat, missed beats or abnormally strong beats, due to increased cardiac output of the post-ectopic sinus beat. On examination the pulse is irregular, with weak or missed beats as a result of the fact that the stroke volume is low because left ventricular contraction occurs before filling is complete (Fig. 16.40). The ECG shows broad and bizarre complexes because the ventricles are activated sequentially rather than simultaneously. The complexes may be unifocal (identical beats arising from a single ectopic focus) or multifocal (varying morphology with multiple foci, Fig. 16.40). ‘Couplet’ and ‘triplet’ are the terms used to describe two or three successive ectopic beats. A run of alternating sinus and ventricular ectopic beats is known as ventricular ‘bigeminy’. The significance depends on the presence or absence of underlying heart disease.

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Ventricular premature beats

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Carotid sinus pressure or intravenous adenosine can terminate the tachycardia. If AF occurs, it may produce a dangerously rapid ventricular rate because the accessory pathway lacks the rate-limiting properties of the AV node (Fig. 16.39D). This is known as pre-excited atrial fibrillation and may cause collapse, syncope and even death. It should be treated as an emergency, usually with DC cardioversion. Catheter ablation is first-line treatment in symptomatic patients and is nearly always curative. Alternatively, prophylactic antiarrhythmic drugs, such as flecainide or propafenone (p. 481), can be used to slow conduction in, and prolong the refractory period of, the accessory pathway. Long-term drug therapy is not the preferred treatment for most patients and amiodarone should not be used, as its side-effect profile cannot be justified and ablation is safer and more effective. Digoxin and verapamil shorten the refractory period of the accessory pathway and should not be used.

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Wolff–Parkinson–White syndrome: atrial fibrillation

Fig. 16.39  Atrioventricular nodal re-entrant tachycardia (AVNRT) and Wolff–Parkinson–White (WPW) syndrome. A AV node re-entrant tachycardia. The mechanism of AVNRT occurs via two right atrial AV nodal input pathways: the slow (S) and fast (F) pathways. Antegrade conduction occurs via the slow pathway; the wavefront enters the AV node and passes into the ventricles, at the same time re-entering the atria via the fast pathway. In WPW syndrome, there is a strip of accessory conducting tissue that allows electricity to bypass the AV node and spread from the atria to the ventricles rapidly and without delay. When the ventricles are depolarised through the AV node the ECG is normal, but when the ventricles are depolarised through the accessory conducting tissue the ECG shows a very short PR interval and a broad QRS complex. B Sinus rhythm. In sinus rhythm, the ventricles are depolarised through (1) the AV node and (2) the accessory pathway, producing an ECG with a short PR interval and broadened QRS complexes; the characteristic slurring of the upstroke of the QRS complex is known as a delta wave. The degree of pre-excitation (the proportion of activation passing down the accessory pathway) and therefore the ECG appearances may vary a lot, and at times the ECG can look normal. C Orthodromic tachycardia. This is the most common form of tachycardia in WPW. The re-entry circuit passes antegradely through the AV node and retrogradely through the accessory pathway. The ventricles are therefore depolarised in the normal way, producing a narrow-complex tachycardia that is indistinguishable from other forms of supraventricular tachycardia. D Atrial fibrillation. In this rhythm, the ventricles are largely depolarised through the accessory pathway, producing an irregular broad-complex tachycardia that is often more rapid than the example shown.

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of the QRS complex, called a delta wave (Fig. 16.39B). This is known as a manifest accessory pathway. As the AV node and accessory pathway have different conduction speeds and refractory periods, a re-entry circuit can develop, causing tachycardia (Fig. 16.39C); when associated with symptoms, the condition is known as Wolff–Parkinson–White syndrome. The ECG during this tachycardia is almost indistinguishable from that of AVNRT (Fig. 16.39A).

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Wolff–Parkinson–White syndrome: orthodromic tachycardia

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Management

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Wolff–Parkinson–White syndrome: sinus rhythm

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AV nodal re-entrant tachycardia

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474 • Cardiology

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Cardiac arrhythmias • 475

Fig. 16.40  Ventricular ectopic beats. A There are broad, bizarre QRS complexes (arrows) with no preceding P wave in between normal sinus beats.

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Prompt action to restore sinus rhythm is required and should usually be followed by prophylactic therapy. Synchronised DC cardioversion is the treatment of choice if systolic BP is less than 90 mmHg. If the arrhythmia is well tolerated, intravenous amiodarone may be given as a bolus, followed by a continuous infusion (p. 481). Intravenous lidocaine can be used but may depress left ventricular function, causing hypotension or acute heart failure. Hypokalaemia, hypomagnesaemia, acidosis and hypoxia should be corrected if present. Beta-blockers are effective at preventing VT by reducing ventricular automaticity. Amiodarone can be added if additional

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Management

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Occasionally, VT occurs in patients with otherwise healthy hearts (‘normal heart VT’), usually because of abnormal automaticity in the right ventricular outflow tract or one of the fascicles of the left bundle branch.

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History of myocardial infarction Atrioventricular dissociation (pathognomonic) Capture/fusion beats (pathognomonic; see Fig. 16.41) Extreme left axis deviation Very broad QRS complexes (> 140 msecs) No response to carotid sinus massage or intravenous adenosine

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16

tachycardia, there is independent atrial and ventricular activity. Occasionally, a P wave is conducted to the ventricles through the AV node, producing a normal sinus beat in the middle of the tachycardia (a capture beat); more commonly, however, the conducted impulse fuses with an impulse from the tachycardia (a fusion beat). This can occur only when there is atrioventricular dissociation and is therefore diagnostic of ventricular tachycardia.

16.25  Features more in keeping with ventricular tachycardia

Ventricular tachycardia (VT) occurs most commonly in the settings of acute MI, chronic coronary artery disease and cardiomyopathy. It is associated with extensive ventricular disease, impaired left ventricular function and ventricular aneurysm. In these settings, VT may cause haemodynamic compromise or degenerate into ventricular fibrillation (p. 456). VT is caused by abnormal automaticity or triggered activity in ischaemic tissue, or by re-entry within scarred ventricular tissue. Patients may complain of palpitation or symptoms of low cardiac output, including dyspnoea, lightheadedness and syncope. The ECG shows tachycardia and broad, abnormal QRS complexes with a rate of more than 120/min (Fig. 16.41). It may be difficult to distinguish VT from SVT with bundle branch block or pre-excitation (WPW syndrome) on ECG but features in favour of VT are listed in Box 16.25. A 12-lead ECG (Fig. 16.42) or electrophysiology study (p. 454) may help establish the diagnosis. When there is doubt, it is safer to manage the problem as VT. Patients recovering from MI sometimes have periods of idioventricular rhythm (‘slow’ VT) at a rate only slightly above the preceding sinus rate and below 120/min. These episodes often reflect reperfusion of the infarct territory and may be a good sign. They are usually self-limiting and asymptomatic, and do not require treatment. Other forms of sustained VT require treatment, often as an emergency.

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Fig. 16.41  Ventricular tachycardia: fusion beat (arrow). In ventricular

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Ventricular tachycardia

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catheter ablation can be used. There is no evidence that antiarrhythmic therapy improves prognosis but the discovery of very frequent VPBs in a patient not known to have heart disease should prompt further investigations with echocardiography and an exercise ECG to screen for structural heart disease and ischaemic heart disease. It is common for VPBs to occur during the course of an acute MI. Persistent, frequent VPBs (over 10/ hr) in patients who have survived the acute phase of MI indicate a poorer long-term outcome. In this situation, anti-arrhythmic drugs do not improve and may even worsen prognosis. The exception is β-blockers, which should be prescribed for other reasons (p. 500). Similarly, heart failure of any cause is associated with VPBs. While they indicate an adverse prognosis, this is not improved by anti-arrhythmic drugs. Effective treatment of the heart failure may suppress the ectopic beats. VPBs are also a feature of digoxin toxicity.

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Their configuration varies, so these are multifocal ectopics. B A simultaneous arterial pressure trace is shown. The ectopic beats result in a weaker pulse (arrows), which may be perceived as a ‘dropped beat’.

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*Many other drugs that are not shown can be associated with prolongation of the QT interval. See www.crediblemeds.org for a complete list.

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Long QT1: gene affected KCNQI: K+ channel, 30–35% Long QT2: gene affected HERG: K+ channel, 25–30% Long QT3: gene affected SCNSA: Na+ channel, 5–10% Long QT4–12: rare; various genes implicated

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• • • •

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very broad QRS complexes and marked left axis deviation. There is also atrioventricular dissociation; some P waves are visible and others are buried in the QRS complexes (arrows).

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Congenital syndromes

Rhythm strip

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• Disopyramide, flecainide and other class Ia, Ic anti-arrhythmic drugs (p. 479) • Sotalol, amiodarone and other class III anti-arrhythmic drugs • Amitriptyline and other tricyclic antidepressants • Chlorpromazine and other phenothiazines • Erythromycin and other macrolides

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Drugs*

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Electrolyte disturbance

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• Bradycardia compounds other factors that cause torsades de pointes

• Hypokalaemia • Hypomagnesaemia • Hypocalcaemia

Fig. 16.42  Ventricular tachycardia: 12-lead ECG. There are typically

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Bradycardia

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16.26  Causes of long QT interval and torsades de pointes

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III

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Intravenous magnesium (8 mmol over 15 mins, then 72 mmol over 24 hrs) should be given in all cases. If this is ineffective,

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Management

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aVR

This form of polymorphic VT is a complication of prolonged ventricular repolarisation (prolonged QT interval). The ECG shows rapid irregular complexes that seem to twist around the baseline as the mean QRS axis changes (Fig. 16.43). The arrhythmia is usually non-sustained and repetitive, but may degenerate into ventricular fibrillation. During periods of sinus rhythm, the ECG will usually show a prolonged QT interval (> 0.44 sec in men, > 0.46 sec in women when corrected to a heart rate of 60/min). Some of the common causes are listed in Box 16.26. The arrhythmia is more common in women and is often triggered by a combination of factors, such as administration of QT-prolonging medications and hypokalaemia. The congenital long QT syndromes are a family of genetic disorders that are characterised by mutations in genes that code for cardiac sodium or potassium channels. Long QT syndrome subtypes have different triggers, which are important when counselling patients. Adrenergic stimulation through vigorous exercise is a common trigger in long QT type 1, and a sudden noise may trigger arrhythmias in long QT type 2. Arrhythmias are more common during sleep in type 3.

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I

Torsades de pointes

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re

control is needed. Class Ic anti-arrhythmic drugs should not be used for prevention of VT in patients with coronary artery disease or heart failure because they depress myocardial function and can increase the likelihood of a dangerous arrhythmia. In patients with poor left ventricular function or where VT is associated with haemodynamic compromise, the use of an implantable cardiac defibrillator is recommended (p. 483). Rarely, surgery with resection of a ventricular aneurysm or catheter ablation can be used to interrupt the arrhythmia focus or circuit in patients with VT associated with a myocardial infarct scar. The treatment of choice for VT occurring in a normal heart is catheter ablation, which often can be curative.

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om

m

e. co

476 • Cardiology

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ok s

re sf ok

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ectopic.

e.

Fig. 16.43  Torsades de pointes. A bradycardia with a long QT interval is followed by polymorphic ventricular tachycardia that is triggered by an R on T

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P

P

P

P

P

P

P

P

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P

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P

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prolonged and measures 0.26 sec.

m

co m

m

Fig. 16.44  First-degree atrioventricular block. The PR interval is

eb

Here dropped beats occur because some impulses from the atria fail to conduct to the ventricles. Two subtypes are recognised. In Mobitz type I second-degree AV block (Fig. 16.45), there is

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eb

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oo k

ks

eb oo ks

Second-degree atrioventricular block

16

The typical presentation is with recurrent syncope or ‘Stokes– Adams’ attacks. These episodes are characterised by sudden

In this condition, AV conduction is delayed and so the PR interval is prolonged (> 0.20 sec; Fig. 16.44). It rarely causes symptoms and does not usually require treatment.

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Clinical features

fre

fre

First-degree atrioventricular block

P

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m

m

m

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ks

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fre

In third-degree AV block, conduction fails completely and the atria and ventricles beat independently. This is known as AV dissociation, as shown in Fig. 16.48. Ventricular activity is maintained by an escape rhythm arising in the AV node or bundle of His (narrow QRS complexes) or the distal Purkinje tissues (broad QRS complexes). Distal escape rhythms tend to be slower and less reliable. Complete AV block (Box 16.27) produces a slow (25–50/min), regular pulse that does not vary with exercise, except in the case of congenital complete AV block. There is usually a compensatory increase in stroke volume, producing a large-volume pulse. Cannon waves may be visible in the neck and the intensity of the first heart sound varies due to the loss of AV synchrony.

m

This usually occurs as the result of disease affecting the AV node. AV block can be intermittent, however, and may become evident only when the conducting tissue is stressed by a rapid atrial rate. Reflecting this fact, atrial tachyarrhythmias are often associated with AV block (see Fig. 16.37). Episodes of ventricular asystole may also complicate complete heart block or Mobitz type II second-degree AV block. Several types of AV block are recognised.

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Third-degree atrioventricular block

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Atrioventricular block

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ks

oo

eb

m

m

m

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progressive lengthening of successive PR intervals, culminating in a dropped beat. The cycle then repeats itself. This is known as the Wenckebach phenomenon and is usually due to impaired conduction in the AV node itself. The phenomenon may be physiological and is sometimes observed at rest or during sleep in athletic young adults with high vagal tone. In Mobitz type II second-degree AV block (Fig. 16.46), the PR interval of the conducted impulses remains constant but some P waves are not conducted. This is usually caused by disease of the His–Purkinje system and carries a risk of asystole. In 2 : 1 AV block (Fig. 16.47), alternate P waves are conducted, so it is impossible to distinguish between Mobitz type I and type II block.

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m

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atrial pacing should be tried, since it can suppress the arrhythmia through rate-dependent shortening of the QT interval. Intravenous isoprenaline is a reasonable alternative to pacing but should be avoided in patients with the congenital long QT syndromes. Once initial control has been achieved, efforts should be made to identify and treat the underlying cause or stop medications that predispose to the arrhythmia. If the underlying cause cannot be corrected or the arrhythmia is the result of an inherited syndrome, then long-term pharmacological therapy may be necessary. Beta-blockers are effective at preventing syncope in patients with congenital long QT syndrome. Some patients, particularly those with extreme QT interval prolongation (> 500 msecs) or certain high-risk genotypes, should be considered for an implantable defibrillator. Left stellate ganglion block may be of value in patients with resistant arrhythmias. Brugada syndrome is a related genetic disorder that may present with polymorphic VT or sudden death. It is characterised by a defect in sodium channel function and an abnormal ECG (right bundle branch block and ST elevation in V1 and V2 but not usually prolongation of the QT interval). The only known effective treatment is an implantable defibrillator.

Cardiac arrhythmias • 477

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wave is not conducted. The cycle then repeats itself. In this example, conduction is at a ratio of 4 : 3, leading to groupings of three ventricular complexes in a row.

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Fig. 16.45  Second-degree atrioventricular block (Mobitz type I – the Wenckebach phenomenon). The PR interval progressively increases until a P

P

P

P

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re sf

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sf

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The constant PR interval distinguishes this from the Wenckebach phenomenon.

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e.

Fig. 16.46  Second-degree atrioventricular block (Mobitz type II). The PR interval of conducted beats is normal but some P waves are not conducted.

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om

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II

aVL

V2

aVF

V3

V1

m

V4

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e.

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m

eb

eb o

V5

III

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m

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V6

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Fig. 16.49  Right bundle branch block. Note the wide QRS complexes with

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‘M’-shaped configuration in leads V1 and V2 and a wide S wave in lead I.

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I

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sf ok

• Aortic valve disease • Cardiomyopathy

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• Coronary artery disease • Hypertension

This depends on the clinical circumstances. Acute inferior MI is often complicated by transient AV block because the right coronary artery (RCA) supplies the AV node. There is usually a reliable escape rhythm and, if the patient remains well, no treatment is required. Symptomatic second- or third-degree AV block may respond to atropine (0.6 mg IV, repeated as necessary) or, if this fails, a temporary pacemaker. In most cases, the AV block will resolve within 7–10 days. Second- or third-degree AV heart block complicating acute anterior MI indicates extensive ventricular damage involving both bundle branches and carries a poor prognosis. Asystole may ensue and a temporary pacemaker should be inserted promptly. If the patient presents with asystole, intravenous atropine (3 mg) or intravenous isoprenaline (2 mg in 500 mL 5% dextrose, infused at 10–60 mL/hr) may help to maintain the circulation until a temporary pacing electrode can be inserted. Temporary pacing can provide effective rhythm support in the short term.

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m

fre

Left bundle branch block

m

m

• Congenital heart disease, e.g. atrial septal defect • Coronary artery disease

• Normal variant • Right ventricular hypertrophy or strain, e.g. pulmonary embolism

m

• Trauma • Drugs: Digoxin β-blockers Calcium antagonists

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m

e. co

Right bundle branch block

fre

eb oo ks

16.28  Common causes of bundle branch block

loss of consciousness that occurs without warning and results in collapse. A brief anoxic seizure (due to cerebral ischaemia) may occur if there is prolonged asystole. There is pallor and a death-like appearance during the attack, but when the heart starts beating again there is a characteristic flush. In distinction to epilepsy, recovery is rapid. Sinoatrial disease and neurocardiogenic syncope (p. 181) may cause similar symptoms.

Management

ks

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eb

16.27  Causes of complete atrioventricular block

m

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eb

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complete dissociation of atrial and ventricular complexes. The atrial rate is 80/min and the ventricular rate is 38/min.

Congenital Acquired • Idiopathic fibrosis • Myocardial infarction/ ischaemia • Inflammation: Infective endocarditis Sarcoidosis Chagas’ disease

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m

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eb

P

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ks

P

oo

P

Damage to the right or left bundle branch of the conducting system can occur as a result of many pathologies, including ischaemic heart disease, hypertensive heart disease and cardiomyopathy. However, right bundle branch block (RBBB) can occur as a normal variant in healthy individuals (Box 16.28). In left bundle branch block (LBBB) and RBBB, depolarisation proceeds through a slow myocardial route in the affected ventricle rather than through the rapidly conducting Purkinje tissues that constitute the bundle branches. This causes delayed conduction into the LV or RV, broadens the QRS complex (≥ 0.12 sec) and produces characteristic alterations in QRS morphology (Figs 16.49 and

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P

fre

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Bundle branch block

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m

m

block. Alternate P waves are not conducted. This may be due to Mobitz type I or II block.

oo

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Fig. 16.48  Complete (third-degree) atrioventricular block. There is

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ks

P

m

P

Fig. 16.47  Second-degree atrioventricular block with fixed 2 : 1

m

P

Patients with symptomatic bradyarrhythmias associated with AV block should be treated with a permanent pacemaker. Asymptomatic first-degree or Mobitz type I second-degree AV block (Wenckebach phenomenon) does not require treatment but may be an indication of underlying heart disease. A permanent pacemaker is usually indicated in patients with asymptomatic Mobitz type II second-degree AV block or third-degree AV heart block because of the risk of asystole and sudden death. Pacing improves prognosis.

oo

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eb o

P

ok s

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eb

P

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478 • Cardiology

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ks

ks

oo

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eb

eb

m

m

16.29  Classification of anti-arrhythmic drugs by effect on the intracellular action potential*

with loss of the Q wave or septal vector in lead I and ‘M’-shaped QRS complexes in V5 and V6.

om

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ks

ks

sf

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oo

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Class II: β-adrenoceptor antagonists (β-blockers) • Atenolol, bisoprolol, metoprolol

eb

eb

eb

Class III: drugs whose main effect is to prolong the action potential

m

m

• Amiodarone, dronedarone, sotalol

m

fre

16

(a) Block Na+ channel and prolong action potential • Quinidine, disopyramide (b) Block Na+ channel and shorten action potential • Lidocaine, mexiletine (c) Block Na+ channel with no effect on action potential • Flecainide, propafenone

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e. co

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m

m

Class I: membrane-stabilising agents (sodium channel blockers)

16.50). Damage to the left bundle can also occur after it divides into anterior and posterior fascicles, when it is called hemiblock. In this case, the QRS complex is not broadened but the direction of ventricular depolarisation is changed, causing left axis deviation in left anterior hemiblock and right axis deviation in left posterior hemiblock (see Fig. 16.7, p. 449). The combination of RBBB and left anterior or posterior hemiblock is known as bifascicular block. LBBB usually signifies important underlying heart disease and also causes ventricular incoordination, which may aggravate symptoms in patients with heart failure. This can be treated in selected patients by cardiac resynchronisation therapy (p. 484).

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ks

m co m

e. co m fre

Fig. 16.51  Classification of anti-arrhythmic drugs by site of action.

V6

Fig. 16.50  Left bundle branch block. Note the wide QRS complexes

m

Ventricles Lidocaine Mexiletine β-blockers

AV node Adenosine β-blockers Digoxin Verapamil Diltiazem

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V3

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aVF

III

Atria, ventricles and accessory conducting tissues Disopyramide Flecainide Propafenone Amiodarone

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V5

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aVL

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II

• 479

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V2

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V4

V1

eb

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Sinoatrial node β-blockers Atropine Verapamil Diltiazem

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aVR

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eb

I

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Principles of management of cardiac arrhythmias

Class IV: slow calcium channel blockers • Verapamil, diltiazem

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co

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eb

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ok s

Class I drugs act principally by suppressing excitability and slowing conduction in atrial or ventricular muscle. They block sodium channels, of which there are several types in cardiac tissue. These drugs should generally be avoided in patients with heart failure because they depress myocardial function, and class Ia and Ic drugs are often pro-arrhythmic.

ks

fre

Class I drugs

Class Ia drugs

m

m

These prolong cardiac action potential duration and increase the tissue refractory period. They are used to prevent both atrial and ventricular arrhythmias.

co

e. co

Disopyramide

ok s

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e.

This is an effective drug but causes anticholinergic side-effects, such as urinary retention, and can precipitate glaucoma. It can

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m

m

Traditionally, the Vaughan Williams system has been used to categorise anti-arrhythmic drugs based on their effects on the action potential. More recently, increased understanding of the mechanisms of action has allowed further subclassification, based on the cardiac ion channels and receptors on which they act (Box 16.29 and Fig. 16.51). The individual agents, dosages and most common side-effects are summarised in Box 16.30 and the general principles of use are summarised in Box 16.31.

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Cardiac arrhythmias can be managed with either anti-arrhythmic drug therapy or external devices that depolarise the heart by passing an electric current through it. These strategies are relevant across a range of indications and are discussed in more detail here.

Anti-arrhythmic drugs

*Some drugs such as digoxin, ivabradine and adenosine have no place in this classification, while others such as amiodarone have properties in more than one class.

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co m

Principles of management of cardiac arrhythmias

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m

ks oo

ks oo eb

m

ks

Flushing, dyspnoea, chest pain Avoid in asthma Gastrointestinal disturbance, xanthopasia, arrhythmias See Box 16.33

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Oral

Dry mouth, thirst, blurred vision, atrial and ventricular extrasystoles

oo

3 mg over 2 secs, followed if necessary by 6 mg, then 12 mg at intervals of 1–2 mins Loading dose: 0.5–1 mg (total), 0.5 mg over 30 mins, then 0.25–0.5 mg after 4–6 hrs 0.5 mg repeated after 6 hrs, then 0.0625–0.25 mg daily

IV

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m

co m

m

IV

m

co m

Digoxin

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0.6–3 mg

co

Adenosine

.c

IV

m

m

Treatment of bradycardia and/or hypotension due to vagal overactivity Teatment of SVT, aid to diagnosis in unidentified tachycardia Treatment and prevention of SVT, rate control of AF

Myocardial depression, hypotension. bradycardia, constipation

m

eb

Other Atropine

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5–10 mg over 30 secs 40–120 mg 3 times daily or 240 mg SR daily

eb

IV Oral

oo

Teatment of SVT, control of AF

10–20 mg slowly 40–160 mg twice daily

sf

IV Oral

400 mg twice daily

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AF, rarely ventricular tachyarrhythmias

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Oral

fre

Paroxysmal atrial fibrillation

ks

Class IV Verapamil

Photosensitivity skin discoloration, corneal deposits, thyroid dysfunction, alveolitis, nausea and vomiting, hepatotoxicity, peripheral neuropathy, torsades de pointes; potentiates digoxin and warfarin Renal and hepatic dysfunction requiring regular blood monitoring Can cause torsades de pointes

m

m e. co

fre

eb oo ks

Sotalol*

fre

5 mg/kg over 20–120 mins, then up to 15 mg/kg/24 hrs Initially 600–1200 mg/day, then 100–400 mg daily

Oral

Dronedarone

ks

eb

IV

Myocardial depression, bradycardia, bronchospasm, fatigue, depression, nightmares, cold peripheries

m

Serious or resistant atrial and ventricular tachyarrhythmias

Oral Oral IV

2.5 mg at 1 mg/min, repeated at 5-min intervals (max 10 mg) 25–100 mg daily 2.5–10 mg daily 5 mg over 2 mins to a maximum of 15 mg

m

eb

m

Class III Amiodarone

Myocardial depression, dizziness

co

oo ks IV

Treatment and prevention of SVT and AF, prevention of VEs and exercise-induced VF

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Oral Oral

Myocardial depression, dizziness

fre

ks fre oo

Bisoprolol Metoprolol

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m

Oral IV

Prevention and treatment of atrial and ventricular tachyarrhythmias

Myocardial depression, gastrointestinal irritation, delirium, dizziness, tremor, nystagmus, ataxia

ks

Prevention and treatment of atrial and ventricular tachyarrhythmias

IV

Myocardial depression, hypotension, dry mouth, urinary retention Myocardial depression, delirium, convulsions

oo

Flecainide

2 mg/kg at 30 mg/min, then 0.4 mg/kg/hr (max 800 mg/day) 300–800 mg daily in divided dosage Bolus 50–100 mg, 4 mg/min for 30 mins, then 2 mg/min for 2 hrs, then 1 mg/min for 24 hrs Loading dose: 100–250 mg at 25 mg/min, then 250 mg in 1 hr, then 250 mg in 2 hrs Maintenance therapy: 0.5 mg/min 200–250 mg 3 times daily 2 mg/kg over 10 mins, then if required 1.5 mg/kg/hr for 1 hr, then 0.1 mg/kg/hr 50–100 mg twice daily 150 mg 3 times daily for 1 week, then 300 mg twice daily

eb

Prevention and treatment of ventricular tachyarrhythmias

Important side-effects

m

Mexiletine

m

Treatment and short-term prevention of VT and VF

Class II Atenolol

eb

Oral IV

Lidocaine

Propafenone

m

IV

eb o

Prevention and treatment of atrial and ventricular tachyarrhythmias

Dose (adult)

oo

Route

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Class I Disopyramide

Main uses

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Drug

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16.30  Uses, dosages and side-effects of anti-arrhythmic drugs

eb

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480 • Cardiology

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m

m

m

This can be given intravenously or orally but has many side-effects.

co

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e.

These affect the slope of the action potential without altering its duration or refractory period. They are used mainly for prophylaxis of AF but are effective in prophylaxis and treatment

sf

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re

e.

These shorten the action potential and tissue refractory period. They act on channels found predominantly in ventricular myocardium and so are used to treat or prevent VT and VF.

sf

Mexiletine

Class Ic drugs

co

Class Ib drugs

m

Now rarely used, quinidine increases mortality and causes gastrointestinal upset.

This must be given intravenously and has a very short plasma half-life.

ok

Quinidine

Lidocaine

m

oo

m

eb

depress myocardial function and should be avoided in cardiac failure.

ok

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ks fre

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*Sotalol also has class II activity as a β-blocker. (AF = atrial fibrillation; IV = intravenous; SR = sustained-release formulation; SVT = supraventricular tachycardia; VE = ventricular ectopic; VF = ventricular fibrillation; VT = ventricular tachycardia)

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e.

Verapamil

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Diltiazem

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This is the most widely used drug in this class. Intravenous verapamil may cause profound bradycardia or hypotension, and should not be used in conjunction with β-blockers.

eb

This has similar properties to verapamil.

Other anti-arrhythmic drugs

m

Atropine sulphate

Atropine is a muscarinic receptor antagonist that increases the sinus rate and SA and AV conduction. It is the treatment of choice for severe bradycardia or hypotension due to vagal over-activity. It is used for initial management of symptomatic bradyarrhythmias complicating inferior MI, and in cardiac arrest due to asystole. The usual dose is 0.6 mg IV, repeated if necessary

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e.

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sf ok

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sf re

e.

These act mainly on myocardial β1 receptors and are relatively well tolerated. Bisoprolol and metoprolol are examples of cardioselective β-blockers.

16

These block the ‘slow calcium channel’, which is important for impulse generation and conduction in atrial and nodal tissue, although it is also present in ventricular muscle. Their main indications are prevention of SVT (by blocking the AV node) and rate control in patients with AF.

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Cardioselective β-blockers

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Class IV drugs

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m

m

eb

These act on both β1 and β2 receptors. Beta2-blockade causes sideeffects, such as bronchospasm and peripheral vasoconstriction. Propranolol is non-selective and is subject to extensive firstpass metabolism in the liver. The effective oral dose is therefore unpredictable and must be titrated after treatment is started with a small dose. Other non-selective drugs include nadolol and carvedilol.

oo

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eb

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m

Dronedarone is related to amiodarone but has a short tissue half-life and fewer side-effects. It has recently been shown to be effective at preventing episodes of atrial flutter and AF. It is contraindicated in patients with permanent AF, or if there is heart failure or left ventricular impairment, because it increases mortality. Regular liver function test monitoring is required.

m

e.

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ks f oo

Non-selective β-blockers

re

Dronedarone

co

This group comprises the β-adrenoceptor antagonists (β-blockers). These agents reduce the rate of SA node depolarisation and cause relative block in the AV node, making them useful for rate control in atrial flutter and AF. They can be used to prevent VT and SVT. They reduce myocardial excitability and the risk of arrhythmic death in patients with coronary artery disease and heart failure.

sf

While amiodarone is primarily considered a class III drug, it also has class I, II and IV activity. It is probably the most effective drug currently available for controlling paroxysmal AF. It is also used to prevent episodes of recurrent VT, particularly in patients with poor left ventricular function or those with implantable defibrillators (to prevent unnecessary DC shocks). Amiodarone has a very long tissue half-life (25–110 days). An intravenous or oral loading regime is often used to achieve therapeutic tissue concentrations rapidly. The drug’s effects may last for weeks or months after treatment has been stopped. Sideeffects are common (up to one-third of patients), numerous and potentially serious. Drug interactions are also common (see Box 16.30).

m

eb

m

co m

Class II drugs

ok

Amiodarone

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fre

oo

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eb oo ks

This also has some β-blocker (class II) properties. Important interactions with digoxin, warfarin and cimetidine have been described.

eb

Class III drugs act by prolonging the plateau phase of the action potential, thus lengthening the refractory period. These drugs are very effective at preventing atrial and ventricular tachyarrhythmias. They cause QT interval prolongation and can predispose to torsades de pointes and VT, especially in patients with other predisposing risk factors (see Box 16.26). Disopyramide and sotalol have some class III activity but the main drug in this class is amiodarone, as discussed below.

m

fre

oo ks

eb

m

m

e. co

fre

This is effective for prevention of AF, and an intravenous infusion may be used for pharmacological cardioversion of AF of less than 24 hours’ duration. Since flecainide can cause slow atrial flutter with a paradoxically rapid ventricular rate, it should be prescribed along with an AV node-blocking drug such as a β-blocker to control the ventricular rate.

m

Class III drugs

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e. co

ks fre oo eb

m

of supraventricular or ventricular arrhythmias. They are useful for WPW syndrome because they block conduction in accessory pathways. They should not be used in patients with previous MI because they increase the risk of arrhythmia in this setting.

Flecainide

m

This is a racemic mixture of two isomers with non-selective β-blocker (mainly l-sotalol) and class III (mainly d-sotalol) activity. It may cause torsades de pointes.

m

ok s

eb o

m

m

m

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oo

ks f

Anti-arrhythmic drugs are potentially toxic and should be used carefully according to the following principles: • Many arrhythmias are benign and do not require specific treatment • Precipitating or causal factors should be corrected if possible: Alcohol excess Caffeine consumption Myocardial ischaemia Hyperthyroidism Acidosis Hypokalaemia Hypomagnesaemia • If drug therapy is required, it is best to use as few drugs as possible • In difficult cases, programmed electrical stimulation (electrophysiological study) may help to identify the optimum therapy • When managing life-threatening arrhythmias, it is essential to ensure that prophylactic treatment is effective. Ambulatory monitoring and exercise testing may be of value • Patients on long-term anti-arrhythmic drugs should be reviewed regularly and attempts made to withdraw therapy if the factors that precipitated the arrhythmias are no longer operative • For patients with recurrent supraventricular tachycardia, radiofrequency ablation is often preferable to long-term drug therapy

Sotalol

• 481

ks

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16.31  Anti-arrhythmic drugs: principles of use

Propafenone

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om

m e. co

Principles of management of cardiac arrhythmias

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om

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eb

m

m

m

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sf

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co

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sf

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m

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A variety of non-pharmacological treatments are available for the treatment of arrhythmias. These include the use of electrical

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Non-pharmacological treatments

ok

Temporary pacing involves delivery of an electrical impulse into the heart to initiate tissue depolarisation and to trigger cardiac contraction. This is achieved by inserting a bipolar pacing electrode through the internal jugular, subclavian or femoral vein and positioning it at the apex of the RV, using fluoroscopic imaging. The electrode is connected to an external pacemaker with an adjustable energy output and pacing rate. The ECG of right ventricular pacing is characterised by regular broad QRS complexes with a left bundle branch block pattern. Each complex is immediately preceded by a ‘pacing spike’ (Fig. 16.52). Nearly all pulse generators are used in the ‘demand’ mode, so that the pacemaker will operate only if the heart rate falls below a preset level. Occasionally, temporary atrial or dual-chamber pacing (see below) is used. Temporary pacing is indicated in the management of transient AV block and other arrhythmias complicating acute MI or cardiac surgery, to maintain the rhythm in other situations of reversible bradycardia (such as metabolic disturbance or drug overdose), or as a bridge to permanent pacing. Complications include pneumothorax, brachial plexus or subclavian artery injury, local infection or sepsis (usually with Staphylococcus aureus), and pericarditis. Failure of the system may be due to lead displacement or a progressive increase in the threshold (exit block) caused by tissue oedema. Complication rates increase with time and so a temporary pacing system should ideally not be used for more than 7 days. Transcutaneous pacing is administered by delivering an electrical stimulus through two large adhesive gel pad electrodes

co

co m

Digoxin is a glycoside purified from the European foxglove, Digitalis lanata, which slows conduction and prolongs the refractory period in the AV node. This effect helps to control the ventricular rate in AF and may interrupt SVTs involving the AV node. Digoxin also shortens refractory periods and enhances excitability and conduction in other parts of the heart, including accessory conduction pathways. It may therefore increase atrial and ventricular ectopic activity and can lead to more complex atrial and ventricular tachyarrhythmias. Digoxin is largely excreted by the kidneys, and the maintenance dose (see Box 16.30) should be reduced in children, older people and those with renal impairment. It is widely distributed and has a long tissue half-life (36 hours), so that effects may persist for several days. Measurement of plasma digoxin concentration helps identify digoxin toxicity or under-treatment (Box 16.33).

Temporary pacemakers

m

ks

oo

eb

m

Digoxin

eb

oo

e. co

fre

fre

eb oo ks

m

eb

m

e. co

m

This works by binding to A1 receptors in conducting tissue, producing a transient AV block lasting a few seconds. It is used to terminate SVTs when the AV node is part of the re-entry circuit, or to help establish the diagnosis in difficult arrhythmias, such as atrial flutter with 2 : 1 AV block (see Fig. 16.35) or broad-complex tachycardia (Boxes 16.30 and 16.32). Adenosine is given as an intravenous bolus, initially 3 mg over 2 secs (see Box 16.30). If there is no response after 1–2 minutes, 6 mg should be given; if necessary, after another 1–2 minutes the maximum dose of 12 mg may be given. Patients should be warned to expect short-lived and sometimes distressing flushing, breathlessness and chest pain. Adenosine can cause bronchospasm and should be avoided in patients with asthma; its effects are greatly potentiated by dipyridamole and inhibited by theophylline and other xanthines.

Defibrillators deliver a DC, high-energy, short-duration shock via two large electrodes or paddles coated with conducting jelly or a gel pad, positioned over the upper right sternal edge and the apex. Defibrillators are primarily used in the management of cardiac arrest due to VF and deliver an unsynchronised shock, since the precise timing of the discharge is not important in this situation. Modern units deliver a biphasic shock, during which the shock polarity is reversed mid-shock. This reduces the total shock energy required to depolarise the heart. In VF and other emergencies, the energy of the first and second shocks should be 150 joules and thereafter up to 200 joules; there is no need for an anaesthetic, as the patient is unconscious.

m

oo ks

to a maximum of 3 mg. Repeat dosing may be necessary because the drug disappears rapidly from the circulation after parenteral administration. Side-effects are listed in Box 16.30.

eb

eb

m

Defibrillation

Adenosine

m

fre e.

fre

• Atrial tachycardia (with variable block) • Ventricular tachycardia • Ventricular fibrillation

oo

ks fre

• Bradycardia • Multiple ventricular ectopics • Ventricular bigeminy (alternate ventricular ectopics)

m

Cardiac manifestations

m

e. co

• Altered colour vision (xanthopsia)

e. co m

m

Extracardiac manifestations

m

m

m

eb

No effect

16.33  Digoxin toxicity • Anorexia, nausea, vomiting • Diarrhoea

ks

ks

oo

Electrical cardioversion, also known as direct current (DC) cardioversion, is useful for terminating an organised rhythm, such as AF or VT. The electric current interrupts the arrhythmia and produces a brief period of asystole, which is usually followed by the resumption of sinus rhythm. Cardioversion is usually carried out as an elective procedure under general anaesthesia. The electric shock is delivered immediately after the R wave because, if it is applied during ventricular repolarisation (on the T wave), it may provoke VF. High-energy shocks may cause chest wall pain post-procedure, so, if there is no urgency, it is appropriate to begin with a lower-amplitude shock of about 50 joules initially, going on to larger shocks if necessary.

eb o

oo

Ventricular tachycardia

Electrical cardioversion

oo

Transient atrioventricular block

ok s

Termination

Atrial fibrillation, atrial flutter, atrial tachycardia

ok s

Supraventricular tachycardia

ks f

Response

fre

devices that work by passing an electric current through the heart, and catheter-based strategies that disrupt abnormal conduction tissues responsible for the generation of arrhythmias.

Arrhythmia

m

eb

fre e. c

re

16.32  Response to intravenous adenosine

e. co m

om

m

e. co

482 • Cardiology

fre e. c

fre

I = inhibited

D = both

D = both

co m

fre e.

oo eb

m

om

m

ks oo

e.

e.

co

co

m

m

m

m

eb

eb

oo k

sf

re e

.c

16

m

m

eb

eb o

ks

• After myocardial infarction, if the left ventricular ejection fraction is  99%) bound to transport proteins, mainly thyroxine-binding globulin (TBG). It is the unbound or free hormones that diffuse into tissues and exert diverse metabolic actions. Some laboratories use assays that measure total T4 and T3 in plasma but it is increasingly common to measure free T4 and free T3. The theoretical advantage of the

oo eb

–

eb

eb

m

m

e. co

fre

eb oo ks

Functional anatomy, physiology and investigations

m

Hypopituitarism

oo

Acromegaly, hypothyroidism

Hashimoto’s thyroiditis Atrophic hypothyroidism

ok s

Coarsening of features

TSHoma

oo m

fre

Thyrotoxicosis, Cushing’s syndrome, hypokalaemia (e.g. Conn’s syndrome), hyperparathyroidism, hypogonadism

oo ks

Muscle weakness (usually proximal)

Graves’ disease Multinodular goitre Adenoma Subacute thyroiditis

fre e.

Acromegaly, pituitary tumour, phaeochromocytoma

Secondary

Hormone hypersensitivity

e. co m

Thyrotoxicosis, phaeochromocytoma

Headache

ks fre

Thyrotoxicosis, menopause

Palpitation

oo eb

m

eb

eb o

m

e. co

m

m

eb

oo Heat intolerance

The thyroid gland

Primary

ks

Hypothyroidism, diabetes mellitus, hyperparathyroidism, hypogonadism, adrenal insufficiency, Cushing’s syndrome

fre

Lethargy and depression

ok s

Most likely endocrine disorder(s)

ks f

Symptom

Diseases of the thyroid, summarised in Box 18.4, predominantly affect females and are common, occurring in about 5% of the population. The thyroid axis is involved in the regulation of cellular differentiation and metabolism in virtually all nucleated cells, so that disorders of thyroid function have diverse manifestations. Structural diseases of the thyroid gland, such as goitre, commonly occur in patients with normal thyroid function.

m

18.4  Classification of thyroid disease

ks

fre e. c

re

18.3  Examples of non-specific presentations of endocrine disease

e. co m

om

m

e. co

634 • Endocrinology

oo eb m co m

T4

8 T3

CH COOH

Protein-bound T4, T3 ( > 99%)

e. co

e. co

ks

fre

oo m

Free T4,T3 ( < 1%)

m

CH2

m

O

HO

eb

Blood

ks

Increased metabolic rate Mimic β-adrenergic action, e.g. on heart rate, gut motility CNS activation Bone demineralisation Cellular differentiation etc.

eb

eb

rT3

Negative feedback

NH2

Target tissues

m

CH COOH

T3 T4

Extracellular Iodide fluid

TSH

m

m Reverse T3 (rT3)

fre e.

CH COOH

eb

CH2

Red blood cells

2

NH2

NH2

O

HO

T3

om

oo

Thyroxine (T4)

T4

ks

CH2

8

fre

ks fre

O

HO

MIT DIT

7

oo ks

e. co

4

Triiodothyronine (T3)

Iodide

e. co m

m

CH COOH

Colloid Follicular epithelium

6

oo

CH2

HO

Follicular cell

Stimulates all 8 steps 1 + hyperplasia

NH2

5

eb

Diiodotyrosine (DIT)

3

1

eb o

CH COOH

m

eb

m

NH2

CH2

T4

m

oo

3

Monoiodotyrosine (MIT) HO

4

Tg

ks

CH COOH

MIT Tg T3

oo

fre e. c MIT Tg

ok s

re

CH2

ks f

HO

Parafollicular (C) cells

DIT

DIT

Colloid

NH2

e. co m

om

m e. co

Tyrosine

The thyroid gland • 635

.c

Fig. 18.3  Structure and function of the thyroid gland. (1) Thyroglobulin (Tg) is synthesised and secreted into the colloid of the follicle. (2) Inorganic

ks oo

eb

e.

oo m

m

co

Clinical assessment

ok s

re

e.

The clinical manifestations of thyrotoxicosis are shown in Box 18.7 and an approach to differential diagnosis is given in

sf

ok

sf re

e.

e. co

co

hormone (TSH) and free T4. Due to the classic negative feedback loop between T4 and TSH, there is an inverse relationship between serum free T4 and the log of serum TSH. To convert pmol/L to ng/dL, divide by 12.87.

ks

fre

m

m

Fig. 18.4  The relationship between serum thyroid-stimulating

re

Thyrotoxicosis describes a constellation of clinical features arising from elevated circulating levels of thyroid hormone. The most common causes are Graves’ disease, multinodular goitre and autonomously functioning thyroid nodules (toxic adenoma) (Box 18.6). Thyroiditis is more common in parts of the world where relevant viral infections occur, such as North America.

m

-2.5

sf

eb

eb

eb o

Thyrotoxicosis

m

-2.0

ok

ok s

oo

oo

-1.5

co

co e.

10 15 20 25 30 35 40 45 50 55 Free T4 (pmol/L)

-1.0

eb

The most common presentations are hyperthyroidism (thyrotoxicosis), hypothyroidism and enlargement of the thyroid (goitre or thyroid nodule). Widespread availability of thyroid function tests has led to the increasingly frequent identification of patients with abnormal results who either are asymptomatic or have non-specific complaints such as tiredness and weight gain.

ok

5

-0.5

ks fre

re

0

m

m

co m

e.

0.5

ks f

LogTSH (mlU/L)

1.0

m

Presenting problems in thyroid disease

1.5

m

re e

eb

m

2.0

18

sf

oo eb

the TSH receptor or other thyroid antigens (see Box 18.8), radioisotope imaging, fine needle aspiration biopsy and ultrasound. Their use is described below.

m

2.5

m

oo k

ks

eb oo ks

fre

fre

iodide (I–) is actively transported into the follicular cell (‘trapping’). (3) Iodide is transported on to the colloidal surface by a transporter (pendrin, defective in Pendred’s syndrome, p. 650) and ‘organified’ by the thyroid peroxidase enzyme, which incorporates it into the amino acid tyrosine on the surface of Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). (4) Iodinated tyrosines couple to form T3 and T4. (5) Tg is endocytosed. (6) Tg is cleaved by proteolysis to free the iodinated tyrosine and thyroid hormones. (7) Iodinated tyrosine is dehalogenated to recycle the iodide. (8) T4 is converted to T3 by 5′-monodeiodinase.

Primary thyrotoxicosis

Normal

Over-treatment of hypothyroidism with levothyroxine Factitious thyrotoxicosis

Normal1

Raised

Primary T3 toxicosis

U.D.

Normal1

Normal1

Subclinical thyrotoxicosis

Raised

Low or normal

Non-thyroidal illness Amiodarone therapy

ks

oo

eb

eb

m

m

Raised

Over-treatment of hypothyroidism with liothyronine (T3)

Low

Secondary hypothyroidism4 Transient thyroiditis in evolution

Low

Low2

Mildly elevated 5–20 mIU/L

Low

2

Elevated > 20 mIU/L

Low

co m

fre e.

Primary hypothyroidism

Normal

Normal

Subclinical hypothyroidism

Elevated 20–500 mIU/L

Normal

Normal

Artefact Heterophilic antibodies (host antibodies with affinity to the animal antibodies used in TSH assays)

Elevated

Raised

Raised

Non-adherence to levothyroxine replacement – recent ‘loading’ dose Secondary thyrotoxicosis4 Thyroid hormone resistance

oo

eb

m

m

eb

m

oo

Mildly elevated 5–20 mIU/L

3

oo

2

ks

Low2

ks

Primary hypothyroidism Secondary hypothyroidism4

fre

Low

Secondary hypothyroidism4

oo ks

m e. co

ks fre

Normal

e. co m

Low Low

eb

eb o

m

ks

U.D.

ok s

Raised

U.D. or low

eb

Raised

Raised

oo eb

m

Most likely interpretation(s)

U.D. or low

U.D.

m

T3

U.D.

U.D. or low

fre

T4

ks f

TSH

re

18.5  How to interpret thyroid function test results

oo

fre e. c

e. co m

om

m

e. co

636 • Endocrinology

om

ks

ks oo

eb

m

m

ok

sf

re

e.

co

e. co sf re ok

oo

eb

m

m

co

e.

fre

eb o

m

co e. re sf

The first-line investigations are serum T3, T4 and TSH. If abnormal values are found, the tests should be repeated and the abnormality confirmed in view of the likely need for prolonged medical treatment or destructive therapy. In most patients, serum T3 and T4 are both elevated, but T4 is in the upper part of the reference range and T3 is raised (T3 toxicosis) in about 5%. Serum TSH is undetectable in primary thyrotoxicosis, but values can be raised in the very rare syndrome of secondary thyrotoxicosis caused by a TSH-producing pituitary adenoma. When biochemical thyrotoxicosis has been confirmed, further investigations should be undertaken to determine the underlying cause, including measurement of TSH receptor antibodies (TRAb, elevated in Graves’ disease; Box 18.8) and radioisotope scanning, as shown in Figure 18.5. Other non-specific abnormalities are common

m

0.1

1 ln a series of 2087 patients presenting to the Royal Infirmary of Edinburgh over a 10-year period. 2Characterised by negligible radioisotope uptake. 3i.e. Ovarian teratoma containing thyroid tissue. 4Human chorionic gonadotrophin has thyroid-stimulating activity. (TSH = thyroid-stimulating hormone)

ok

Investigations

ok s

oo eb

0.2 –

m

Follicular carcinoma ± metastases

co

ks fre

re

0.2 –

ks f oo

TSH-induced TSH-secreting pituitary adenoma Choriocarcinoma and hydatidiform mole4

e.

e.

1 – –

Extrathyroidal source of thyroid hormone Factitious thyrotoxicosis2 Struma ovarii2,3

.c

eb

m

5

m

Iodide-induced Drugs (amiodarone)2 Radiographic contrast media2 Iodine supplementation programme2

eb

14

3 0.5

co m

Thyroiditis Subacute (de Quervain’s)2 Post-partum2

m

m

Solitary thyroid adenoma

m

eb

76

Multinodular goitre

ok s

oo

Graves’ disease

m

sf

Frequency1 (%)

Cause

Figure 18.5. The most common symptoms are weight loss with a normal or increased appetite, heat intolerance, palpitations, tremor and irritability. Tachycardia, palmar erythema and lid lag are common signs. Not all patients have a palpable goitre, but experienced clinicians can discriminate the diffuse soft goitre of Graves’ disease from the irregular enlargement of a multinodular goitre. All causes of thyrotoxicosis can cause lid retraction and lid lag, due to potentiation of sympathetic innervation of the levator palpebrae muscles, but only Graves’ disease causes other features of ophthalmopathy, including periorbital oedema, conjunctival irritation, exophthalmos and diplopia. Pretibial myxoedema (p. 646) and the rare thyroid acropachy (a periosteal hypertrophy, indistinguishable from finger clubbing) are also specific to Graves’ disease.

oo k

ks

eb oo ks

18.6  Causes of thyrotoxicosis and their relative frequencies

re e

fre

fre

e. co

e. co

m

m

1 Usually upper part of reference range. 2T3 is not a sensitive indicator of hypothyroidism and should not be requested. 3Usually lower part of reference range. 4i.e. Secondary to pituitary or hypothalamic disease. Note that TSH assays may report detectable TSH. (TSH = thyroid-stimulating hormone; U.D. = undetectable)

oo

m

m

eb

eb

eb ~30–40

.c

re e

ks

sf

oo

oo k

eb

eb

5–20

0

50–70

80–95

80–90

10–20

m

m

TSH receptor2

~30–40

0

~30–40 2

0

e.

e.

e.

Thyroglobulin

m

Transient thyroiditis

18

co

~30–40

m

Multinodular goitre

co

90–100

om

m fre

ks

oo

eb

8–27 50–80

co m

Ileus, ascites Pericardial and pleural effusions Cerebellar ataxia Myotonia

Antibodies to:

Thyroid peroxidase1

Autoimmune hypothyroidism

ks

fre e.

co m

Hoarse voice Facial features: Purplish lips Malar flush Periorbital oedema Loss of lateral eyebrows Anaemia Carotenaemia Erythema ab igne Bradycardia hypertension Delayed relaxation of reflexes Dermal myxoedema

oo

oo ks

fre

e. co m

m

m

eb

eb

eb o m

m

Graves’ disease

1

e. co

m

m

e. co

e. co

fre

18.8  Prevalence of thyroid autoantibodies (%)

Normal population

Weight gain

Psychosis (myxoedema madness) Galactorrhoea Impotence

Gynaecomastia Spider naevi Onycholysis Pigmentation

ln Graves’ disease only. 2Features found particularly in elderly patients.

eb oo ks

1

ks

Constipation Hoarseness Carpal tunnel syndrome Alopecia Aches and pains Muscle stiffness Deafness Depression Infertility

Signs

oo

Goitre with bruit1 Atrial fibrillation2 Systolic hypertension/increased pulse pressure Cardiac failure2 Hyper-reflexia Ill-sustained clonus Proximal myopathy Bulbar myopathy2

ks fre oo eb

m

fre

Weight gain Cold intolerance Fatigue, somnolence Dry skin Dry hair Menorrhagia

Less common Osteoporosis (fracture, loss of height) Diarrhoea, steatorrhoea Angina Ankle swelling Anxiety, psychosis Muscle weakness Periodic paralysis (predominantly in Chinese and other Asian groups) Pruritus, alopecia Amenorrhoea/oligomenorrhoea Infertility, spontaneous abortion Loss of libido, impotence Excessive lacrimation

Symptoms

ks

Weight loss Tremor Palmar erythema Sinus tachycardia Lid retraction, lid lag

ok s

Signs

Common Weight loss despite normal or increased appetite Heat intolerance, sweating Palpitations, tremor Dyspnoea, fatigue Irritability, emotional lability

Rare Vomiting Apathy Anorexia Exacerbation of asthma

m

Hypothyroidism

Symptoms

m

m

eb

oo

ks f

Thyrotoxicosis

ks

re

18.7  Clinical features of thyroid dysfunction

oo

fre e. c

e. co m

om

m e. co

The thyroid gland • 637

oo

eb

m

Management

Definitive treatment of thyrotoxicosis depends on the underlying cause and may include antithyroid drugs, radioactive iodine or surgery. A non-selective β-adrenoceptor antagonist (β-blocker), such as propranolol (160 mg daily) or nadolol (40–80 mg daily), will alleviate but not abolish symptoms in most patients within 24–48 hours. Beta-blockers should not be used for long-term

m

ok s

ok

sf

re

e.

co

e. co

sf re

ok

ks

fre

ok s

eb o

conventional thyrotoxicosis) is increased to above 70 : 1 because circulating T3 in factitious thyrotoxicosis is derived exclusively from the peripheral monodeiodination of T4 and not from thyroid secretion. The combination of negligible iodine uptake, high T4:T3 ratio and a low or undetectable thyroglobulin is diagnostic.

m

oo

eb

m

m

co

e.

re

sf ok

m

eb

oo

(Box 18.9). An electrocardiogram (ECG) may demonstrate sinus tachycardia or atrial fibrillation. Radio-iodine uptake tests measure the proportion of isotope that is trapped in the whole gland but have been largely superseded by 99m technetium scintigraphy scans, which also indicate trapping, are quicker to perform with a lower dose of radioactivity, and provide a higher-resolution image. In low-uptake thyrotoxicosis, the cause is usually a transient thyroiditis (p. 646). Occasionally, patients induce ‘factitious thyrotoxicosis’ by consuming excessive amounts of a thyroid hormone preparation, most often levothyroxine. The exogenous levothyroxine suppresses pituitary TSH secretion and hence iodine uptake, serum thyroglobulin and release of endogenous thyroid hormones. The T4:T3 ratio (typically 30 : 1 in

m

ks f

ks fre

re

Thyroid peroxidase (TPO) antibodies are the principal component of what was previously measured as thyroid ‘microsomal’ antibodies. Thyroid-stimulating hormone receptor antibodies (TRAb) can be agonists (stimulatory, causing Graves’ thyrotoxicosis) or antagonists (‘blocking’, causing hypothyroidism).

fre

oo eb m co m fre e.

ks

ks

oo eb m om

Graves’ disease

re e

.c

Toxic multinodular goitre

fre

m

m

m

ks

ok s

fre

e.

co

co

oo

eb

eb o

Atrial fibrillation occurs in about 10% of patients with thyrotoxicosis. The incidence increases with age, so that almost half of all males with thyrotoxicosis over the age of 60 are affected. Moreover, subclinical thyrotoxicosis (p. 642) is a risk factor for atrial fibrillation. Characteristically, the ventricular rate is little influenced by digoxin but responds to the addition of a β-blocker. Thromboembolic vascular complications are particularly common in thyrotoxic atrial fibrillation so that anticoagulation is required, unless contraindicated. Once thyroid hormone and TSH concentrations have been returned to normal, atrial fibrillation will spontaneously revert to sinus rhythm in about 50% of patients but cardioversion may be required in the remainder.

m

m

ok

sf

re

e.

co

e. co

sf re ok

oo

eb

eb

m

m

co

sf

re

e.

*These abnormalities are not useful in differential diagnosis, so the tests should be avoided and any further investigation undertaken only if abnormalities persist when the patient is euthyroid.

ok

Atrial fibrillation in thyrotoxicosis

m

• Serum enzymes: raised creatine kinase, aspartate aminotransferase, lactate dehydrogenase (LDH) • Hypercholesterolaemia • Anaemia: normochromic normocytic or macrocytic • Hyponatraemia

treatment of thyrotoxicosis but are extremely useful in the short term, while patients are awaiting hospital consultation or following 131I therapy. Verapamil may be used as an alternative to β-blockers, e.g. in patients with asthma, but usually is only effective in improving tachycardia and has little effect on the other systemic manifestations of thyrotoxicosis.

m

oo

eb

Hypothyroidism

m

eb

oo

ks f

ks fre

re

• Serum enzymes: raised alanine aminotransferase, γ-glutamyl transferase (GGT), and alkaline phosphatase from liver and bone • Raised bilirubin • Mild hypercalcaemia • Glycosuria: associated diabetes mellitus, ‘lag storage’ glycosuria

e.

e.

Thyrotoxicosis

co m

18.9  Non-specific laboratory abnormalities in thyroid dysfunction*

ks

sf

oo k

ks

oo

eb

m

m

eb oo ks

Fig. 18.5  Establishing the differential diagnosis in thyrotoxicosis. 1Graves’ ophthalmopathy refers to clinical features of exophthalmos and periorbital and conjunctival oedema, not simply the lid lag and lid retraction that can occur in all forms of thyrotoxicosis. 2Thyroid-stimulating hormone (TSH) receptor antibodies are very rare in patients without autoimmune thyroid disease but occur in only 80–95% of patients with Graves’ disease; a positive test is therefore confirmatory but a negative test does not exclude Graves’ disease. Other thyroid antibodies (e.g. anti-peroxidase and anti-thyroglobulin antibodies) are unhelpful in the differential diagnosis since they occur frequently in the population and are found with several of the disorders that cause thyrotoxicosis. 3 Scintigraphy is not necessary in most cases of drug-induced thyrotoxicosis. 4 99mTechnetium pertechnetate scans of patients with thyrotoxicosis. In low-uptake thyrotoxicosis, most commonly due to a viral, post-partum or iodine-induced thyroiditis, there is negligible isotope detected in the region of the thyroid, although uptake is apparent in nearby salivary glands (not shown here). In a toxic adenoma there is lack of uptake of isotope by the rest of the thyroid gland due to suppression of serum TSH. In multinodular goitre there is relatively low, patchy uptake within the nodules; such an appearance is not always associated with a palpable thyroid. In Graves’ disease there is diffuse uptake of isotope.

ok s

fre

Toxic adenoma

e. co

e. co

m

m

m

m

eb

eb

oo

oo

oo ks

fre

ks fre

Thyroid scintigraphy4

Low-uptake thyrotoxicosis • Transient thyroiditis • Extrathyroidal T4 source

ks

ks

eb

e. co

Yes

eb

m

Repeat when acute illness has resolved

No

e. co m

m

Any features of non-Graves’ thyrotoxicosis? • Recent (< 6 months) pregnancy • Neck pain/flu-like illness • Drugs (amiodarone, T4)3 • Palpable multinodular goitre or solitary nodule

m

eb o

m

Any features of Graves’ disease? • Diffuse goitre with bruit • Ophthalmopathy1 Yes • Pretibial myxoedema 2 • Positive TSH receptor antibodies

Possible non-thyroidal illness

oo

Scenario?

ok s

ks f

Clinically thyrotoxic

oo eb

m

fre e. c

↓TSH and ↑T3 ± T4

No

m

e. co m

om

m

re

e. co

638 • Endocrinology

ks oo

eb

m

om

.c ++ – +

± – ±

+ +

± –

m

eb

oo

ks

18

±

++

– –

++ –

+

++

m

m

ks

–

oo

± ±

eb

co

± ±

+ +

e.

fre

ok s

Infiltrative Amyloidosis, Riedel’s thyroiditis, sarcoidosis etc. Secondary hypothyroidism TSH deficiency

–

–

m

m 1

ok s

sf

re

e.

co

As shown in Box 18.8, thyroid autoantibodies are common in the healthy population, so might be present in anyone. ++ high titre; + more likely to be detected than in the healthy population; – not especially likely. 2Goitre: – absent; ± may be present; ++ characteristic. (TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone)

ok

e. co

sf re

ok

ks

eb

m co m

fre e.

sf

m

eb o

oo

Congenital Dyshormonogenesis Thyroid aplasia

eb

Goitre2

+ –

Transient thyroiditis Subacute (de Quervain’s) thyroiditis Post-partum thyroiditis Iodine deficiency e.g. In mountainous regions

m

m

co

e.

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Anti-TPO antibodies1

+

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e.

This is a rare but life-threatening complication of thyrotoxicosis. The most prominent signs are fever, agitation, delirium, tachycardia or atrial fibrillation and, in the older patient, cardiac failure. The Burch–Wartofsky system may be used to help establish the diagnosis (Box 18.10). Thyrotoxic crisis is a medical emergency and has a mortality of 10% despite early recognition and treatment. It is most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated thyrotoxicosis. It may also develop in known thyrotoxicosis shortly after thyroidectomy in an ill-prepared patient or within a few days of 131I therapy, when acute radiation damage may lead to a transient rise in serum thyroid hormone levels. Patients should be rehydrated and given propranolol, either orally (80 mg 4 times daily) or intravenously (1–5 mg 4 times daily). Sodium ipodate (500 mg per day orally) will restore serum T3 levels to normal in 48–72 hours. This is a radiographic contrast medium that not only inhibits the release of thyroid

ok

Autoimmune Hashimoto’s thyroiditis Spontaneous atrophic hypothyroidism Graves’ disease with TSH receptorblocking antibodies Iatrogenic Radioactive iodine ablation Thyroidectomy Drugs:   Carbimazole, methimazole, propylthiouracil   Amiodarone   Lithium

Scores should be totalled. Score ≥ 45 = likely thyrotoxic crisis; 25–44 = impending thyrotoxic crisis;  20 mIU/L to confirm the diagnosis of primary hypothyroidism. 2The usual abnormality in sick euthyroidism is a low TSH but any pattern can occur. 3Thyroid peroxidase (TPO) antibodies are highly sensitive but not very specific for autoimmune thyroid disease (see Boxes 18.8 and 18.11). 4Specialist advice is most appropriate where indicated. Secondary hypothyroidism is rare, but is suggested by deficiency of pituitary hormones or by clinical features of pituitary tumour such as headache or visual field defect (p. 683). Rare causes of hypothyroidism with goitre include dyshormonogenesis and infiltration of the thyroid (see Box 18.11).

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Temporary T4 replacement4 • After 4 months with normal TSH, reduce to 50 µg/day for 6 weeks and repeat TSH • If normal, stop T4 for 6 weeks and repeat

Thyroid ablation? • > 6 months since 131I or thyroidectomy

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Yes

Yes

No

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Relevant drugs? • Amiodarone • Lithium

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No

Repeat when acute illness has resolved

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Any features of transient thyroiditis? • Neck pain • < 12 months post-partum • Recent symptoms of thyrotoxicosis • < 6 months since 131I or thyroidectomy

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Possible non-thyroidal illness2

TSH > 20 mlU/L

No

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Scenario?

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TSH < 20 mlU/L1

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↑TSH and ↓T4

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Any features of secondary hypothyroidism? 4

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640 • Endocrinology

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The classic symptoms of hypothyroidism are, by their very nature, non-specific (see Box 18.3). There is a wide differential diagnosis for symptoms such as ‘fatigue’, ‘weight gain’ and ‘low mood’. As has been noted, outside the context of pituitary and hypothalamic disease, serum TSH is an excellent measure of an individual’s thyroid hormone status. However, some individuals believe that they have hypothyroidism despite normal serum TSH concentrations. There are a large number of websites that claim that serum TSH is not a good measure of thyroid hormone status and suggest that other factors, such as abnormalities of T4 to T3 conversion, may lead to low tissue levels of active thyroid hormones. Such websites often advocate a variety of tests of thyroid function of dubious scientific validity, including measurement of serum reverse T3, 24-hour urine T3, basal body temperature, skin iodine absorption, and levels of selenium in blood and urine. Individuals who believe they have hypothyroidism, despite normal conventional tests of thyroid function, can be difficult to manage. They require reassurance that their symptoms are being taken seriously and that organic disease has been carefully considered; if their symptoms persist, referral to a

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18

Symptoms of hypothyroidism with normal thyroid function tests

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Hypothyroidism and ischaemic heart disease are common conditions that often occur together. Although angina may remain unchanged in severity or paradoxically disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and sudden death are recognised complications of levothyroxine replacement, even using doses as low as 25 µg per day. In patients with known ischaemic heart disease, thyroid hormone

sf

This is a very rare presentation of hypothyroidism in which there is a depressed level of consciousness, usually in an elderly patient who appears myxoedematous. Body temperature may be as low as 25°C, convulsions are not uncommon, and cerebrospinal fluid (CSF) pressure and protein content are raised. The mortality rate is 50% and survival depends on early recognition and treatment of hypothyroidism and other factors contributing to the altered consciousness level, such as medication, cardiac failure, pneumonia, dilutional hyponatraemia and respiratory failure. Myxoedema coma is a medical emergency and treatment must begin before biochemical confirmation of the diagnosis. Suspected cases should be treated with an intravenous injection of 20 µg liothyronine, followed by further injections of 20 µg 3 times daily until there is sustained clinical improvement. In survivors, there is a rise in body temperature within 24 hours and, after 48–72 hours, it is usually possible to switch patients to oral levothyroxine in a dose of 50 µg daily. Unless it is apparent that the patient has primary hypothyroidism, the thyroid failure should also be assumed to be secondary to hypothalamic or pituitary disease and treatment given with hydrocortisone 100 mg IM 3 times daily, pending the results of T4, TSH and cortisol measurement (p. 680). Other measures include slow rewarming (p. 166), cautious use of intravenous fluids, broad-spectrum antibiotics and high-flow oxygen.

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Levothyroxine replacement in ischaemic heart disease

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combined replacement with T4 (levothyroxine) and T3 (liothyronine) or preparations of animal thyroid extract but this approach remains controversial and is not supported by robust evidence. Some patients remain symptomatic despite normalisation of TSH and may wish to take extra levothyroxine, which suppresses TSH. However, suppressed TSH is a risk factor for osteoporosis and atrial fibrillation (see below; subclinical thyrotoxicosis), so this approach cannot be recommended. It is important to measure thyroid function every 1–2 years once the dose of levothyroxine is stabilised. This encourages adherence to therapy and allows adjustment for variable underlying thyroid activity and other changes in levothyroxine requirements (Box 18.12). Some patients have a persistent elevation of serum TSH despite an ostensibly adequate replacement dose of levothyroxine; most commonly, this is a consequence of suboptimal adherence to therapy. There may be differences in bioavailability between the numerous generic preparations of levothyroxine and so, if an individual is experiencing marked changes in serum TSH despite optimal adherence, the prescription of a branded preparation of levothyroxine could be considered. There is some limited evidence that suggests levothyroxine absorption may be better when the drug is taken before bed and can be further optimised by adding a vitamin C supplement; such strategies may be considered in patients with malabsorption. In some poorly compliant patients, levothyroxine is taken diligently or even in excess for a few days prior to a clinic visit, resulting in the seemingly anomalous combination of a high serum T4 and high TSH (see Box 18.5).

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Women with hypothyroidism usually require an increased dose of levothyroxine in pregnancy; inadequately treated hypothyroidism in pregnancy has been associated with impaired cognitive development in the fetus. This is discussed in more detail on page 1279 (see also Box 18.18).

Ageing • Decreases T4 clearance Graves’ disease developing in patient with long-standing primary hypothyroidism • Switch from production of blocking to stimulating TSH receptor antibodies

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Hypothyroidism in pregnancy

Myxoedema coma

Decreased dose required

*Mechanism not fully established.

replacement should be introduced at low dose and increased very slowly under specialist supervision. It has been suggested that T3 has an advantage over T4, since T3 has a shorter half-life and any adverse effect will reverse more quickly, but the more distinct peak in hormone levels after each dose of T3 is a disadvantage. Coronary intervention may be required if angina is exacerbated by levothyroxine replacement therapy.

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Use of other medication • Increase T4 clearance: phenobarbital, phenytoin, carbamazepine, rifampicin, sertraline*, chloroquine* • Interfere with intestinal T4 absorption: colestyramine, sucralfate, aluminium hydroxide, ferrous sulphate, dietary fibre supplements, calcium carbonate Pregnancy or oestrogen therapy • Increases concentration of serum thyroxine-binding globulin After surgical or 131I ablation of Graves’ disease • Reduces thyroidal secretion with time Malabsorption

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Increased dose required

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18.12  Situations in which an adjustment of the dose of levothyroxine may be necessary

The thyroid gland • 641

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Thyroid scintigraphy

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Thyroid scintigraphy with 99mtechnetium should be performed in an individual with a low serum TSH and a nodular thyroid to confirm the presence of an autonomously functioning (‘hot’) nodule (see Fig. 18.5). In such circumstances, further evaluation is not necessary. ‘Cold’ nodules on scintigraphy have a much higher likelihood of malignancy, but the majority are benign and so scintigraphy is not routinely used in the evaluation of thyroid nodules when TSH is normal.

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Swellings in the anterior part of the neck most commonly originate in the thyroid and this can be confirmed by demonstrating that the swelling moves on swallowing (p. 631). It is often possible to distinguish clinically between the three main causes of thyroid swelling. There is a broad differential diagnosis of anterior neck swellings, which includes lymphadenopathy, branchial cysts, dermoid cysts and thyroglossal duct cysts (the latter are classically located in the midline and move on protrusion of the tongue). An ultrasound scan should be performed urgently, if there is any doubt as to the aetiology of an anterior neck swelling. Serum T3, T4 and TSH should be measured in all patients with a goitre or solitary thyroid nodule. The finding of biochemical thyrotoxicosis or hypothyroidism (both of which may be subclinical) should lead to investigations, as already described on pages 636 and 640.

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A lump or swelling in the thyroid gland can be a source of considerable anxiety for patients. There are numerous causes but, broadly speaking, a thyroid swelling is either a solitary nodule, a multinodular goitre or a diffuse goitre (Box 18.13). Nodular thyroid disease is more common in women and occurs in approximately 30% of the adult female population. The majority of thyroid nodules are impalpable but may be identified when imaging of the neck is performed for another reason, such as during Doppler ultrasonography of the carotid arteries or computed tomographic pulmonary angiography. Increasingly, thyroid nodules are identified during staging of patients with cancer with computed tomography (CT), magnetic resonance

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Clinical assessment and investigations

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imaging (MRI) or positron emission tomography (PET) scans. Palpable thyroid nodules occur in 4–8% of adult women and 1–2% of adult men, and classically present when the individual (or a friend or relative) notices a lump in the neck. Multinodular goitre and solitary nodules sometimes present with acute painful enlargement due to haemorrhage into a nodule. Patients with thyroid nodules often worry that they have cancer but the reality is that only 5–10% of thyroid nodules are malignant. A nodule presenting in childhood or adolescence, particularly if there is a past history of head and neck irradiation, or one presenting in an elderly patient should heighten suspicion of a primary thyroid malignancy (p. 649). The presence of cervical lymphadenopathy also increases the likelihood of malignancy. Rarely, a secondary deposit from a renal, breast or lung carcinoma presents as a painful, rapidly growing, solitary thyroid nodule. Thyroid nodules identified on PET scanning have an approximately 33% chance of being malignant.

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This typically presents with a low serum TSH, raised T4 and normal or low T3 in a patient with systemic illness who does not have clinical evidence of thyroid disease. These abnormalities are caused by decreased peripheral conversion of T4 to T3 (with conversion instead to reverse T3), altered levels of binding proteins and their affinity for thyroid hormones, and often reduced secretion of TSH. During convalescence, serum TSH concentrations may increase to levels found in primary hypothyroidism. As thyroid function tests are difficult to interpret in patients with non-thyroidal illness, it is wise to avoid performing thyroid function tests unless there is clinical evidence of concomitant thyroid disease. If an abnormal result is found, treatment should only be given with specialist advice and the diagnosis should be re-evaluated after recovery.

Thyroid lump or swelling

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Goitre likely to shrink with levothyroxine therapy. 2Usually tender.

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Non-thyroidal illness (‘sick euthyroidism’)

Medullary cell carcinoma Anaplastic carcinoma Lymphoma Metastasis

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Serum TSH is raised and serum T3 and T4 concentrations are at the lower end of the reference range. This may persist for many years, although there is a risk of progression to overt thyroid failure, particularly if antibodies to thyroid peroxidase are present or if the TSH rises above 10 mIU/L. In patients with non-specific symptoms, a trial of levothyroxine therapy may be appropriate. In those with positive autoantibodies or a TSH greater than 10 mIU/L, it is better to treat the thyroid failure early rather than risk loss to follow-up and subsequent presentation with profound hypothyroidism. Levothyroxine should be given in a dose sufficient to restore the serum TSH concentration to normal.

1

• • • •

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Serum TSH is undetectable and serum T3 and T4 are at the upper end of the reference range. This combination is most often found in older patients with multinodular goitre. These patients are at increased risk of atrial fibrillation and osteoporosis, and hence the consensus view is that they have mild thyrotoxicosis and require therapy, usually with 131I. Otherwise, annual review is essential, as the conversion rate to overt thyrotoxicosis with elevated T4 and/or T3 concentrations is 5% each year.

Subclinical hypothyroidism

• Transient thyroiditis2 • Dyshormonogenesis1 • Infiltrative: amyloidosis, sarcoidosis etc. • Riedel’s thyroiditis2

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Subclinical thyrotoxicosis

Diffuse goitre • Simple goitre • Hashimoto’s thyroiditis1 • Graves’ disease • Drugs: iodine, amiodarone, lithium • Iodine deficiency (endemic goitre)1 • Suppurative thyroiditis2 Multinodular goitre Solitary nodule • Colloid cyst • Hyperplastic nodule • Follicular adenoma • Papillary carcinoma • Follicular carcinoma

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One of the most common problems in medical practice is how to manage patients with abnormal thyroid function tests who have no obvious signs or symptoms of thyroid disease. These can be divided into three categories.

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Asymptomatic abnormal thyroid function tests

18.13  Causes of thyroid enlargement

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team specialising in medically unexplained symptoms should be considered.

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642 • Endocrinology

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B

e. fre Thyrotoxic

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2 3 Time in years Euthyroid

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Hypothyroid

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Fig. 18.7  Natural history of the thyrotoxicosis of Graves’ disease.

A and B The majority (60%) of patients have either prolonged periods of thyrotoxicosis of fluctuating severity, or periods of alternating relapse and remission. C It is the minority who experience a single short-lived episode followed by prolonged remission and, in some cases, by the eventual onset of hypothyroidism.

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The thyrotoxicosis results from the production of immunoglobulin G (IgG) antibodies directed against the TSH receptor on the thyroid follicular cell, which stimulate thyroid hormone production and proliferation of follicular cells, leading to goitre in the majority of patients. These antibodies are termed thyroid-stimulating immunoglobulins or TSH receptor antibodies (TRAb) and can be detected in the serum of 80–95% of patients with Graves’ disease. The concentration of TRAb in the serum is presumed to fluctuate to account for the natural history of Graves’ thyrotoxicosis (Fig. 18.7). Thyroid failure seen in some patients may result from the presence of blocking antibodies against the TSH receptor, and from tissue destruction by cytotoxic antibodies and cell-mediated immunity.

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Pathophysiology

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Graves’ thyrotoxicosis

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Nodules with a benign appearance on ultrasound may be observed in an ultrasound surveillance programme; when the suspicion of malignancy is very low, the patient may be reassured and discharged. In parts of the world with borderline low iodine intake, there is evidence that levothyroxine therapy, in doses that suppress serum TSH, may reduce the size of some nodules. This should not be routine practice in iodine-sufficient populations. Nodules that are suspicious for malignancy are treated by surgical excision, by either lobectomy or thyroidectomy. Nodules that are radiologically and/or cytologically indeterminate are more of a management challenge and often end up being surgically excised. Molecular techniques may, in the future, improve the diagnostic accuracy of thyroid cytology and allow a more conservative strategy for individuals with an indeterminate biopsy. Nodules in which malignancy is confirmed by formal histology are treated as described on page 649. A diffuse or multinodular goitre may also require surgical treatment for cosmetic reasons or if there is compression of local structures (resulting in stridor or dysphagia). 131I therapy may also cause some reduction in size of a multinodular goitre. Levothyroxine therapy may shrink the goitre of Hashimoto’s disease, particularly if serum TSH is elevated.

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Graves’ disease can occur at any age but is unusual before puberty and most commonly affects women aged 30–50 years. The most common manifestation is thyrotoxicosis with or without a diffuse goitre. The clinical features and differential diagnosis are described on page 635. Graves’ disease also causes ophthalmopathy and, rarely, pretibial myxoedema (p. 646). These extrathyroidal features usually occur in thyrotoxic patients but can arise in the absence of thyroid dysfunction.

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Management

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Graves’ disease

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Fine needle aspiration cytology is recommended for thyroid nodules that are suspicious for malignancy or are radiologically indeterminate. Fine needle aspiration of a thyroid nodule can be performed in the outpatient clinic, usually under ultrasound guidance. Aspiration may be therapeutic for a cyst, although recurrence on more than one occasion is an indication for surgery. Fine needle aspiration cytology cannot differentiate between a follicular adenoma and a follicular carcinoma, and in 10–20% of cases an inadequate specimen is obtained.

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Thyroid diseases are amongst the most prevalent antibodymediated autoimmune diseases and are associated with other organ-specific autoimmunity (Ch. 4 and p. 689). Autoantibodies may produce inflammation and destruction of thyroid tissue, resulting in hypothyroidism, goitre (in Hashimoto’s thyroiditis) or sometimes even transient thyrotoxicosis (‘Hashitoxicosis’), or they may stimulate the TSH receptor to cause thyrotoxicosis (in Graves’ disease). There is overlap between these conditions, since some patients have multiple autoantibodies.

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Fine needle aspiration cytology

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Autoimmune thyroid disease

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If thyroid function tests are normal, an ultrasound scan will often determine the nature of the thyroid swelling. Ultrasound can establish whether there is generalised or localised swelling of the thyroid. Inflammatory disorders causing a diffuse goitre, such as Graves’ disease and Hashimoto’s thyroiditis, demonstrate a diffuse pattern of hypoechogenicity and, in the case of Graves’ disease, increased thyroid blood flow may be seen on colour-flow Doppler. The presence of thyroid autoantibodies will support the diagnosis of Graves’ disease or Hashimoto’s thyroiditis, while their absence in a younger patient with a diffuse goitre and normal thyroid function suggests a diagnosis of ‘simple goitre’ (p. 648). Ultrasound can readily determine the size and number of nodules within the thyroid and can distinguish solid nodules from those with a cystic element. Ultrasound is used increasingly as the key investigation in defining the risk of malignancy in a nodule. Size of the nodule is not a predictor of the risk of malignancy but there are other ultrasound characteristics that are associated with a higher likelihood of malignancy. These include hypoechoicity, intranodular vascularity, the presence of microcalcification and irregular or lobulated margins. A purely cystic nodule is highly unlikely to be malignant and a ‘spongiform’ appearance is also highly predictive of a benign aetiology. Individual nodules within a multinodular goitre have the same risk of malignancy as a solitary nodule. Thyroid ultrasonography is a highly specialised investigation and the accurate stratification of risk of malignancy of a thyroid nodule requires skill and expertise.

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Thyroid ultrasound

The thyroid gland • 643

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Hypothyroidism: ~40% in first year, 80% after 15 years Most likely treatment to result in exacerbation of ophthalmopathy4

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Pregnancy or planned pregnancy within 6 months of treatment Active Graves’ ophthalmopathy4

Hypothyroidism (~25%) Transient hypocalcaemia (10%) Permanent hypoparathyroidism (1%) Recurrent laryngeal nerve palsy2 (1%)

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Patients > 40 years3 Recurrence following surgery irrespective of age Other serious comorbidity

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Previous thyroid surgery Dependence on voice, e.g. opera singer, lecturer2

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Large goitre Poor drug adherence, especially in young patients Recurrent thyrotoxicosis after course of antithyroid drugs in young patients

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Radio-iodine

Hypersensitivity rash 2% Agranulocytosis 0.2% Hepatotoxicity (with propylthiouracil) – very rare but potentially fatal > 50% relapse rate usually within 2 years of stopping drug

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Subtotal thyroidectomy1

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Disadvantages/complications

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Breastfeeding (propylthiouracil suitable)

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Contraindications

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Common indications First episode in patients 55

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Simple and multinodular goitre

15–25

26–55

Age (in years)

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These patterns can overlap and may be difficult to distinguish clinically, as iodine uptake is low in both. There is no widely accepted management algorithm, although the iodine excess renders the gland resistant to 131I. Antithyroid drugs may be effective in patients with the type I form but are ineffective in type II thyrotoxicosis. Prednisolone is beneficial in the type II form. A pragmatic approach is to commence combination therapy with an antithyroid drug and glucocorticoid in patients with significant thyrotoxicosis. A rapid response (within 1–2 weeks) usually indicates a type II picture and permits withdrawal of the antithyroid therapy; a slower response suggests a type I picture, in which case antithyroid drugs may be continued and prednisolone withdrawn. Potassium perchlorate can also be used to inhibit iodine trapping in the thyroid. If the cardiac state allows, amiodarone should be discontinued, but it has a long half-life (50–60 days) and so its effects are long-lasting. To minimise the risk of type I thyrotoxicosis, thyroid function should be measured in all patients prior to commencement of amiodarone therapy, and amiodarone should be avoided if TSH is suppressed. Hypothyroidism should be treated with levothyroxine, which can be given while amiodarone is continued.

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nodular goitre or latent Graves’ disease (an example of the Jod–Basedow effect). • type II: thyroiditis due to a direct cytotoxic effect of amiodarone administration.

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648 • Endocrinology

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*Patients with medullary carcinoma as part of multiple endocrine neoplasia (MEN) types 2 and 3 (p. 688) may present in childhood.

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> 60

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The management of thyroid cancers should be individualised and planned in multidisciplinary team meetings that include all specialists involved in the service; this should include thyroid surgeons, endocrinologists, oncologists, pathologists, radiologists and nurse specialists. Large tumours, those with adverse histological features and/or tumours with metastatic disease at presentation are usually managed by total thyroidectomy followed by a large dose of 131I (1100 or 3700 MBq (approximately 30 or 100 mCi)) to ablate any remaining normal or malignant thyroid tissue. Thereafter, long-term treatment with levothyroxine in a dose sufficient to suppress TSH (usually 150–200 µg daily) is given, as there is evidence that growth of differentiated thyroid carcinomas is TSH-dependent. Smaller tumours with no adverse histological features may require only thyroid lobectomy. Follow-up involves measurement of serum thyroglobulin, which should be undetectable in patients whose normal thyroid has been ablated and who are taking a suppressive dose of levothyroxine. Thyroglobulin antibodies may interfere with the assay and, depending on the method employed, may result in a falsely low or high result. Detectable thyroglobulin, in the absence of assay interference, is suggestive of tumour recurrence or metastases, particularly if the thyroglobulin titre is rising across serial measurements. Local recurrence or metastatic disease may be localised by ultrasound, CT, MRI and/or whole-body scanning with 131I, and may be treated with further surgery and/or 131I therapy. 131I treatment in thyroid cancer and isotope scanning both require serum TSH concentrations to be elevated (> 20 mIU/L). This may be achieved by stopping levothyroxine for 4–6 weeks, inducing symptomatic hypothyroidism, or by administering intramuscular injections of recombinant human TSH. Patients usually find the latter approach preferable but it is more expensive. Those with locally advanced or metastatic papillary and follicular carcinoma that is refractive to 131I may be considered for therapy with sorafenib or lenvatinib. These drugs are multi-targeted tyrosine kinase inhibitors and have been shown in trials to prolong progression-free survival by between 5 and 14 months. They have multiple toxicities, however, including poor appetite, weight loss, fatigue, diarrhoea, mucositis, rashes, hypertension and blood dyscrasias. The potential benefits of

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> 40*

Lymphocytes Lymphoma

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Management

co e.

Parafollicular C cells Medullary carcinoma 5–8

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This is usually a single encapsulated lesion. Spread to cervical lymph nodes is rare. Metastases are blood-borne and are most often found in bone, lungs and brain.

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98 94 9

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10-year survival (%)

20–40 40–60 > 60

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Follicular carcinoma

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75–85 10–20  2.5:1 Minor elevation of androgens* Mild hyperprolactinaemia

Congenital adrenal hyperplasia (95% 21-hydroxylase deficiency)

Pigmentation History of salt-wasting in childhood, ambiguous genitalia, or adrenal crisis when stressed Jewish background

Elevated androgens* that suppress with dexamethasone Abnormal rise in 17-OH-progesterone with ACTH

Glucocorticoid replacement administered in reverse rhythm to suppress early morning ACTH

Exogenous androgen administration

Athletes Virilisation

Low LH and FSH Analysis of urinary androgens may detect drug of misuse

Stop steroid misuse

Androgen-secreting tumour of ovary or adrenal cortex

Rapid onset Virilisation: clitoromegaly, deep voice, balding, breast atrophy

High androgens* that do not suppress with dexamethasone Low LH and FSH CT or MRI usually demonstrates a tumour

Surgical excision

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Normal or mild elevation of adrenal androgens* See investigations (p. 667)

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Weight loss Cosmetic measures Anti-androgens (Metformin, glitazones may be useful)

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Clinical features of Cushing’s syndrome (p. 667)

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Cosmetic measures Anti-androgens

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Treatment

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Investigation findings

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Cause

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18.27  Causes of hirsutism

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658 • Endocrinology

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Anovulatory menstrual cycles

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Oligomenorrhoea Secondary amenorrhoea Cystic ovaries Infertility

Androgen excess

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Hirsutism Acne

Obesity

Hyperglycaemia Elevated oestrogens

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Dyslipidaemia Hypertension

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e.

Insulin resistance

ks oo eb

eb o

ok s

*These mechanisms are interrelated; it is not known which, if any, is primary. PCOS probably represents the common endpoint of several different pathologies. (LH = luteinising hormone)

Women with PCOS are at increased risk of glucose intolerance and some authorities recommend screening for type 2 diabetes and other cardiovascular risk factors associated with the metabolic syndrome (p. 730).

m

Management

m

This should be directed at the presenting complaint but all PCOS patients who are overweight should be encouraged to lose weight, as this can improve several symptoms, including menstrual irregularity, and reduces the risk of type 2 diabetes.

ok s

ok

sf

re

e.

co

e. co

sf re

ok

ks

sf

oo k

High serum LH High serum prolactin

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eb

m

m

co

e.

re

sf

Manifestations

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e. ks fre

re

oo

ks f

Polycystic ovarian syndrome (PCOS) affects up to 10% of women of reproductive age. It is a heterogeneous disorder (Box 18.28), often associated with obesity, for which the primary cause remains uncertain. Genetic factors probably play a role, since PCOS often affects several family members. The severity and clinical features of PCOS vary markedly between individual patients but diagnosis is usually made during the investigation of hirsutism (p. 657) or amenorrhoea/oligomenorrhoea (p. 655). Infertility may also be present (p. 656). There is no universally accepted definition but it has been recommended that a diagnosis of PCOS requires the presence of two of the following three features: • menstrual irregularity • clinical or biochemical androgen excess • multiple cysts in the ovaries (most readily detected by transvaginal ultrasound; Fig. 18.15).

ok

Pituitary dysfunction

co

co m

e.

Polycystic ovarian syndrome

eb

Mechanisms*

eb

ks

oo

eb

Management

This depends on the cause (Box 18.27). Options for the treatment of PCOS and idiopathic hirsutism are similar and are described below.

m

18.28  Features of polycystic ovarian syndrome

m

m

eb oo ks

fre

fre

circumstances, other causes of androgen excess should be sought. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is diagnosed by a short ACTH stimulation test with measurement of 17-OH-progesterone (p. 676). In patients with androgen-secreting tumours, serum testosterone does not suppress following a 48-hour low-dose dexamethasone suppression test. The tumour should then be sought by CT or MRI of the adrenals and ovaries.

.c

e. co

e. co

m

m

*e.g. Serum testosterone levels in women:  144 ng/dL) is high and requires further investigation. (ACTH = adrenocorticotrophic hormone; CT = computed tomography; FH = follicle-stimulating hormone; LH = luteinising hormone; MRI = magnetic resonance imaging)

Hazards

Spironolactone Flutamide

2, 50 or 100 mg on days 1–11 of 28-day cycle with ethinylestradiol 30 µg on days 1–21 100–200 mg daily Not recommended

Hepatic dysfunction Feminisation of male fetus Progesterone receptor agonist Dysfunctional uterine bleeding Electrolyte disturbance Hepatic dysfunction

5α-reductase inhibition (prevent conversion of testosterone to active dihydrotestosterone)

Finasteride

5 mg daily

Suppression of ovarian steroid production and elevation of sex hormone-binding globulin

Oestrogen

See combination with cyproterone acetate above or Conventional oestrogen-containing contraceptive

ks oo

eb

m

om

.c

re e

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ks

sf

eb

m

m

co

ks oo

m

m

eb

eb o

ok s

fre

e.

These are shown in Figure 18.16. Individuals with Turner’s syndrome invariably have short stature from an early age and this is often the initial presenting symptom. It is probably due to haploinsufficiency of the SHOX gene, one copy of which is found on both the X and Y chromosomes, which encodes a protein that is predominantly found in bone fibroblasts. The genital tract and external genitalia in Turner’s syndrome are female in character, since this is the default developmental outcome in the absence of testes. Ovarian tissue develops normally until the third month of gestation, but thereafter there is gonadal dysgenesis with accelerated degeneration of oöcytes and increased ovarian stromal fibrosis, resulting in ‘streak ovaries’. The inability of ovarian tissue to produce oestrogen results in loss of negative feedback and elevation of FSH and LH concentrations. There is a wide variation in the spectrum of associated somatic abnormalities. The severity of the phenotype is, in part, related to

m

ok s

ok

sf

re

e.

co

e. co

sf re

ok

ks

co m

fre e.

ks

oo

oo k

eb

m

m

Clinical features

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eb

m

co

m

re

e.

For hirsutism, most patients will have used cosmetic measures, such as shaving, bleaching and waxing, before consulting a

sf

18

Turner’s syndrome affects around 1 in 2500 females. It is classically associated with a 45XO karyotype but other cytogenetic abnormalities may be responsible, including mosaic forms (e.g. 45XO/46XX or 45XO/46XY) and partial deletions of an X chromosome.

co

e.

e.

re

ks f oo

oo

eb

eb

m

m e. co fre ks oo eb

m

co m

Most women with PCOS have oligomenorrhoea, with irregular, heavy menstrual periods. This may not require treatment unless fertility is desired. Metformin (p. 746), by reducing insulin resistance, may restore regular ovulatory cycles in overweight women, although it is less effective than clomifene (p. 656) at restoring fertility as measured by successful pregnancy. Thiazolidinediones (p. 747) also enhance insulin sensitivity and restore menstrual regularity in PCOS but are contraindicated in women planning pregnancy. In women who have very few periods each year or are amenorrhoeic, the high oestrogen concentrations associated with PCOS can cause endometrial hyperplasia. Progestogens can be administered on a cyclical basis to induce regular shedding of the endometrium and a withdrawal bleed, or a progestogenimpregnated intrauterine coil can be fitted.

ok

m

fre oo ks eb m m

e. co fre eb oo ks

Turner’s syndrome

Menstrual irregularity and infertility

eb

Venous thromboembolism Hypertension Weight gain Dyslipidaemia Increased breast and endometrial carcinoma

e. co m

m

m

e. co

ks fre oo eb

m

eb

ok s

eb o

oo eb

m

Limited clinical experience; possibly less efficacious than other treatments

doctor. Electrolysis and laser treatment are effective for small areas like the upper lip and for chest hair but are expensive. Eflornithine cream inhibits ornithine decarboxylase in hair follicles and may reduce hair growth when applied daily to affected areas of the face. If conservative measures are unsuccessful, anti-androgen therapy is given (Box 18.29). The life cycle of a hair follicle is at least 3 months and no improvement is likely before this time, when follicles have shed their hair and replacement hair growth has been suppressed. Metformin and thiazolidinediones are less effective at treating hirsutism than at restoring menstrual regularity. Unless weight is lost, hirsutism will return if therapy is discontinued. The patient should know that prolonged exposure to some agents may not be desirable and they should be stopped before pregnancy.

multiple cysts (some indicated by small arrows) in the ovary (highlighted by bigger arrows) of a woman with polycystic ovarian syndrome.

Hirsutism

m

Cyproterone acetate

ks

Dose

oo

Androgen receptor antagonism

fre

fre e. c

Drug

ks f

Mechanism of action

Fig. 18.15  Polycystic ovary. A transvaginal ultrasound scan showing

m

e. co m

om

m e. co re

18.29  Anti-androgen therapy

m

The reproductive system • 659

fre e. c

fre

Psychological problems Impaired visuospatial processing Reduced IQ (ring chromosome X) Low-set ears Sensorineural/conduction hearing loss Widely spaced nipples

co m

fre

fre e.

Horseshoe kidneys and other renal and collecting system abnormalities Reduced bone mineral density

oo eb m om

.c

oo eb

m

m

co

e.

fre

ks oo eb

m

m

ok s

ok

sf

re

e.

co

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sf re

ok

ks

sf

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eb o

m

The diagnosis is typically made in adolescents who have presented with gynaecomastia and failure to progress normally through puberty. Affected individuals usually have small, firm testes. Tall stature is apparent from early childhood, reflecting characteristically long leg length associated with 47XXY, and may be exacerbated by androgen deficiency with lack of epiphyseal closure in puberty. Other clinical features may include learning difficulties and behavioural disorders, as well as an increased risk of breast cancer and type 2 diabetes in later life. The spectrum of clinical features is wide and some individuals, especially

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m

m

co

e.

re

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oo k

co

e.

ks fre

oo eb

Clinical features

Klinefelter’s syndrome affects approximately 1 in 1000 males and is usually associated with a 47XXY karyotype. However, other cytogenetic variants may be responsible, especially 46XY/47XXY mosaicism. The principal pathological abnormality is dysgenesis of the seminiferous tubules. This is evident from infancy (and possibly even in utero) and progresses with age. By adolescence, hyalinisation and fibrosis are present within the seminiferous tubules and Leydig cell function is impaired, resulting in hypogonadism.

ok

eb

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co m

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oo eb

• Post-menopausal osteoporosis: a major public health issue due to the high incidence of associated fragility fractures, especially of hip. • Hormone replacement therapy: should be prescribed only above the age of 50 for the short-term relief of symptoms of oestrogen deficiency. • Sexual activity: many older people remain sexually active. • ‘Male menopause’: does not occur, although testosterone concentrations do fall with age. Testosterone therapy in mildly hypogonadal men may be of benefit for body composition, muscle and bone. Large randomised trials are required to determine whether benefits outweigh potentially harmful effects on the prostate and cardiovascular system. • Androgens in older women: hirsutism and balding occur. In those rare patients with elevated androgen levels, this may be pathological, e.g. from an ovarian tumour.

m

eb

The diagnosis of Turner’s syndrome can be confirmed by karyotype analysis. Short stature, although not directly due to growth hormone deficiency, responds to high doses of growth hormone. Prophylactic gonadectomy is recommended for individuals with 45XO/46XY mosaicism because there is an increased risk of gonadoblastoma. Pubertal development can be induced with oestrogen therapy but causes fusion of the epiphyses and cessation of growth. The timing of pubertal induction therefore needs to be carefully planned. Adults with Turner’s syndrome require long-term oestrogen replacement therapy and should be monitored periodically for the development of aortic root dilatation, hearing loss and other somatic complications.

18.30  Gonadal function in old age

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eb oo ks

the underlying cytogenetic abnormality. Mosaic individuals may have only mild short stature and may enter puberty spontaneously before developing gonadal failure.

re e

fre

fre

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e. co

Fig. 18.16  Clinical features of Turner’s syndrome (45XO). (IGT = impaired glucose tolerance; LFTs = liver function tests)

m

ks

ks

Lymphoedema of hands and feet ( 30%)

m

m

m

m

eb

eb

oo

oo

oo ks

Streak gonads Gonadoblastoma (XY mosaic)

m

m

Inflammatory bowel disease (0.2–0.3%)

e. co m

m

ks fre

e. co

Abnormal LFTs (30 – 80%)

eb

Wide carrying angle of elbows Type 2 diabetes/IGT (10–30%)

Hypertension

m

Shield chest

eb

eb m

m

m

Bicuspid aortic valve Aortic root dilatation Coronary artery disease

Klinefelter’s syndrome

oo

oo

eb o

Webbing of neck (25–40%)

Coarctation of aorta

Diagnosis and management

ks

ks

ok s

ks f

Autoimmune thyroid disease (20%)

eb

oo

Fish-like mouth High-arched palate

e. co m

om

m

Short stature

re

e. co

660 • Endocrinology

ks

ks

ks oo

eb m m co

ok s

re sf ok

sf re ok

ok

sf

re

e.

Parathyroid carcinomas may or may not produce parathyroid hormone. 2ln multiple endocrine neoplasia (MEN) syndromes (p. 688). (CASR = calcium-sensing receptor)

e.

Parathyroid carcinoma1

oo

eb

m

m co

fre ok s eb o m

Pseudohypoparathyroidism Familial hypocalciuric hypercalcaemia

m

Autosomal dominant hypercalciuric hypocalcaemic (CASR-activating mutation)

e. co

co

Non-functioning tumours

Secondary hyperparathyroidism Chronic kidney disease Malabsorption Vitamin D deficiency

e.

e.

ks fre

oo

Hypoparathyroidism Post-surgical Autoimmune Inherited

eb

m

Hormone resistance

1

Secondary

Primary hyperparathyroidism Parathyroid adenoma Parathyroid carcinoma1 Parathyroid hyperplasia2 Tertiary hyperparathyroidism Following prolonged secondary hyperparathyroidism

m

Hormone hypersensitivity

oo

eb

m

om

.c

re e

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co

co m

e.

re ks f oo

Hormone deficiency

eb

m

Primary

18

sf

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m

m

eb

eb

oo

Hypercalcaemia is one of the most common biochemical abnormalities and is often detected during routine biochemical analysis in asymptomatic patients. However, it can present with chronic symptoms, as described below, and occasionally as an acute emergency with severe hypercalcaemia and dehydration.

18.31  Classification of diseases of the parathyroid glands Hormone excess

oo

eb

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co m

ks

oo

eb

m

Presenting problems in parathyroid disease Hypercalcaemia

ks

eb oo ks

fre

fre

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e. co

The four parathyroid glands lie behind the lobes of the thyroid and weigh between 25 and 40 mg. The parathyroid chief cells respond directly to changes in calcium concentrations via a G protein-coupled cell surface receptor (the calcium-sensing receptor) located on the cell surface (see Fig. 25.55). When serum ionised calcium levels fall, PTH secretion rises. PTH is a single-chain polypeptide of 84 amino acids. It acts on the renal tubules to promote reabsorption of calcium and reduce reabsorption of phosphate, and on the skeleton to increase osteoclastic bone resorption and bone formation. PTH also promotes the conversion of 25-hydroxyvitamin D to the active

m

m

m

Functional anatomy, physiology and investigations

fre e.

fre

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oo eb

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m

e. co m

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Parathyroid hormone (PTH) plays a key role in the regulation of calcium and phosphate homeostasis and vitamin D metabolism, as shown in Figure 24.61 (p. 1051). The consequences of altered function of this axis in gut and renal disease are covered on pages 783 and 418, respectively. Other metabolic bone diseases are explored on page 1044. Here, the investigation of hypercalcaemia and hypocalcaemia and disorders of the parathyroid glands are discussed.

ks

ks

oo

eb

eb o

m

m

m

eb

oo

Klinefelter’s syndrome is suggested by the typical phenotype in a patient with hypergonadotrophic hypogonadism and can be confirmed by karyotype analysis. Individuals with clinical and biochemical evidence of androgen deficiency require androgen replacement (see Box 18.24). There are reports of successful pregnancy occurring following ICSI therapy where spermatocytes have been retrieved from the gonads of men with Klinefelter’s syndrome.

The parathyroid glands

m

metabolite, 1,25-dihydroxyvitamin D; the 1,25-dihydroxyvitamin D, in turn, enhances calcium absorption from the gut. More than 99% of total body calcium is in bone. Prolonged exposure of bone to high levels of PTH is associated with increased osteoclastic activity and new bone formation, but the net effect is to cause bone loss with mobilisation of calcium into the extracellular fluid. In contrast, pulsatile release of PTH causes net bone gain, an effect that is exploited therapeutically in the treatment of osteoporosis (p. 1048). The differential diagnosis of disorders of calcium metabolism requires measurement of calcium phosphate, alkaline phosphatase, renal function, PTH and 25-hydroxyvitamin D. Although the parathyroid glands detect and respond to ionised calcium levels, most clinical laboratories measure only total serum calcium levels. About 50% of total calcium is bound to organic ions, such as citrate or phosphate, and to proteins, especially albumin. Accordingly, if the serum albumin level is reduced, total calcium concentrations should be ‘corrected’ by adjusting the value for calcium upwards by 0.02 mmol/L (0.08 mg/dL) for each 1 g/L reduction in albumin below 40 g/L. If albumin concentrations are significantly low, as in severe acute illness and other chronic illness such as liver cirrhosis, this correction is less accurate and measurement of ionised calcium is needed. Calcitonin is secreted from the parafollicular C cells of the thyroid gland. Although it is a useful tumour marker in medullary carcinoma of thyroid (p. 650) and can be given therapeutically in Paget’s disease of bone (p. 1053), its release from the thyroid is of no clinical relevance to calcium homeostasis in humans. Disorders of the parathyroid glands are summarised in Box 18.31.

fre

fre e. c

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ks f

Diagnosis and management

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re

those with 46XY/47XXY mosaicism, may pass through puberty normally and be identified only during investigation for infertility.

The parathyroid glands • 661

fre e. c

fre

↔ or ↑

↓

↑

↓

↑

↑

↓

↑

↓

↓

↑

↑

Characteristic phenotype (see text)

↓

↓

↔ or ↓

↑

Usually clinically obvious Serum amylase ↑

↓

↓

Variable

↓ or ↔

Treatment of hypomagnesaemia may correct hypocalcaemia

ks

ks

ks oo eb

co

m

See text

m

Due to impaired vitamin D hydroxylation Serum creatinine ↑

ok s

sf re ok

p. 1049

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eb

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e.

(↑ = levels increased; ↓ = levels reduced; ↔ = levels normal)

p. 366

e.

Acute pancreatitis

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m

↔

↓

fre

↓

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↓

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↓

Pseudohypoparathyroidism

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.c Adjust calcium upwards by 0.02 mmol/L (0.1 mg/dL) for every 1 g/L reduction in albumin below 40 g/L

sf

Hypoparathyroidism

co

↔

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↔

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↓

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co m

fre e.

Comments

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Chronic renal failure

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Serum PTH

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↓

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↔

Vitamin D deficiency

co

Alkalosis

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Serum phosphate

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↔

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ks

Hypocalcaemia is much less common than hypercalcaemia. The differential diagnosis is shown in Box 18.33. The most common

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↓

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eb

Aetiology

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co m

Ionised serum calcium

e.

Total serum calcium

sf

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ks

sf

fre

fre

eb oo ks

Hypocalcaemia

18.33  Differential diagnosis of hypocalcaemia

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ks

Treatment of severe hypercalcaemia and primary hyper­ parathyroidism is described on pages 663 and 1327, respectively. FHH does not require any specific intervention.

• Malignancy (lung, breast, myeloma, renal, lymphoma, thyroid) • Elevated 1,25-dihydroxyvitamin D (vitamin D intoxication, sarcoidosis, human immunodeficiency virus, other granulomatous disease) • Thyrotoxicosis • Paget’s disease with immobilisation • Milk-alkali syndrome • Thiazide diuretics • Glucocorticoid deficiency

ok

oo

Management

With low PTH levels

eb

oo

m

e. co

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m

• Primary or tertiary hyperparathyroidism • Lithium-induced hyperparathyroidism • Familial hypocalciuric hypercalcaemia

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eb

fre

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eb

m

With normal or elevated parathyroid hormone (PTH) levels

m

The most discriminatory investigation is measurement of PTH. If PTH levels are detectable or elevated in the presence of hypercalcaemia, then primary hyperparathyroidism is the most likely diagnosis. High plasma phosphate and alkaline phosphatase accompanied by renal impairment suggest tertiary hyperparathyroidism. Hypercalcaemia may cause nephrocalcinosis and renal tubular impairment, resulting in hyperuricaemia and hyperchloraemia. Patients with FHH can present with a similar biochemical picture to primary hyperparathyroidism but typically have low urinary calcium excretion (a ratio of urinary calcium clearance to creatinine clearance of  2.85 mmol/L (> 11.4 mg/dL)). Patients who are treated conservatively without surgery should have calcium biochemistry and renal function checked annually and bone density monitored periodically. They should be encouraged to maintain a high oral fluid intake to avoid renal stones. Occasionally, primary hyperparathyroidism presents with severe life-threatening hypercalcaemia. This is often due to dehydration and should be managed medically with intravenous fluids and bisphosphonates, as described on page 1327. If this is not effective, then urgent parathyroidectomy should be considered. Cinacalcet (p. 419) is a calcimimetic that enhances the sensitivity of the calcium-sensing receptor, so reducing PTH levels, and is licensed for tertiary hyperparathyroidism and as a treatment for patients with primary hyperparathyroidism who are unwilling to have surgery or are medically unfit.

oo

oo m

m m

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m

m

99m Tc-sestamibi scan of a patient with primary hyperparathyroidism secondary to a parathyroid adenoma. A After 1 hour, there is uptake in the thyroid gland (thick arrow) and the enlarged left inferior parathyroid gland (thin arrow). B After 3 hours, uptake is evident only in the parathyroid (thin arrow).

eb

eb o

eb

m Management

ks

ks

ok s

ks f oo

Fig. 18.17 

(p. 664). Parathyroid scanning by 99mTc-sestamibi scintigraphy (MIBI; Fig. 18.17) and an ultrasound examination can be performed prior to surgery, in an attempt to localise an adenoma; a concordant finding of tissue consistent with a parathyroid gland and uptake on the MIBI scan allows a targeted resection. Negative imaging does not exclude the diagnosis, however, and four-gland exploration may be needed.

m

fre

fre e. c

B

re

A

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664 • Endocrinology

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ks

ks oo

eb

m

m co e. fre

ks oo

ok s

eb m m co e.

ok s

re sf ok

sf re ok

re

m

m

Adenoma Carcinoma (usually functioning) Metastatic tumours

(ACTH = adrenocorticotrophic hormone)

sf

Hypopituitarism

eb o

oo eb

Pseudohypoaldosteronism Glucocorticoid resistance syndrome

e.

co

m

Non-functioning tumours

ACTH-dependent Cushing’s syndrome Secondary hyperaldosteronism

11β-hydroxysteroid dehydrogenase type 2 deficiency Liddle’s syndrome

e. co

Hormone resistance

Addison’s disease Congenital adrenal hyperplasia

m

Hormone hypersensitivity

oo

m

om

.c

re e

eb

m

m co

ks fre

re

Hormone deficiency

ok

Secondary

Non-ACTH-dependent Cushing’s syndrome Primary hyperaldosteronism Phaeochromocytoma

ks f oo eb

m

e.

e.

18.37  Classification of diseases of the adrenal glands Primary

18

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The adrenals comprise several separate endocrine glands within a single anatomical structure. The adrenal medulla is an extension of the sympathetic nervous system that secretes catecholamines into capillaries rather than synapses. Most of the adrenal cortex is made up of cells that secrete cortisol and adrenal androgens, and form part of the hypothalamic–pituitary–adrenal (HPA) axis. The small outer glomerulosa of the cortex secretes aldosterone under

Hormone excess

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fre e.

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Cortisol is the major glucocorticoid in humans. Levels are highest in the morning on waking and lowest in the middle of the night. Cortisol rises dramatically during stress, including any illness. This elevation protects key metabolic functions (such as the maintenance of cerebral glucose supply during starvation) and inhibits potentially damaging inflammatory responses to infection and injury. The clinical importance of cortisol deficiency is, therefore, most obvious at times of stress. More than 95% of circulating cortisol is bound to protein, principally cortisol-binding globulin, which is increased by oestrogens. It is the free fraction that is biologically active. Cortisol regulates cell function by binding to glucocorticoid receptors that regulate the transcription of many genes. Cortisol can also activate mineralocorticoid receptors, but it does not normally do so because most cells containing mineralocorticoid receptors also express an enzyme called 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol by converting it to cortisone. Inhibitors of 11β-HSD2 (such as liquorice) or mutations in the gene that encodes 11β-HSD2 cause cortisol to act as a mineralocorticoid, resulting in sodium retention and hypertension (see Box 18.46).

m

m

e. co

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fre

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Glucocorticoids

eb

• Osteoporosis: always exclude osteomalacia and hyperparathyroidism by checking vitamin D and calcium concentrations. • Primary hyperparathyroidism: more common with ageing. Older people can often be observed without surgical intervention. • Hypercalcaemia: may cause delirium. • Vitamin D deficiency: common because of limited exposure to the sun and reduced ability of older skin to synthesise cholecalciferol.

m

co m

e. co m

m

e. co

ks fre oo eb

Adrenal anatomy and function are shown in Figure 18.18. Histologically, the cortex is divided into three zones, but these function as two units (zona glomerulosa and zonae fasciculata/ reticularis) that produce corticosteroids in response to humoral stimuli. Pathways for the biosynthesis of corticosteroids are shown in Figure 18.19. Investigation of adrenal function is described under specific diseases below. The different types of adrenal disease are shown in Box 18.37.

18.36  The parathyroid glands in old age

The adrenal glands

m

Functional anatomy and physiology

eb

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eb

eb o

Persistent hypoparathyroidism and pseudohypoparathyroidism are treated with oral calcium salts and vitamin D analogues, either 1α-hydroxycholecalciferol (alfacalcidol) or 1,25dihydroxycholecalciferol (calcitriol). This therapy needs careful monitoring because of the risks of iatrogenic hypercalcaemia, hypercalciuria and nephrocalcinosis. Recombinant PTH is available as subcutaneous injection therapy for osteoporosis (p. 1048) and, although not currently licensed, has been used in hypoparathyroidism (but not in pseudohypoparathyroidism). It is much more expensive than calcium and vitamin D analogue therapy but has the advantage that it is less likely to cause hypercalciuria. There is no specific treatment for AHO other than to try to maintain calcium levels within the reference range using active vitamin D metabolites.

ks

ks

fre

fre e. c

ok s

the control of the renin–angiotensin system. These functions are important in the integrated control of cardiovascular, metabolic and immune responses to stress. There is increasing evidence that subtle alterations in adrenal function contribute to the pathogenesis of common diseases such as hypertension, obesity and type 2 diabetes mellitus. However, classical syndromes of adrenal hormone deficiency and excess are relatively rare.

m

m

eb

oo

Management of hypoparathyroidism

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om

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re

serum calcium and phosphate levels largely by an effect on the renal tubule), and why paternal inheritance is associated with skeletal and other abnormalities in the absence of hypocalcaemia and raised PTH values.

The adrenal glands • 665

fre e. c

ks oo eb m

co m

Androgen receptor

Glucocorticoid receptor

ks m

Renin

oo

eb

Angiotensinogen

Protein catabolism Insulin resistance Immune response Hypertension Increased appetite Memory

eb

oo

ks

Pubic and axillary hair Libido, especially females

m

m

.c re e

ks oo

oo k

eb

Renin – angiotensin – aldosterone axis

sf

ks

Aldosterone

juxtaglomerular apparatus; MR = mineralocorticoid receptor)

m

co

e.

ks oo

eb

m

m

m co

ok s

sf

re

e.

Cushing’s syndrome is caused by excessive activation of glucocorticoid receptors. It is most commonly iatrogenic, due to prolonged administration of synthetic glucocorticoids such as

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ok

sf re

e.

re

sf ok

Cushing’s syndrome

e. co

co

m

In humans, only a small proportion of circulating noradrenaline (norepinephrine) is derived from the adrenal medulla; much more is released from sympathetic nerve endings. Conversion of noradrenaline to adrenaline (epinephrine) is catalysed by catechol O-methyltransferase (COMT), which is induced by glucocorticoids.

Presenting problems in adrenal disease

m

Catecholamines

fre

ok s

Adrenal androgens are secreted in response to ACTH and are the most abundant steroids in the blood stream. They are probably important in the initiation of puberty (adrenarche). The adrenals are also the major source of androgens in adult females and may be important in female libido.

eb o

oo

eb

Adrenal androgens

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eb

oo

ks f

ks fre

re

e.

e.

co

Aldosterone is the most important mineralocorticoid. It binds to mineralocorticoid receptors in the kidney and causes sodium retention and increased excretion of potassium and protons (p. 351). The principal stimulus to aldosterone secretion is angiotensin II, a peptide produced by activation of the renin–angiotensin system (see Fig. 18.18). Renin activity in the juxtaglomerular apparatus of the kidney is stimulated by low perfusion pressure in the afferent arteriole, low sodium filtration leading to low sodium concentrations at the macula densa, or increased sympathetic nerve activity. As a result, renin activity is increased in hypovolaemia and renal artery stenosis, and is approximately doubled when standing up from a recumbent position.

Blood flow in the adrenal is centripetal, so that the medulla is bathed in high concentrations of cortisol and is the major source of circulating adrenaline. However, after surgical removal of the adrenal medullae, there appear to be no clinical consequences attributable to deficiency of circulating catecholamines.

m

co m

Mineralocorticoids

m

m

m

m

Fig. 18.18  Structure and function of the adrenal glands. (ACE = angiotensin-converting enzyme; ACTH = adrenocorticotrophic hormone; JGA =

eb

m e. co fre

Angiotensin II Cortex Zona glomerulosa

MR

om

ACE

oo eb

Cortisol

Angiotensin I

JGA

m e. co fre

Na retention K wasting Metabolic alkalosis

Androgens

fre e.

fre oo ks

eb

Adrenal cortex Zona glomerulosa

Low renal perfusion Low filtered Na Sympathetic activation

eb oo ks

fre

eb e. co m

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ks fre oo eb

Vasodilatation Vasoconstriction Tachycardia Insulin resistance

m

ACTH

Cortex Zonae fasciculata and reticularis

m Adrenal gland

β-adrenoceptor α-adrenoceptor

m

ks oo

ok s

Noradrenaline (norepinephrine)

m

Adrenaline (epinephrine)

Negative feedback

Adrenal cortex Zonae fasciculata and reticularis

Adrenal medulla

m

m

Medulla

Hypothalamic – pituitary– adrenal axis

eb o

eb

oo

ks f

re

Sympathetic nervous system

Sympathetic nervous system

e. co m

om

m

e. co

666 • Endocrinology

e. co m

fre

Aldo synthase

ks oo

Key

m

m

Glucocorticoids

eb

oo

ks

Aldosterone

Cortisol

Mineralocorticoids Androgens

Dihydrotestosterone

co m

Oestrogens

fre e.

Progesterone

Oestradiol

Enzymes in the adrenal

Enzymes outside the adrenal

fre

17β-HSD

Oestrone

5α-reductase

m

Aromatase

ks fre

e. co

Testosterone

e. co m

Androstenedione

DHEAS

Corticosterone

eb

ok s 11-deoxycortisol

m

17-OHprogesterone

17,20-lyase

11β-hydroxylase

11-deoxycorticosterone

eb o

3β-HSD

ks f

m

eb

oo

17-hydroxylase

17-OHpregnenolone

21-hydroxylase

Progesterone

Pregnenolone

fre e. c

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m e. co

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Cholesterol

The adrenal glands • 667

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m

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pigmentation because of binding to melanocortin 1 receptors on melanocytes in the skin. The high cortisol levels also overcome the capacity of 11β-HSD2 to inactivate cortisol in the kidney (p. 665), causing hypokalaemic alkalosis that aggravates myopathy and hyperglycaemia (by inhibiting insulin secretion). When the tumour that is secreting ACTH is malignant, then the onset is usually rapid and may be associated with cachexia. For these reasons, the classical features of Cushing’s syndrome are less common in ectopic ACTH syndrome; if present, they suggest that a less aggressive tumour, such as a bronchial carcinoid, is responsible. In Cushing’s disease, the pituitary tumour is usually a microadenoma ( 3:1 at 5–10 mins after 100 mg CRH IV

ks

eb

m

HDDST: > 50% suppression in serum cortisol from baseline

No

oo

fre oo ks

m

Yes

Yes

Ectopic ACTH

re e

.c

Cushing’s disease

fre

PPNAD Exogenous glucocorticoid

fre

Yes

Positive CRH test: after 100 mg hCRH IV (> 20% rise of cortisol; or 50% rise ACTH)

eb

eb

m

No

Pituitary MRI: adenoma > 6 mm

No adrenal lesion

co m

e. co m

e. co ks fre

Adrenal imaging with CT

Adenoma Carcinoma AIMAH

m

m ACTH-dependent Cushing’s syndrome

m

ACTH-independent Cushing’s syndrome

Adrenal lesion

oo

oo eb

> 3.3 pmol/L

m

m

eb o

Measure plasma ACTH

< 1.1 pmol/L on more than two occasions

oo

ks

ok s

ks f

re

Cushing’s syndrome confirmed

oo eb

e. co m

om

m

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670 • Endocrinology

oo

eb

m co e. eb

oo

ks

fre

ok s

eb o

m

ok s

ok

sf

re

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co

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sf re

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m

m

The clinical features of glucocorticoid excess are illustrated in Figure 18.20. Adverse effects are related to dose, duration of therapy, and pre-existing conditions that might be worsened by glucocorticoid therapy, such as diabetes mellitus or osteoporosis. Osteoporosis is a particularly important problem because, for a given bone mineral density, the fracture risk is greater in glucocorticoid-treated patients than in post-menopausal osteoporosis. Therefore, when systemic glucocorticoids are prescribed and the anticipated duration of steroid therapy is more than 3 months, bone-protective therapy should be considered, as detailed on page 1005. Rapid changes in glucocorticoid levels can also lead to marked mood disturbances, including depression, mania and insomnia. Glucocorticoid use also increases the white blood cell count (predominantly neutrophils), which must be taken into account when assessing patients with possible infection.

m

m

co

e.

re

sf ok

Adverse effects of glucocorticoids

m

oo

eb

The remarkable anti-inflammatory properties of glucocorticoids have led to their use in a wide variety of clinical conditions but the hazards are significant. Equivalent doses of commonly used glucocorticoids are listed in Box 18.39. Topical preparations (dermal, rectal and inhaled) can also be absorbed into the systemic circulation, and although this rarely occurs to a sufficient degree to produce clinical features of Cushing’s syndrome, it can result in significant suppression of endogenous ACTH and cortisol secretion. Severe Cushing’s syndrome can result if there is concomitant administration of inhaled glucocorticoids and strong inhibitors of the liver enzyme CYP450 3A4, such as the antiretroviral drug ritonavir (p. 324).

m

eb

oo

Therapeutic use of glucocorticoids

Hydrocortisone: 20 mg Cortisone acetate: 25 mg Prednisolone: 5 mg Dexamethasone: 0.5 mg

m

ks f

ks fre

re

e.

e.

co

Localised tumours, such as bronchial carcinoid, should be removed surgically. In patients with incurable malignancy, it is important to reduce the severity of the Cushing’s syndrome using medical therapy (see above) or, if appropriate, bilateral adrenalectomy.

• • • •

m

co m

Ectopic ACTH syndrome

m

18.39  Approximate equivalent doses of glucocorticoids

m

m

the risk of local recurrence; systemic therapy consists of the adrenolytic drug mitotane and chemotherapy, but responses are often poor.

eb

eb

oo

oo k

hormone; AIMAH = ACTH-independent macronodular adrenal hyperplasia; BIPSS = bilateral inferior petrosal sinus sampling; hCRH = human corticotrophinreleasing hormone; HDDST = high-dose dexamethasone suppression test; PPNAD = primary pigmented nodular adrenal disease)

ks

sf

ks

eb oo ks

Fig. 18.22  Determining the cause of confirmed Cushing’s syndrome. To convert pmol/L to ng/L, multiply by 4.541. (ACTH = adrenocorticotrophic

fre

ks

eb

m

ks oo

eb

m

om

ks oo

eb

m m

co

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fre

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ok s

re

(ACTH = adrenocorticotrophic hormone)

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co

m

m

m

m

ks

ok s

Addison’s disease Common causes Rare causes • Autoimmune: • Lymphoma Sporadic • Intra-adrenal haemorrhage Polyglandular (Waterhouse–Friderichsen syndromes (p. 688) syndrome following • Tuberculosis meningococcal sepsis) • Amyloidosis • HIV/AIDS • Metastatic carcinoma • Haemochromatosis • Bilateral adrenalectomy Corticosteroid biosynthetic enzyme defects • Congenital adrenal hyperplasias • Drugs: metyrapone, ketoconazole, etomidate

sf

sf re ok

ok

sf

re

e.

e. co

co

m

• Patients should be encouraged to buy a bracelet and have it engraved with the diagnosis, current treatment and a reference number for a central database • Patients should be given a hydrocortisone emergency pack and trained in the self-administration of hydrocortisone 100 mg IM; they should be advised to take the pack on holidays/trips abroad

• Withdrawal of suppressive glucocorticoid therapy • Hypothalamic or pituitary disease

eb o

eb

• Patient should carry this at all times; it should give information regarding diagnosis, steroid, dose and doctor Bracelet and emergency pack

co m

oo k

eb

m m co

oo

• Patients must have parenteral hydrocortisone if unable to take it by mouth

Steroid card

Secondary (↓ACTH)

Primary (↑ACTH)

m

eb

oo

Vomiting

18.41  Causes of adrenocortical insufficiency

ok

ks f

ks fre

re

e.

e.

• Minor operation: hydrocortisone 100 mg IM with pre-medication • Major operation: hydrocortisone 100 mg 4 times daily for 24 hrs, then 50 mg IM 4 times daily until ready to take tablets

18

sf

re e

.c

e. co

fre

ks

oo

eb

Surgery

fre e.

ks

oo

The clinical features of adrenal insufficiency are shown in Box 18.42. In Addison’s disease, either glucocorticoid or mineralocorticoid deficiency may come first, but eventually all patients fail to secrete both classes of corticosteroid. Patients may present with chronic features and/or in acute circulatory shock. With a chronic presentation, initial symptoms are often misdiagnosed as chronic fatigue syndrome or depression. In primary adrenal insufficiency, weight loss is a uniform presenting feature. Adrenocortical insufficiency should also be considered in patients with hyponatraemia, even in the absence of symptoms (p. 357). Features of an acute adrenal crisis include circulatory shock with severe hypotension, hyponatraemia, hyperkalaemia and, in some instances, hypoglycaemia and hypercalcaemia. Muscle cramps, nausea, vomiting, diarrhoea and unexplained fever

m

co m

• Febrile illness: double dose of hydrocortisone

oo

oo

eb

m

eb

m

fre

oo ks

eb

m

m

e. co

fre

eb oo ks

Clinical assessment

m

e. co

ks fre oo eb

m

m

Adrenal insufficiency results from inadequate secretion of cortisol and/or aldosterone. It is potentially fatal and notoriously variable in its presentation. A high index of suspicion is therefore required in patients with unexplained fatigue, hyponatraemia or hypotension. Causes are shown in Box 18.41. The most common is ACTH deficiency (secondary adrenocortical failure), usually because of inappropriate withdrawal of chronic glucocorticoid therapy or a pituitary tumour (p. 683). Congenital adrenal hyperplasia and Addison’s disease (primary adrenocortical failure) are rare causes.

18.40  Advice to patients on glucocorticoid replacement therapy Intercurrent stress

m

Adrenal insufficiency

e. co m

m

All glucocorticoid therapy, even if inhaled or applied topically, can suppress the HPA axis. In practice, this is likely to result in a crisis due to adrenal insufficiency on withdrawal of treatment only if glucocorticoids have been administered orally or systemically for longer than 3 weeks, if repeated courses have been prescribed within the previous year, or if the dose is higher than the equivalent of 7.5 mg prednisolone per day. In these circumstances, the drug, when it is no longer required for the underlying condition, must be withdrawn slowly at a rate dictated by the duration of treatment. If glucocorticoid therapy has been prolonged, then it may take many months for the HPA axis to recover. All patients must be advised to avoid sudden drug withdrawal. They should be issued with a steroid card and/or wear an engraved bracelet (Box 18.40). Recovery of the HPA axis is aided if there is no exogenous glucocorticoid present during the nocturnal surge in ACTH secretion. This can be achieved by giving glucocorticoid in the morning. Giving ACTH to stimulate adrenal recovery is of no value, as the pituitary remains suppressed. In patients who have received glucocorticoids for longer than a few weeks, especially if the period is months to years, it is often valuable to confirm that the HPA axis is recovering during glucocorticoid withdrawal. Withdrawal has to be very slow, usually by a dose reduction equivalent of prednisolone 1 mg per month or slower. Once the dose of glucocorticoid is reduced to a minimum (e.g. 5 mg prednisolone or 0.5 mg

dexamethasone per day), then serum cortisol can be measured at 0900 hrs before the next dose. If this is  100 nmol/L, then an ACTH stimulation test should be performed (see Box 18.43) to confirm if glucocorticoids can be withdrawn completely. Even when glucocorticoids have been successfully withdrawn, short-term replacement therapy is often advised during significant intercurrent illness occurring in subsequent months, as the HPA axis may not be able to respond fully to severe stress.

ks

fre e. c

ok s

m

eb o

oo eb

m

Management of glucocorticoid withdrawal

e. co m

om

m e. co

ks f

re

The anti-inflammatory effect of glucocorticoids may mask signs of disease. For example, perforation of a viscus may be masked and the patient may show no febrile response to an infection. Although there is debate about whether or not glucocorticoids increase the risk of peptic ulcer when used alone, they act synergistically with NSAIDs, including aspirin, to increase the risk of serious gastrointestinal adverse effects. Latent tuberculosis may be reactivated and patients on glucocorticoids are at risk of severe varicella zoster virus infection, so should avoid contact with chickenpox or shingles if they are non-immune.

The adrenal glands • 671

+

Weight loss, anorexia Malaise, weakness Nausea, vomiting Diarrhoea or constipation Postural hypotension Shock Hypoglycaemia Hyponatraemia (dilutional) Hypercalcaemia

Hypotension Shock Hyponatraemia (depletional) Hyperkalaemia

• Normal subjects: plasma cortisol > 500 nmol/L (approximately 18 µg/dL)* either at baseline or at 30 mins • Incremental change in cortisol is not a criterion

ks

ks

ks oo

eb

This is not necessary in men because testosterone from the testes is the principal androgen. In women, dehydroepiandrosterone sulphate (DHEAS) and androstenedione may be measured in a random specimen of blood, though levels are highest in the morning.

m

m

m

m

co

Other tests to establish the cause

ok s

re

e.

Patients with unexplained secondary adrenocortical insufficiency should be investigated as described on page 680. In patients with elevated ACTH, further tests are required to establish

sf

sf re

ok

oo

eb

m

m

Assessment of adrenal androgens

e. co

co

m

Treatment should not be delayed to wait for results in patients with suspected acute adrenal crisis. Here, a random blood sample should be stored for subsequent measurement of serum cortisol and, if possible, plasma ACTH; if the patient’s clinical condition permits, it may be appropriate to spend 30 minutes performing a short ACTH stimulation test (Box 18.43) before administering hydrocortisone, but delays must be avoided if there

e.

ks oo oo eb

m

om

.c

co

e.

fre

ok s

oo

eb

m

eb o

ks fre

may be present. The crisis is often precipitated by intercurrent disease, surgery or infection. Vitiligo occurs in 10–20% of patients with autoimmune Addison’s disease (p. 630).

re

Mineralocorticoid secretion in patients with suspected Addison’s disease cannot be adequately assessed by electrolyte measurements since hyponatraemia occurs in both aldosterone and cortisol deficiency (see Box 18.42 and p. 357). Hyperkalaemia is common, but not universal, in aldosterone deficiency. Plasma renin and aldosterone should be measured in the supine position. In mineralocorticoid deficiency, plasma renin activity is high, with plasma aldosterone being either low or in the lower part of the reference range.

co

e.

e.

re ks f

re e

sf

oo k

eb

m

m

co m

Assessment of mineralocorticoids

*The exact cortisol concentration depends on the cortisol assay being used. (ACTH = adrenocorticotrophic hormone; HPA = hypothalamic–pituitary–adrenal)

oo

eb

ks

oo m

m

m

Results

sf

Decreased body hair and loss of libido, especially in females

e. co

fre

ks

oo

eb

• 0 and 30 mins for plasma cortisol • 0 mins also for ACTH (on ice) if Addison’s disease is being considered (patient not known to have pituitary disease or to be taking exogenous glucocorticoids)

ok

Pigmentation of: Sun-exposed areas Pressure areas (e.g. elbows, knees) Palmar creases, knuckles Mucous membranes Conjunctivae Recent scars

Random plasma cortisol is usually low in patients with adrenal insufficiency but it may be within the reference range, yet inappropriately low, for a seriously ill patient. Random measurement of normal levels of plasma cortisol cannot therefore be used to confirm or refute the diagnosis, unless the value is above 500 nmol/L (> 18 µg/dL), which effectively excludes adrenal insufficiency. More useful is the short ACTH stimulation test (also called the tetracosactrin or short Synacthen test) described in Box 18.43. Cortisol levels fail to increase in response to exogenous ACTH in patients with primary or secondary adrenal insufficiency. These can be distinguished by measurement of ACTH (which is low in ACTH deficiency and high in Addison’s disease).

• 250 µg ACTH1–24 (Synacthen) by IM injection at any time of day

eb

–

eb

eb m

m

e. co

fre

eb oo ks

Dose

m

+

+

Assessment of glucocorticoids

• Diagnosis of primary or secondary adrenal insufficiency • Assessment of HPA axis in patients taking suppressive glucocorticoid therapy • Relies on ACTH-dependent adrenal atrophy in secondary adrenal insufficiency, so may not detect acute ACTH deficiency (e.g. in pituitary apoplexy, p. 683)

m

+

fre e.

fre

oo eb

m Use

Investigations

+

is circulatory compromise. Investigations should be performed before treatment is given in patients who present with features suggestive of chronic adrenal insufficiency.

18.43  How and when to do an ACTH stimulation test

Blood samples

+

co m

+

+

(ACTH = adrenocorticotrophic hormone)

fre

–

ks

–

ok

m e. co ks fre

–

oo ks

eb

m

Clinical features

–

Adrenal androgen insufficiency

oo

+

Congenital adrenal hyperplasia (21-hydroxylase deficiency)

ACTH excess

eb

Addison’s disease

Mineralocorticoid insufficiency

m

+

ok s

Hypopituitarism

m

+

oo

Withdrawal of exogenous glucocorticoid

eb o

ks f

Glucocorticoid insufficiency

e. co m

re

18.42  Clinical and biochemical features of adrenal insufficiency

m

fre e. c

e. co m

om

m

e. co

672 • Endocrinology

fre e. c

fre

ks oo

eb

m

om

.c

re e

ks oo

eb

m

m

co

e.

eb

oo

ks

fre

ok s

eb o

m

m

co

e.

ok s

re

sf

sf re ok

ok

co

e.

• Consider acute precipitant, such as infection • Consider adrenal or pituitary pathology (see Box 18.41)

e. co

m

• Acute hypoglycaemia: IV 10% glucose • Hyperkalaemia: should respond to volume replacement but occasionally requires specific therapy (see Box 14.17, p. 363)

18

sf

oo k

m

Correct other metabolic abnormalities

m

m

eb

• IV hydrocortisone succinate 100 mg stat, and 100 mg 4 times daily for first 12–24 hrs • Continue parenteral hydrocortisone (50–100 mg IM 4 times daily) until patient is well enough for reliable oral therapy

Identify and treat underlying cause

ks

m

fre e.

ks

oo

eb

m

There are two key questions to be resolved: is the lesion secreting hormones, and is it benign or malignant? Patients with an adrenal incidentaloma are usually asymptomatic. However, clinical signs and symptoms of excess glucocorticoids (p. 665), mineralocorticoids (see below), catecholamines (p. 666) and, in women, androgens (p. 666) should be sought. Investigations should include a dexamethasone suppression test, urine or plasma metanephrines and, in virilised women, measurement of serum testosterone, DHEAS and androstenedione. Patients with hypertension should be investigated for mineralocorticoid excess, as described below. In bilateral masses consistent with adrenocortical lesions, 17-OH-progesterone should also be measured. CT and MRI are equally effective in assessing the malignant potential of an adrenal mass, using the following parameters: • Size. The larger the lesion, the greater the malignant potential. Around 90% of adrenocortical carcinomas are over 4 cm in diameter, but specificity is poor since only approximately 25% of such lesions are malignant. • Configuration. Homogeneous and smooth lesions are more likely to be benign. The presence of metastatic lesions elsewhere increases the risk of malignancy, but as many as two-thirds of adrenal incidentalomas in patients with cancer are benign. • Presence of lipid. Adenomas are usually lipid-rich, resulting in an attenuation of below 10 Hounsfield units (HU) on

m

oo

Replace glucocorticoids

re

Clinical assessment and investigations

m

ks f

ks fre

re

e.

e.

• IV saline as required to normalise blood pressure and pulse • In severe hyponatraemia ( 10 mmol/L/day to prevent pontine demyelination (p. 358) • Fludrocortisone is not required during the acute phase of treatment

sf

It is not uncommon for a mass in the adrenal gland to be identified on a CT or MRI scan of the abdomen that has been performed for another indication. Such lesions are known as adrenal ‘incidentalomas’. The prevalence increases with age and they are present in up to 10% of adults aged 70 years and older. Eighty-five per cent of adrenal incidentalomas are nonfunctioning adrenal adenomas. The remainder includes functional tumours of the adrenal cortex (secreting cortisol, aldosterone or androgens), phaeochromocytomas, primary and secondary carcinomas, hamartomas and other rare disorders, including granulomatous infiltrations.

co

Correct volume depletion

oo

Incidental adrenal mass

eb

ks

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eb

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18.44  Management of adrenal crisis

ok

Androgen replacement with DHEAS (50 mg/day) is occasionally given to women with primary adrenal insufficiency who have symptoms of reduced libido and fatigue, but the evidence in support of this is not robust and treatment may be associated with side-effects such as acne and hirsutism.

e. co

fre

Fludrocortisone (9α-fluoro-hydrocortisone) is administered at the usual dose of 0.05–0.15 mg daily, and adequacy of replacement may be assessed by measurement of blood pressure, plasma electrolytes and plasma renin. It is indicated for virtually every patient with primary adrenal insufficiency but is not needed in secondary adrenal insufficiency.

eb oo ks

Androgen replacement

m

m

e. co

fre

Mineralocorticoid replacement

eb

co m

e. co m

fre

oo ks

eb

Adrenal replacement therapy consists of oral hydrocortisone (cortisol) 15–20 mg daily in divided doses, typically 10 mg on waking and 5 mg at around 1500 hrs. These are physiological replacement doses that should not cause Cushingoid side-effects. The dose may need to be adjusted for the individual patient but this is subjective. Excess weight gain usually indicates overreplacement, while persistent lethargy or hyperpigmentation may be due to an inadequate dose or lack of absorption. Measurement of serum cortisol levels is not usually helpful. Advice to patients dependent on glucocorticoid replacement is given in Box 18.40.

m

m

eb

oo

Glucocorticoid replacement

m

eb

eb

m

m

m

ks fre

e. co

Patients with adrenocortical insufficiency always need glucocorticoid replacement therapy and usually, but not always, mineralocorticoid therapy. There is some evidence that adrenal androgen replacement may also be beneficial in women. Other treatments depend on the underlying cause. The emergency management of adrenal crisis is described in Box 18.44.

oo

oo

ks

ok s

• Adrenocortical insufficiency: often insidious and may present with tiredness, drowsiness, delirium, falls, immobility and orthostatic hypotension. • Glucocorticoid therapy: especially hazardous in older people, who are already relatively immunocompromised and susceptible to osteoporosis, diabetes, hypertension and other complications. • ‘Physiological’ glucocorticoid replacement therapy: increased risk of adrenal crisis because adherence may be poor and there is a greater incidence of intercurrent illness. Patient and carer education, with regular reinforcement of the principles described in Box 18.40, is crucial.

eb o

oo eb

m

18.45  Glucocorticoids in old age

Management

m

e. co m

om

m e. co

ks f

re

the cause of Addison’s disease. Adrenal autoantibodies are frequently positive in autoimmune adrenal failure. If antibody tests are negative, imaging of the adrenal glands with CT or MRI is indicated. Tuberculosis causes adrenal calcification, visible on plain X-ray or ultrasound scan. A human immunodeficiency virus (HIV) test should be performed if risk factors for infection are present (p. 310). Adrenal metastases are a rare cause of adrenal insufficiency. Patients with evidence of autoimmune adrenal failure should be screened for other organ-specific autoimmune diseases, such as thyroid disease, pernicious anaemia and type 1 diabetes.

The adrenal glands • 673

fre e. c

fre

eb

oo

ks

ks

oo

m

co m

fre e.

eb

oo

ks

ks

m

om

.c

re e

eb

oo

ks

sf

oo k

m

m

co

e.

eb

oo

ks

fre

m

m

ok s

ok

sf

re

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co

e. co

sf re ok

eb

m m

m

co

e.

(11β-HSD2 = 11β-hydroxysteroid dehydrogenase type 2; ACTH = adrenocorticotrophic hormone)

Imaging with CT or MRI will identify most APAs (Fig. 18.23) but it is important to recognise the risk of false positives (non-functioning adrenal adenomas are common) and false negatives (imaging may have insufficient resolution to identify adenomas with a diameter of less than 0.5 cm). If the imaging is inconclusive and there is an intention to proceed with surgery on the basis of strong biochemical evidence of an APA, then adrenal vein catheterisation with measurement of aldosterone (and cortisol to confirm positioning of the catheters) is required. In some centres, this is performed even in the presence of a unilateral ‘adenoma’, to avoid inadvertent removal of an incidental non-functioning adenoma contralateral to a radiologically inapparent cause of aldosterone excess.

m

m

Ectopic ACTH syndrome Liquorice misuse (inhibition of 11β-HSD2) Liddle’s syndrome 11-deoxycorticosterone-secreting adrenal tumour Rare forms of congenital adrenal hyperplasia and 11β-HSD2 deficiency

Imaging and localisation

ok s

oo

eb

With renin low and aldosterone low (non-aldosterone-dependent activation of mineralocorticoid pathway)

re

m

m

• Adrenal adenoma secreting aldosterone (Conn’s syndrome) • Idiopathic bilateral adrenal hyperplasia • Glucocorticoid-suppressible hyperaldosteronism (rare)

eb o

ks f

ks fre

re

With renin low and aldosterone high (primary hyperaldosteronism)

oo

co

e.

e.

• Inadequate renal perfusion (diuretic therapy, cardiac failure, liver failure, nephrotic syndrome, renal artery stenosis) • Renin-secreting renal tumour (very rare)

sf

Routine blood tests may show a hypokalaemic alkalosis. Sodium is usually at the upper end of the reference range in primary hyperaldosteronism, but is characteristically low in secondary hyperaldosteronism (because low plasma volume stimulates vasopressin (antidiuretic hormone, ADH) release and high angiotensin II levels stimulate thirst). The key measurements are plasma renin and aldosterone (Box 18.46), and in many centres the aldosterone : renin ratio (ARR) is employed as a screening test for primary hyperaldosteronism in hypertensive patients. Almost all antihypertensive drugs interfere with this ratio (β-blockers inhibit while diuretics stimulate renin secretion). Thus, individuals with an elevated ARR require further testing after stopping antihypertensive drugs for at least 4 weeks. If necessary, antihypertensive agents that have minimal effects on the renin–angiotensin system, such as calcium antagonists and α-blockers, may be substituted. Oral potassium supplementation may also be required, as hypokalaemia itself suppresses renin activity. If, on repeat testing, plasma renin is low and aldosterone concentrations are elevated, then further investigation under specialist supervision may include suppression tests (sodium loading) and/or stimulation tests (captopril or furosemide administration) to differentiate angiotensin II-dependent aldosterone secretion in idiopathic hyperplasia from autonomous aldosterone secretion typical of an APA.

e. co

fre

ks

oo

eb

m

co m

With renin high and aldosterone high (secondary hyperaldosteronism)

ok

oo

m

m

m

e. co

fre

eb oo ks

18.46  Causes of mineralocorticoid excess

eb

Investigations

eb

fre

oo ks

eb

oo eb

m

m

Individuals with primary hyperaldosteronism are usually asymptomatic but may have features of sodium retention or potassium loss. Sodium retention may cause oedema, while hypokalaemia may cause muscle weakness (or even paralysis, especially in South-east Asian populations), polyuria (secondary to renal tubular damage, which produces nephrogenic diabetes insipidus) and occasionally tetany (because of associated metabolic alkalosis and low ionised calcium). Blood pressure is elevated but accelerated phase hypertension is rare.

Biochemical

Primary hyperaldosteronism

Estimates of the prevalence of primary hyperaldosteronism vary according to the screening tests employed, but it may occur in as many as 10% of people with hypertension. Indications to test for mineralocorticoid excess in hypertensive patients include hypokalaemia (including hypokalaemia induced by thiazide diuretics), poor control of blood pressure with conventional therapy, a family history of early-onset hypertension, or presentation at a young age. Causes of excessive activation of mineralocorticoid receptors are shown in Box 18.46. It is important to differentiate primary hyperaldosteronism, caused by an intrinsic abnormality of the adrenal glands resulting in aldosterone excess, from secondary

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Clinical features

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In patients with radiologically benign, non-functioning lesions of less than 4 cm in diameter, surgery is required only if serial imaging suggests tumour growth. Functional lesions and tumours of more than 4 cm in diameter should be considered for surgery, though many centres will not operate on tumours of more than 4 cm if all other characteristics suggest benign disease. Optimal management of patients with low-grade cortisol secretion, as demonstrated by the dexamethasone suppression test, remains to be established.

• • • • •

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Histology in a sample obtained by CT-guided biopsy is rarely indicated, and is not useful in distinguishing an adrenal adenoma from an adrenocortical carcinoma. Biopsy is occasionally helpful in confirming adrenal metastases from other cancers, but should be avoided if either phaeochromocytoma or primary adrenal cancer is suspected in order to avoid precipitation of a hypertensive crisis or seeding of tumour cells, respectively.

hyperaldosteronism, which is usually a consequence of enhanced activity of renin in response to inadequate renal perfusion and hypotension. Most individuals with primary hyperaldosteronism have bilateral adrenal hyperplasia (idiopathic hyperaldosteronism), while only a minority have an aldosterone-producing adenoma (APA; Conn’s syndrome). Glucocorticoid-suppressible hyperaldosteronism is a rare autosomal dominant condition in which aldosterone is secreted ‘ectopically’ from the adrenal zonae fasciculata/reticularis in response to ACTH. Rarely, the mineralocorticoid receptor pathway in the distal nephron is activated, even though aldosterone concentrations are low.

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an unenhanced CT, and in signal dropout on chemical shift MRI. • Enhancement. Benign lesions demonstrate rapid washout of contrast, whereas malignant lesions tend to retain contrast.

Management

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674 • Endocrinology

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Management

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In functioning tumours, medical therapy is required to prepare the patient for surgery, preferably for a minimum of 6 weeks,

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These are rare neuro-endocrine tumours that may secrete catecholamines (adrenaline/epinephrine, noradrenaline/ norepinephrine). Approximately 80% of these tumours occur in the adrenal medulla (phaeochromocytomas), while 20% arise elsewhere in the body in sympathetic ganglia (paragangliomas). Most are benign but approximately 15% show malignant features. Around 40% are associated with inherited disorders, including neurofibromatosis (p. 1131), von Hippel–Lindau syndrome (p. 1132), MEN 2 and MEN 3 (p. 688). Paragangliomas are particularly associated with mutations in the succinate

Phaeochromocytomas are usually identified by abdominal CT or MRI (Fig. 18.24). Localisation of paragangliomas may be more difficult. Scintigraphy using meta-iodobenzyl guanidine (MIBG) can be useful, particularly if combined with CT, for adrenal phaeochromocytoma but is often negative in paraganglioma. 18 F-deoxyglucose PET is especially useful for detection of malignant disease and for confirming an imaging abnormality as a paraganglioma in an individual with underlying risk due to genetic mutation. Less widely available, 68gallium dotatate PET/ CT imaging has high sensitivity for paraganglioma.

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Phaeochromocytoma and paraganglioma

Localisation

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Mineralocorticoid receptor antagonists (spironolactone and eplerenone) are valuable in treating both hypokalaemia and hypertension in all forms of mineralocorticoid excess. Up to 20% of males develop gynaecomastia on spironolactone. Amiloride (10–40 mg/day), which blocks the epithelial sodium channel regulated by aldosterone, is an alternative. In patients with an APA, medical therapy is usually given for a few weeks to normalise whole-body electrolyte balance before unilateral adrenalectomy. Laparoscopic surgery cures the biochemical abnormality but, depending on the pre-operative duration, hypertension remains in as many as 70% of cases, probably because of irreversible damage to the systemic microcirculation.

sf

Excessive secretion of catecholamines can be confirmed by measuring metabolites in plasma and/or urine (metanephrine and normetanephrine). There is a high ‘false-positive’ rate, as misleading metanephrine concentrations may be seen in stressed patients (during acute illness, following vigorous exercise or severe pain) and following ingestion of some drugs such as tricyclic antidepressants. For this reason, a repeat sample should usually be requested if elevated levels are found, although, as a rule, the higher the concentration of metanephrines, the more likely the diagnosis of phaeochromocytoma/paraganglioma. Serum chromogranin A is often elevated and may be a useful tumour marker in patients with non-secretory tumours and/or metastatic disease. Genetic testing should be considered in individuals with other features of a genetic syndrome, in those with a family history of phaeochromocytoma/paraganglioma, and in those presenting under the age of 50 years.

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Management

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Investigations

syndrome. A CT scan of left adrenal adenoma (arrow). B The tumour is ‘canary yellow’ because of intracellular lipid accumulation.

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These depend on the pattern of catecholamine secretion and are listed in Box 18.47. Some patients present with hypertension, although it has been estimated that phaeochromocytoma accounts for less than 0.1% of cases of hypertension. The presentation may be with a complication of hypertension, such as stroke, myocardial infarction, left ventricular failure, hypertensive retinopathy or accelerated phase hypertension. The apparent paradox of postural hypotension between episodes is explained by ‘pressure natriuresis’ during hypertensive episodes so that intravascular volume is reduced. There may also be features of the familial syndromes associated with phaeochromocytoma. Paragangliomas are often non-functioning.

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Abdominal pain, vomiting Constipation Weight loss Glucose intolerance

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Clinical features

Fig. 18.23  Aldosterone-producing adenoma causing Conn’s

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• • • •

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• Hypertension (usually paroxysmal; often postural drop of blood pressure) • Paroxysms of: Pallor (occasionally flushing) Palpitations, sweating Headache Anxiety (angor animi)

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18.47  Clinical features of phaeochromocytoma

dehydrogenase B, C and D genes. Other genetic causes include mutations in SDHA, SDHAF2, TMEN127 and MAX.

B

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The adrenal glands • 675

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The aim is to replace deficient corticosteroids and to suppress ACTH-driven adrenal androgen production. A careful balance is required between adequate suppression of adrenal androgen excess and excessive glucocorticoid replacement resulting in features of Cushing’s syndrome. In children, growth velocity is an important measurement, since either under- or over-replacement with glucocorticoids suppresses growth. In adults, there is no uniformly agreed adrenal replacement regime, and clinical features (menstrual cycle, hirsutism, weight gain, blood pressure) and biochemical profiles (plasma renin, 17-OH-progesterone and testosterone levels) provide a guide. Women with late-onset 21-hydroxylase deficiency may not require corticosteroid replacement. If hirsutism is the main problem, anti-androgen therapy may be just as effective (p. 659).

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Spontaneous hypoglycaemia

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Presenting problems in endocrine pancreas disease

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A series of hormones are secreted from cells distributed throughout the gastrointestinal tract and pancreas. Functional anatomy and physiology are described on pages 723 and 848. Diseases associated with abnormalities of these hormones are listed in Box 18.48. Most are rare, with the exception of diabetes mellitus (Ch. 20).

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The endocrine pancreas and gastrointestinal tract

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Hypoglycaemia most commonly occurs as a side-effect of treatment with insulin or sulphonylurea drugs in people with

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Management

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Circulating 17-OH-progesterone levels are raised in 21-hydroxylase deficiency but this may be demonstrated only after ACTH administration in late-onset cases. To avoid salt-wasting crises in infancy, 17-OH-progesterone can be routinely measured in heelprick blood spot samples taken from all infants in the first week of life. Assessment is otherwise as described for adrenal insufficiency on page 672. In siblings of affected children, antenatal genetic diagnosis can be made by amniocentesis or chorionic villus sampling. This allows prevention of virilisation of affected female fetuses by administration of dexamethasone to the mother to suppress ACTH levels.

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Inherited defects in enzymes of the cortisol biosynthetic pathway (see Fig. 18.19) result in insufficiency of hormones downstream of the block, with impaired negative feedback and increased ACTH secretion. ACTH then stimulates the production of steroids upstream of the enzyme block. This produces adrenal hyperplasia and a combination of clinical features that depend on the severity and site of the defect in biosynthesis. All of these enzyme abnormalities are inherited as autosomal recessive traits. The most common enzyme defect is 21-hydroxylase deficiency. This results in impaired synthesis of cortisol and aldosterone, and accumulation of 17-OH-progesterone, which is then diverted to form adrenal androgens. In about one-third of cases, this defect is severe and presents in infancy with features of glucocorticoid and mineralocorticoid deficiency (see Box 18.42) and androgen excess,

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Pathophysiology and clinical features

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to allow restoration of normal plasma volume. The most useful drug in the face of very high circulating catecholamines is the α-blocker phenoxybenzamine (10–20 mg orally 3–4 times daily) because it is a non-competitive antagonist, unlike prazosin or doxazosin. If α-blockade produces a marked tachycardia, then a β-blocker such as propranolol can be added. On no account should a β-blocker be given before an α-blocker, as this may cause a paradoxical rise in blood pressure due to unopposed α-mediated vasoconstriction. During surgery, sodium nitroprusside and the short-acting α-antagonist phentolamine are useful in controlling hypertensive episodes, which may result from anaesthetic induction or tumour mobilisation. Post-operative hypotension may occur and require volume expansion and, very occasionally, noradrenaline (norepinephrine) infusion, but is uncommon if the patient has been prepared with phenoxybenzamine. Metastatic tumours may behave in an aggressive or a very indolent fashion. Management options include debulking surgery, radionuclide therapy with 131I-MIBG, chemotherapy and (chemo) embolisation of hepatic metastases; some may respond to tyrosine kinase and angiogenesis inhibitors.

Congenital adrenal hyperplasia

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phaeochromocytoma. The normal right adrenal (white arrow) contrasts with the large heterogeneous phaeochromocytoma arising from the left adrenal gland (black arrow).

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such as ambiguous genitalia in girls. In the other two-thirds, mineralocorticoid secretion is adequate but there may be features of cortisol insufficiency and/or ACTH and androgen excess, including precocious pseudo-puberty, which is distinguished from ‘true’ precocious puberty by low gonadotrophins. Sometimes the mildest enzyme defects are not apparent until adult life, when females may present with amenorrhoea and/or hirsutism (pp. 762 and 763). This is called ‘non-classical’ or ‘late-onset’ congenital adrenal hyperplasia. Defects of all the other enzymes in Figure 18.19 are rare. Both 17-hydroxylase and 11β-hydroxylase deficiency may produce hypertension due to excess production of 11-deoxycorticosterone, which has mineralocorticoid activity.

Investigations

Fig. 18.24  CT scan of abdomen showing large left adrenal

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676 • Endocrinology

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Alcohol Drugs Critical illnesses Hypopituitarism (rare) Primary adrenocortical failure (rare in adults) Non-islet cell tumour (e.g. sarcoma) Inborn errors of metabolism

Exogenous insulin

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In the acute setting, the underlying diagnosis is often obvious. In non-diabetic individuals, alcohol excess is the most common cause of hypoglycaemia in the UK but other drugs – e.g. salicylates, quinine and pentamidine – may also be implicated. Hypoglycaemia is one of many metabolic derangements that occur in patients with hepatic failure, renal failure, adrenal insufficiency, sepsis or malaria. Hypoglycaemia in the absence of insulin, or any insulin-like factor, in the blood indicates impaired gluconeogenesis and/or availability of glucose from glycogen in the liver. Hypoglycaemia associated with high insulin and low C-peptide concentrations is indicative of administration of exogenous insulin, either factitiously or feloniously. Adults with high insulin and C-peptide concentrations during an episode of hypoglycaemia are most likely to have an insulinoma but sulphonylurea ingestion should also be considered (particularly in individuals with access to such medication, such as health-care professionals or family members of someone with type 2 diabetes). Suppressed plasma β-hydroxybutyrate helps confirm inappropriate insulin secretion during fasting. Usually, insulinomas in the pancreas

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Patients who present acutely with delirium, coma or convulsions should be tested for hypoglycaemia at the bedside with a capillary blood sample and an automated meter. While this is sufficient to exclude hypoglycaemia, blood glucose meters are relatively inaccurate in the hypoglycaemic range and the diagnosis should

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What is the cause of the hypoglycaemia?

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Does the patient have a hypoglycaemic disorder?

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always be confirmed by a laboratory-based glucose measurement. At the same time, a sample should be taken for later measurement of alcohol, insulin, C-peptide, cortisol and sulphonylurea levels, if hypoglycaemia is confirmed. Taking these samples during an acute presentation prevents subsequent unnecessary dynamic tests and is of medico-legal importance in cases where poisoning is suspected. Patients who attend the outpatient clinic with episodic symptoms suggestive of hypoglycaemia present a more challenging problem. The main diagnostic test is the prolonged (72-hour) fast. If symptoms of hypoglycaemia develop during the fast, then blood samples should be taken to confirm hypoglycaemia and for later measurement of insulin and C-peptide. Hypoglycaemia is then corrected with oral or intravenous glucose and Whipple’s triad completed by confirmation of the resolution of symptoms. The absence of clinical and biochemical evidence of hypoglycaemia during a prolonged fast effectively excludes the diagnosis of a hypoglycaemic disorder.

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The clinical features of hypoglycaemia are described in the section on insulin-induced hypoglycaemia on page 738. Individuals with chronic spontaneous hypoglycaemia often have attenuated autonomic responses and ‘hypoglycaemia unawareness’, and may present with a wide variety of features of neuroglycopenia, including odd behaviour and convulsions. The symptoms are usually episodic and relieved by consumption of carbohydrate. Symptoms occurring while fasting (such as before breakfast) or following exercise are much more likely to be representative of pathological hypoglycaemia than those that develop after food (post-prandial or ‘reactive’ symptoms). Hypoglycaemia should be considered in all comatose patients, even if there is an apparently obvious cause, such as hemiplegic stroke or alcohol intoxication.

Investigations

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Measurement of insulin and C-peptide concentrations during an episode is helpful in determining the underlying cause.

diabetes mellitus. In non-diabetic individuals, symptomatic hypoglycaemia is rare, but it is not uncommon to detect venous blood glucose concentrations below 3.0 mmol/L (54 mg/dL) in asymptomatic patients. For this reason, and because the symptoms of hypoglycaemia are non-specific, a hypoglycaemic disorder should be diagnosed only if all three conditions of Whipple’s triad are met (Fig. 18.25). There is no specific blood glucose concentration at which spontaneous hypoglycaemia can be said to occur, although the lower the blood glucose concentration, the more likely it is to have pathological significance. Investigations are unlikely to be needed unless glucose concentrations below 3.0 mmol/L are observed, many patients with true hypoglycaemia demonstrating glucose levels below 2.2 mmol/L (40 mg/dL).

Clinical assessment

Insulinoma Sulphonylureas Other drugs Hyperinsulinism of infancy

Fig. 18.25  Differential diagnosis of spontaneous hypoglycaemia.

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(5-HT = 5-hydroxytryptamine, serotonin)

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Pancreatic carcinoma Pancreatic neuro-endocrine tumour

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Non-functioning tumours

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Insulin resistance syndromes (e.g. type 2 diabetes mellitus, lipodystrophy, Donohue’s syndrome)

↑ Insulin ↑ C-peptide

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Hormone resistance

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Diabetes mellitus

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Hormone deficiency

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↓ Insulin ↓ C-peptide

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Hypergastrinaemia of achlorhydria Hyperinsulinaemia after bariatric surgery

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Insulinoma Gastrinoma (Zollinger– Ellison syndrome, p. 802) Carcinoid syndrome (secretion of 5-HT) Glucagonoma VIPoma Somatostatinoma

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Primary

Whipple’s triad confirmed Patient had symptoms of hypoglycaemia Low blood glucose measured at the time of symptoms Symptoms resolved on correction of hypoglycaemia

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18.48  Classification of endocrine diseases of the pancreas and gastrointestinal tract

Hormone excess

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The endocrine pancreas and gastrointestinal tract • 677

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Glucagon

Somatostatinoma

Somatostatin

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Diabetes mellitus, necrolytic migratory erythema

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Diabetes mellitus and steatorrhoea

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• Episodic flushing, wheezing and diarrhoea • Facial telangiectasia • Cardiac involvement (tricuspid regurgitation, pulmonary stenosis, right ventricular endocardial plaques) leading to heart failure

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18.51  Clinical features of the carcinoid syndrome

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Clinical features

Patients with gastroenteropancreatic NETs often have a history of abdominal pain over many years prior to diagnosis and usually present with local mass effects, such as small-bowel obstruction, appendicitis, and pain from hepatic metastases. Thymic and bronchial carcinoids occasionally present with ectopic ACTH syndrome (p. 667). Pancreatic NETs can also cause hormone excess (Box 18.50) but most are non-functional. The classic ‘carcinoid syndrome’ (Box 18.51) occurs when vasoactive hormones reach the systemic circulation. In the case of gastrointestinal carcinoids, this invariably means that the tumour has metastasised to the liver or there are peritoneal deposits, which allow secreted hormones to gain access to the systemic circulation; hormones secreted by the primary tumour into the portal vein are metabolised and inactivated in the liver. The features of Zollinger–Ellison syndrome are described on page 802.

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Investigations

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A combination of imaging with ultrasound, CT, MRI and/or radio-labelled somatostatin analogue (Fig. 18.26) will usually identify the primary tumour and allow staging, which is crucial for determining prognosis. Biopsy of the primary tumour or a metastatic deposit is required to confirm the histological type. NETs demonstrate immunohistochemical staining for the proteins chromogranin A and synaptophysin, and the histological grade provides important prognostic information: the higher the Ki67 proliferation index, the worse the prognosis. Carcinoid syndrome is confirmed by measuring elevated concentrations of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in a 24-hour urine collection. False positives can occur, particularly if the individual has been eating certain foods, such as avocado and pineapple. Plasma chromogranin A can be measured in a fasting blood sample, along with the hormones listed in Box 18.50. All of these can be useful as tumour markers.

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Watery diarrhoea and hypokalaemia

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Vasoactive intestinal peptide (VIP)

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Neuro-endocrine tumours (NETs) are a heterogeneous group derived from neuro-endocrine cells in many organs, including the gastrointestinal tract, lung, adrenals (phaeochromocytoma, p. 675) and thyroid (medullary carcinoma, p. 650). Most NETs occur sporadically but a proportion are associated with genetic cancer syndromes, such as MEN 1, 2 and 3 and neurofibromatosis type 1 (pp. 688 and 1131). NETs may secrete hormones into the circulation. Gastroenteropancreatic NETs arise in organs that are derived embryologically from the gastrointestinal tract. Most commonly, they occur in the small bowel but they can also arise elsewhere in the bowel, pancreas, thymus and bronchi. The term ‘carcinoid’ is often used when referring to non-pancreatic gastroenteropancreatic NETs because, when initially described, they were thought to behave in an indolent fashion compared with conventional cancers. It is now recognised that there is a wide spectrum of malignant potential for all NETs; some are benign (most insulinomas and appendiceal carcinoid tumours), while others have an aggressive clinical course with widespread metastases (small-cell carcinoma of the lung). The majority of gastroenteropancreatic NETs behave in an intermediate manner, with relatively slow growth but a propensity to invade and metastasise to remote organs, especially the liver.

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Recurrent hypoglycaemia (see above)

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Insulin

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Treatment of acute hypoglycaemia should be initiated as soon as laboratory blood samples have been taken and should not be deferred until formal laboratory confirmation has been obtained. Intravenous dextrose (5% or 10%) is effective in the short term in the obtunded patient and should be followed on recovery with oral unrefined carbohydrate (starch). Continuous dextrose infusion may be necessary, especially in sulphonylurea poisoning. Intramuscular glucagon (1 mg) stimulates hepatic glucose release but is ineffective in patients with depleted glycogen reserves, such as in alcohol excess or liver disease. Chronic recurrent hypoglycaemia in insulin-secreting tumours can be treated by regular consumption of oral carbohydrate combined with agents that inhibit insulin secretion (diazoxide or somatostatin analogues). Insulinomas are resected when benign, providing the individual is fit enough to undergo surgery. Metastatic malignant insulinomas may be incurable and are managed along the same lines as other metastatic neuro-endocrine tumours (see below).

Gastroenteropancreatic neuro-endocrine tumours

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VIPoma

Peptic ulcer and steatorrhoea (Zollinger– Ellison syndrome, p. 802)

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Gastrin

Effects

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Gastrinoma

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Hormone

Insulinoma

are small ( 30 IU/L and LH > 20 IU/L) TSH deficiency • Measure random serum T4 • Note that TSH is often detectable in secondary hypothyroidism Growth hormone deficiency Only investigate if growth hormone replacement therapy is being contemplated (p. 682) • Measure immediately after exercise • Consider other stimulatory tests (see Box 18.55) Cranial diabetes insipidus Only investigate if patient complains of polyuria/polydipsia, which may be masked by ACTH or TSH deficiency • Exclude other causes of polyuria with blood glucose, potassium and calcium measurements • Water deprivation test (see Box 18.61) or 5% saline infusion test

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Identify pituitary hormone deficiency

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Although pituitary disease presents with diverse clinical manifestations (see below), the approach to investigation is similar in all cases (Box 18.53). The approach to testing for hormone deficiency is outlined in Box 18.53. Details are given in the sections on individual glands elsewhere in this chapter. Tests for hormone excess vary according to the hormone in question. For example, prolactin is not secreted in pulsatile fashion, although it rises with significant psychological stress. Assuming that the patient was not distressed by venepuncture, a random measurement of serum prolactin is sufficient to diagnose hyperprolactinaemia. In contrast, growth hormone is secreted in a pulsatile fashion. A high random level does not confirm acromegaly; the diagnosis is confirmed only by failure of growth hormone to be suppressed during an oral glucose tolerance test, and a high serum insulin-like growth factor-1 (IGF-1). Similarly, in suspected ACTH-dependent Cushing’s disease (p. 666), random measurement of plasma cortisol is unreliable and the diagnosis is usually made by a dexamethasone suppression test. The most common local complication of a large pituitary tumour is compression of the optic pathway. The resulting visual field defect can be documented using a Goldman’s perimetry chart. MRI reveals ‘abnormalities’ of the pituitary gland in as many as 10% of ‘healthy’ middle-aged people. It should therefore be performed only if there is a clear biochemical abnormality or if a patient presents with clinical features of pituitary tumour (see below). A pituitary tumour may be classified as either a macroadenoma (> 10 mm diameter) or a microadenoma ( 10 mm diameter

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*The most common causes of pituitary hormone deficiency. (CRH = corticotrophin-releasing hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotrophin-releasing hormone; TRH = thyrotrophinreleasing hormone)

Growth hormone • Lethargy

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• Post-partum necrosis (Sheehan’s syndrome) • Opiate analgesia

Hyperprolactinaemia • Galactorrhoea • Amenorrhoea • Hypogonadism

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• Head injury* • (Para)sellar surgery* • (Para)sellar radiotherapy*

Hypopituitarism

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• Excessive exercise

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Other

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• Chronic systemic illness • Anorexia nervosa

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Functional*

Hormone excess

Cushing’s disease • Weight gain • Bruising • Myopathy • Hypertension • Striae • Depression

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• TRH • CRH

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• GnRH (Kallmann’s syndrome)* • GHRH*

Local complications • Headache • Visual field defect • Disconnection hyperprolactinaemia • Diplopia (cavernous sinus involvement) • Acute infarction/expansion (pituitary apoplexy)

Acromegaly • Headache • Sweating • Change in shoe and ring size

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Congenital deficiencies

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The presentation is highly variable. For example, following radiotherapy to the pituitary region, there is a characteristic sequence of loss of pituitary hormone secretion. Growth hormone secretion is often the earliest to be lost. In adults, this produces lethargy, muscle weakness and increased fat mass but these features are not obvious in isolation. Next, gonadotrophin (LH and FSH) secretion becomes impaired with loss of libido in the male and oligomenorrhoea or amenorrhoea in the female. Later, in the male there may be gynaecomastia and decreased frequency of shaving. In both sexes, axillary and pubic hair eventually become

Chordoma Germinoma (pinealoma) Arachnoid cyst Rathke’s cleft cyst Haemorrhage (apoplexy)

• Lymphocytic hypophysitis • Haemochromatosis • Langerhans cell histiocytosis

• Sarcoidosis • Infections, e.g. pituitary abscess, tuberculosis, syphilis, encephalitis

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Clinical assessment

• • • • •

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Primary pituitary tumour Adenoma* Carcinoma (exceptionally rare) Craniopharyngioma* Meningioma* Secondary tumour (including leukaemia and lymphoma)

Inflammatory/infiltrative

Hypopituitarism describes combined deficiency of any of the anterior pituitary hormones. The clinical presentation is variable and depends on the underlying lesion and the pattern of resulting hormone deficiency. The most common cause is a pituitary macroadenoma but other causes are listed in Box 18.54.

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Hypopituitarism

Structural

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The clinical features of pituitary disease are shown in Figure 18.28. Younger women with pituitary disease most commonly present with secondary amenorrhoea (p. 654) or galactorrhoea (in hyperprolactinaemia). Post-menopausal women and men of any age are less likely to report symptoms of hypogonadism and so are more likely to present late with larger tumours causing visual field defects. Nowadays, many patients present with the incidental finding of a pituitary tumour on a CT or MRI scan.

• 681

18.54  Causes of anterior pituitary hormone deficiency

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Presenting problems in hypothalamic and pituitary disease

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The hypothalamus and the pituitary gland

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thyroid-stimulating hormone)

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Fig. 18.28  Common symptoms and signs to consider in a patient with suspected pituitary disease. (ACTH = adrenocorticotrophic hormone; TSH =

Contraindications

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Results

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• 0, 30, 45, 60, 90, 120 mins for blood glucose, plasma cortisol and growth hormone

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Blood samples

ks

• To produce adequate hypoglycaemia (tachycardia and sweating with blood glucose 6.7 µg/L (20 mIU/L)* • Normal subjects: cortisol > 550 nmol/L (approximately 20.2 µg/dL)* *The precise cut-off figure for a satisfactory cortisol and GH response depends on the assay used and so varies between centres. (GH = growth hormone; HPA = hypothalamic–pituitary–adrenal)

om

.c re e

ks oo

m

m

eb

eb

oo k

sf

TSH is not helpful in adjusting the replacement dose because patients with hypopituitarism often secrete glycoproteins that are measured in the TSH assays but are not bioactive. The aim is to maintain serum T4 in the upper part of the reference range. It is dangerous to give thyroid replacement in adrenal insufficiency without first giving glucocorticoid therapy, since this may precipitate adrenal crisis.

Sex hormone replacement

m

m

This is indicated if there is gonadotrophin deficiency in women under the age of 50 and in men to restore normal sexual function and to prevent osteoporosis (p. 1044).

co

e.

Growth hormone replacement

ks oo

eb

eb o

ok s

fre

Growth hormone (GH) is administered by daily subcutaneous self-injection to children and adolescents with GH deficiency and, until recently, was discontinued once the epiphyses had fused. However, although hypopituitary adults receiving ‘full’ replacement with hydrocortisone, levothyroxine and sex steroids are usually much improved by these therapies, some individuals remain lethargic and unwell compared with a healthy population. Some of these patients feel better, and have objective improvements in their fat:muscle mass ratio and other metabolic parameters, if they are also given GH replacement. Treatment with GH may also help young adults to achieve a higher peak bone mineral density. The principal side-effect is sodium retention, manifest as peripheral oedema or carpal tunnel syndrome if given in excess. For this reason, GH replacement should be started at a low dose, with monitoring of the response by measurement of serum IGF-1.

m

m

m

m

co

e.

ok s

re

sf ok

ok

sf re

e.

Levothyroxine 50–150 µg once daily should be given as described on page 640. Unlike in primary hypothyroidism, measuring

re

Aim

e. co

Thyroid hormone replacement

sf

• 0.15 U/kg body weight soluble insulin IV

co

e.

ks fre

oo

eb

m

co

m

Hydrocortisone should be given if there is ACTH deficiency. Suitable doses are described in the section on adrenal disease on page 672. Mineralocorticoid replacement is not required.

ok

Dose

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fre

ks

oo

eb

m

co m

e.

re

ks f

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• Ischaemic heart disease • Epilepsy • Severe hypopituitarism (0800 hrs plasma cortisol  300 mOsmol/kg with a urine osmolality  300 mOsmol/kg and urine osmolality 10% = 2

m m

co

Total = 0 – Low risk • Routine clinical care • Repeat screen weekly

e.

e.

e.

e.

ks f oo eb

Triceps skinfold thickness. Lean patients 6–12 mm; obese patients 40–50 mm.

Measurement of knee height.

BMI score > 20 = 0 18.5 – 20 = 1 < 18.5 = 2

m

m

m co

Normal activity Slightly reduced activity Inactive 30

e. co

Normal weight

25 – 30

fre

e. co

< 25

m

1 0

Accumulation of fat results from a discrepancy between energy consumption and energy expenditure that is too large to be defended by the hypothalamic regulation of BMR. A continuous small daily positive energy balance of only 0.2–0.8 MJ (50–200 kcal; 29

fre

5

• ↓ Sports in schools • ↑ Time spent on computer games and watching TV • ↑ Central heating

e. co m

25– 28.9

oo ks

6 4

m

• ↑ Car ownership • ↓ Walking to school/work • ↑ Automation; ↓ manual labour

eb

eb

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7

• ↑ Energy-dense food (fat and sugars) • ↑ Affluence

Decreasing energy expenditure

Relative risk for type 2 diabetes

ks fre 8

ks

ok s 21– 22.9 23– 24.9

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< 21

m

0

9

• ↑ Portion sizes • ↑ Snacking and loss of regular meals

m

m

1

10

Increasing energy intake

eb o

2

eb

oo

ks f

3

19.5  Some reasons for the increasing prevalence of obesity – the ‘obesogenic’ environment

 

fre

re

Relative risk for cardiovascular disease

e. co m

om

m e. co

4

Disorders of altered energy balance • 699

fre e. c

ks oo

eb

m

ks oo

eb

m

om

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re e

eb

oo

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sf

eb

m

m

m

m

co

co

e.

e.

Class III

–

ks

eb

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ok s

Very severe Very severe

Very severe

Very severe

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1

Severe Very severe

m

Moderate –

co

m

> 40.0

Class I Class II

Moderate Severe

m

30.0–34.9 35.0–39.9

Obese

Mildly increased

Moderate

co

m

> 30.0

fre

Negligible Negligible

Men > 102 cm Women > 88 cm

Men 94–102 cm Women 80–88 cm

eb o

Reference range

m

25.0–29.9

Men  25.0 is obese. Lower cut-offs for waist circumference have also been proposed for Asians but have not been validated. 2When BMI is > 35 kg/m2, waist circumference does not add to the increased risk.

ok

m

m

fre

fre

e. co

e. co

m

In assessing an individual presenting with obesity, the aims are to: • quantify the problem • exclude an underlying cause • identify complications • reach a management plan.

Drug treatments

co m

ks

Clinical features and investigations

• Hypothyroidism • Cushing’s syndrome • Insulinoma

fre

ks

oo

oo

m

m

eb

eb

eb

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oo ks

In a small minority of patients presenting with obesity, specific causal factors can be identified and treated (Box 19.6). These patients are distinguished from those with idiopathic obesity by their short history, with a recent marked change in the trajectory of their adult weight gain.

fre e.

Reversible causes of obesity and weight gain

m

m

fre

ks fre

e. co

e. co m

m

m

eb

eb o

oo eb

m

Severity of obesity can be quantified using the BMI and waist circumference. The risk of metabolic and cardiovascular complications of obesity is higher in those with a high waist circumference; lower levels of BMI and waist circumference indicate higher risk in Asian populations (Box 19.7). A dietary history may be helpful in guiding dietary advice (p. 693) but is notoriously susceptible to under-reporting of food consumption. It is important to consider ‘pathological’ eating behaviour (such as binge eating, nocturnal eating or bulimia; p. 1204), which may be the most important issue to address in some patients. Alcohol is an important source of energy intake and should be considered in detail. The history of weight gain may help diagnose underlying causes. A patient who has recently gained substantial weight or has gained weight at a faster rate than previously, and is not taking relevant drugs (see Box 19.6), is more likely to have an underlying disorder such as hypothyroidism (p. 639) or Cushing’s syndrome (p. 666). All obese patients should have thyroid function tests performed on one occasion, and an overnight dexamethasone suppression test or 24-hour urine free cortisol if Cushing’s syndrome is suspected. Monogenic and ‘syndromic’ causes of obesity are usually relevant only in children presenting with severe obesity. Assessment of the diverse complications of obesity (see Fig. 19.5) requires a thorough history, examination and screening investigations. The impact of obesity on the patient’s life and work is a major consideration. Assessment of other cardiovascular risk factors is important. Blood pressure should be measured with a large cuff, if required (p. 510). Associated type 2 diabetes and dyslipidaemia are detected by measurement of blood glucose or HbA1c and a serum lipid profile, ideally in a fasting morning sample. Elevated serum transaminases occur in patients with non-alcoholic fatty liver disease (p. 884).

ok s

ks f

re

identified a handful of genes that influence obesity, some of which encode proteins known to be involved in the control of appetite or metabolism and some of which have an unknown function. These genes account for less than 5% of the variation in body weight, however. Genes also influence fat distribution and therefore the risk of the metabolic consequences of obesity, such as type 2 diabetes and fatty liver disease. A few rare single-gene disorders have been identified that lead to severe childhood obesity. These include mutations of the melanocortin-4 receptor (MC4R), which account for approximately 5% of severe early-onset obesity; defects in the enzymes processing propiomelanocortin (POMC, the precursor for adrenocorticotrophic hormone (ACTH)) in the hypothalamus; and mutations in the leptin gene (see Fig. 19.3). The latter can be treated by leptin injections. Additional genetic conditions in which obesity is a feature include Prader–Willi (see Box 3.8, p. 51) and Lawrence–Moon–Biedl syndromes.

 

e. co m

om

m

e. co

700 • Nutritional factors in disease

fre

ks oo

ks

ks

oo

m

co

e.

30

27

Protein has greater satiety effect than other macronutrients

13

17

ok s

ok

sf

re

e.

co

Induction of ketosis may suppress hunger

e. co

ks oo

eb m

43

m

High protein (e.g. Zone)

Maintains balance in macronutrients and micronutrients while reducing energy-dense fats

30

sf re

oo

eb

m

om .c re e

fre

ok s

60

eb o

10

Comments

m

Low carbohydrate (e.g. Atkins)

m

15

ok

eb

m m

co

e.

ks fre

oo

15

25

m

sf

eb

eb

eb

30

60

m

50

co

25

include type 2 diabetes, hypertension, cardiovascular disease, sleep apnoea, and waist circumference of > 102 cm in men or 88 cm in women. This is an approximate consensus of the numerous national guidelines, which vary slightly in their recommendations and are revised every few years.

Moderate fat (e.g. Weight Watchers)

e.

↑Exercise Eating behaviour modification Treat cardiovascular risk factors

25

Normal (typical developed country)

re

Supervised low-calorie diet

Fig. 19.7  Therapeutic options for obesity. Relevant comorbidities

% Protein

sf

27

m

oo

Drugs

m

co m

e.

re

ks f oo

19

35

oo k

ks

40

% Fat

70

BMI cut-offs in presence of comorbidity

Surgery

% Carbohydrate

Low fat (e.g. Ornish)

eb

co m

fre e.

ks

oo

fre

BMI cut-offs in absence of comorbidity

19.8  Low-calorie diet therapy for obesity

Diet

ok

m

m

eb

m

e. co

m

fre

oo ks

eb

m

m

e. co

fre

eb oo ks eb

 

ks

eb

In overweight people, adherence to the lifestyle advice given above may gradually induce weight loss. In obese patients, more active intervention is usually required to lose weight before conversion to the ‘weight maintenance’ advice given above. A significant industry has developed in marketing diets for weight loss. These vary substantially in their balance of macronutrients (Box 19.8) but there is little evidence that they vary in their medium-term (1-year) efficacy. Most involve recommending a reduction of daily total energy intake of −2.5 MJ (600 kcal) from the patient’s normal consumption. Modelling data that take into account the reduced energy expenditure as weight is lost suggest that a reduction of energy intake of 100 kJ per day will lead to an eventual body weight change of about 1 kg, with half of the weight change being achieved in about 1 year and 95% of the weight change in about 3 years. Weight loss is highly variable and patient adherence is the major determinant of success. There is some evidence that weight loss diets are most effective in their early weeks and that adherence is improved by novelty of the diet; this provides some justification for switching to a different dietary regimen when weight loss slows on the first diet. Vitamin

e. co m

e. co

ks fre oo eb

Weight loss diets

30

Behavioural modification to avoid some of the effects of the ‘obesogenic’ environment (see Box 19.5) is the cornerstone of long-term control of weight. Adopting regular eating patterns and maximising physical activity are advised, with reference to the modest extra activity required to increase physical activity level (PAL) ratios (see Fig. 19.2C). Where possible, this should be incorporated in the daily routine (e.g. walking rather than driving to work), as this is more likely to be sustained. Alternative exercise (e.g. swimming) may be considered if musculoskeletal complications prevent walking. Changes in eating behaviour (including food selection, portion size control, avoidance of

m

snacking, regular meals to encourage satiety, and substitution of sugar with artificial sweeteners) should be discussed. Regular support from a dietitian or attendance at a weight loss group may be helpful.

oo

fre e. c

ok s

m

m

eb o

oo eb

m

m

Lifestyle advice

m

e. co m

om

m e. co

ks f

re

and cycling options for commuters, and liaising with the food industry to reduce energy, sugar and fat content and to label foods appropriately; taxes on high-sugar drinks have also been introduced in some countries. Unfortunately, ‘low-fat’ foods are often still energy-dense, and current lifestyles with labour-saving devices, sedentary work and passive leisure activities have much lower energy requirements than the manual labour and household duties of previous generations. Most patients seeking assistance with obesity are motivated to lose weight but have attempted to do so previously without long-term success. Often weight will have oscillated between periods of successful weight loss and then regain of weight. These patients may hold misconceptions that they have an underlying disease, inaccurate perceptions of their energy intake and expenditure, and an unrealistic view of the target weight that they would regard as a ‘success’. An empathetic explanation of energy balance, which recognises that some individuals are more susceptible to obesity than others and may find it more difficult to lose body weight and sustain this loss, is important. Exclusion of underlying ‘hormone imbalance’ with simple tests is reassuring and shifts the focus on to consideration of energy balance. Appropriate goals for weight loss should be agreed, recognising that the slope of the relationship between obesity and many of its complications becomes steeper with increasing BMI, so that a given amount of weight loss achieves greater risk reduction at higher levels of BMI. A reasonable goal for most patients is to lose 5–10% of body weight. The management plan will vary according to the severity of the obesity (see Box 19.7) and the associated risk factors and complications. It will also be influenced by availability of resources; health-care providers and regulators have generally been careful not to recommend expensive interventions (especially long-term drug therapy and surgery) for everyone who is overweight. Instead, most guidelines focus resources on short-term interventions in those who have high health risks and comorbidities associated with their obesity, and who have demonstrated their capacity to alter their lifestyle to achieve weight loss (Fig. 19.7).

Disorders of altered energy balance • 701

fre e. c

fre

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eb

ks oo

eb

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ks

sf

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ks oo

eb

m

m

co

e.

ok s

15

re

8 10 Years of follow-up

m

co

e.

-27%

m 6

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4

sf re

3

ok

co

m re

sf ok

2

e.

1

fre

m

Gastric bypass

0

-13%

ok s

Banding

-30 -35

-2%

-18% Vertical banded gastroplasty

m

-25

Control

sf

eb

-15

(B) and bariatric surgery (C) on weight loss. For the bariatric surgery data, each obese subject undergoing surgery was matched with a control subject whose obesity was managed according to the standard of care for non-operative interventions. Note that the maximum weight loss achieved with orlistat and liraglutide was approximately 10 kg, and that the follow-up period is relatively short; surgery achieves much more substantial and prolonged weight loss. A, Data from Torgerson JS Hauptman J, Boldrin MS, et al. A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27:155–161. B, Data from le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet; published online 22 Feb 2017. C, Data from Sjöström L, Narbro K, Sjöström D, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357:741–752.

eb o

e. ks fre oo

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-10

-20

3

Fig. 19.8  Effects of orlistat (A), liraglutide

m

1 2 Years of follow-up

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-40

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-40 0

co

C

-30 -35

3

co m

1 2 Years of follow-up

-25

m

-40 0

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m

-20

m

m

-30 -35

Change in body weight (%)

-15

ks

eb

-25

0

Liraglutide + lifestyle

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-20

5

-10

Placebo + lifestyle

ok

-15

-5

fre

Orlistat + lifestyle

Change in body weight (%)

fre

p < 0.001

-10

e. co

m e. co

-5

0

eb oo ks

Change in body weight (%)

5

Placebo + lifestyle

0

eb

m

B

5

m

m

co m

fre e.

ks

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m

m A

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ks

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A huge investment has been made by the pharmaceutical industry in finding drugs for obesity. The side-effect profile has limited the use of many agents, with notable withdrawals from clinical use of sibutramine (increased cardiovascular events) and

m

eb

m

fre

ks fre

e. co

e. co m

m

m

eb

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m

rimonabant (psychiatric side-effects) in recent years. Orlistat has been available for many years, and four drugs or drug combinations have recently been approved in the USA and two of these in Europe. There is no role for diuretics, or for thyroxine therapy without biochemical evidence of hypothyroidism. Drug therapy should always be used as an adjunct to lifestyle advice and support, which should be continued throughout treatment. Orlistat inhibits pancreatic and gastric lipases and thereby decreases the hydrolysis of ingested triglycerides, reducing dietary fat absorption by approximately 30%. The drug is not absorbed and adverse side-effects relate to the effect of the resultant fat malabsorption on the gut: namely, loose stools, oily spotting, faecal urgency, flatus and the potential for malabsorption of fat-soluble vitamins. Orlistat at the standard dose of 120 mg is taken with each of the three main meals of the day; a lower dose (60 mg) is available without prescription in some countries. Its efficacy is shown in Figure 19.8; these effects may be explained because patients taking orlistat adhere better to low-fat diets in order to avoid unpleasant gastrointestinal side-effects. The combination of low-dose phentermine and topiramate extended release has been approved in the USA; this results in weight loss of approximately 6% greater than placebo and benefits lipids and glucose concentrations. Concerns over teratogenicity of topiramate and cardiovascular effects of phentermine have so far

ok s

ks f

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supplementation is wise in those diets in which macronutrient balance is markedly disturbed. In some patients, more rapid weight loss is required, e.g. in preparation for surgery. There is no role for starvation diets, which risk profound loss of muscle mass and the development of arrhythmias (and even sudden death) secondary to elevated free fatty acids, ketosis and deranged electrolytes. Very-lowcalorie diets (VLCDs) can be considered for short-term rapid weight loss, producing losses of 1.5–2.5 kg/week, compared to 0.5 kg/week on conventional regimens, but require the supervision of an experienced physician and nutritionist. The composition of the diet should ensure a minimum of 50 g of protein each day for men and 40 g for women to minimise muscle degradation. Energy content should be a minimum of 1.65 MJ (400 kcal) for women of height  30 kg/m2. Only experienced specialist surgeons should undertake these procedures, in collaboration with a multidisciplinary team. Several approaches are used (Fig. 19.9) and all can be performed laparoscopically. The mechanism of weight loss may not simply relate to limiting the stomach or absorptive capacity, but rather in disrupting the release of ghrelin from the stomach or promoting the release of other peptides from the small bowel, thereby enhancing satiety signalling in the hypothalamus. Diabetes may improve rapidly

Duodenal switch

Up to 100%

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re e

ks

oo

m m

co

e. fre

ks oo

ok s

Removed portion of stomach

eb

Digestive loop

m

m

Biliopancreatic loop

m

75 –100 cm common loop

D

co

m

co

e. co

m

m

Unused portion of the small intestine

eb o

Pylorus

C

19

eb

eb m m

co e. ks fre

eb

eb

Steatorrhoea Protein-calorie malnutrition Iron deficiency Vitamin B12 deficiency Calcium, zinc, copper deficiency Mortality 1%

sf

oo k

ks

oo

The small intestine is connected to the stomach pouch

Gastric sleeve

Resected stomach

ks

om

m

Internal hernia Stomal ulcer Dumping syndrome Hypoglycaemia Iron deficiency Vitamin B12 deficiency Vitamin D deficiency Mortality 0.5%

Duodenal switch

oo

oo

ks f

Access port

ks

eb

70–80%

eb

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Gastric band

m

co m

Iron deficiency Vitamin B12 deficiency Mortality  35 kg/m2 and significant complications, such as type 2 diabetes or obstructive sleep apnoea, although some evidence-based guidelines now suggest surgery can be considered at a lower weight in people with

A

eb

eb

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m

m

m

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19.9  Effectiveness and adverse effects of laparoscopic bariatric surgical procedures

 

Procedure

Surgery

oo

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ks

fre

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m

m

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om

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precluded its approval in Europe. The 5-HT2c inhibitor lorcaserin is also approved in the USA; it is moderately effective and has a relatively low rate of adverse effects. The combination of the opioid antagonist naltrexone and the noradrenaline (norepinephrine)/ dopamine re-uptake inhibitor bupropion is also effective. The main adverse effects are dry mouth and constipation. Finally, a higher dose of the injectable glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (3 mg) is also approved for use and has been shown to reduce the risk of diabetes in patients with pre-diabetes. Drug therapy is usually reserved for patients with high risk of complications from obesity (see Fig. 19.7), and its optimum timing and duration are controversial. There is evidence that those patients who demonstrate early weight loss (usually defined as 5% after 12 weeks on the optimum dose) achieve greater and longer-term weight loss, and this is reflected in most guidelines for the use of drugs for obesity. Treatment can be stopped in non-responders at this point and an alternative treatment considered. Although life-long therapy is advocated for many drugs that reduce risk on the basis of relatively short-term research trials (e.g. drugs for hypertension and osteoporosis), some patients who continue to take anti-obesity drugs tend to regain weight with time; this may partly reflect age-related weight gain, but significant weight gain should prompt reinforcement of lifestyle advice and, if this is unsuccessful, drug therapy should be discontinued (see Fig. 19.8).

Disorders of altered energy balance • 703

Fig. 19.9  Bariatric surgical procedures. A Laparoscopic banding, with the option of a reservoir band and subcutaneous access to restrict the stomach

e.

ok s

re

sf ok

sf re

ok

ok

sf

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further after compensatory expansion has occurred. B Sleeve gastrectomy. C Roux-en-Y gastric bypass. D Biliopancreatic diversion with duodenal switch.

fre e. c

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m

co m

fre e.

19.11  Causes of under-nutrition and weight loss in adults

m

m

eb

oo

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ks

oo

In a famine, laboratory investigations may be impractical but will show that plasma free fatty acids are increased and there is ketosis and a mild metabolic acidosis. Plasma glucose is low

eb

fre

oo ks

Investigations

m

eb

Obesity must not be treated in isolation and other risk factors must be addressed, including smoking, excess alcohol consumption, diabetes mellitus, hyperlipidaemia, hypertension and obstructive sleep apnoea. Treatment of these is discussed in the relevant chapters.

oo

eb

eb

oo

ks

fre

In starvation, the severity of malnutrition can be assessed by anthropometric measurements, such as BMI (see p. 693 and Box 19.10). Demispan and mid-arm circumference measurements are most useful in monitoring progress during treatment. The clinical features of severe under-nutrition in adults are listed in Box 19.12. Under-nutrition often leads to vitamin deficiencies, especially of thiamin, folate and vitamin C (see below). Diarrhoea can lead to depletion of sodium, potassium and magnesium. The high mortality rate in famine situations is often due to outbreaks of infection, such as typhus or cholera, but the usual signs of infection may not be apparent. In advanced starvation, patients become completely inactive and may assume a flexed, fetal position. In the last stage of starvation, death comes quietly and often quite suddenly. The very old are most vulnerable. All organs are atrophied at necropsy, except the brain, which tends to maintain its weight.

e. co m

e. co

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oo eb

Clinical features

m

eb o

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m

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after surgery, particularly after gastric bypass, and although this may be attributed to severe energy restriction in the perioperative period, it is possible that increased release of incretin hormones such as GLP-1 may contribute to the improvement in glucose control. Complications depend on the approach. Mortality is low in experienced centres but post-operative respiratory problems, wound infection and dehiscence, staple leaks, stomal stenosis, marginal ulcers and venous thrombosis may occur. Additional problems may arise at a later stage, such as pouch and distal oesophageal dilatation, persistent vomiting, ‘dumping’ (p. 801), hypoglycaemia and micronutrient deficiencies, particularly of folate, vitamin B12 and iron, which are of special concern to women contemplating pregnancy; this should be delayed for at least 2 years following surgery. Cosmetic surgical procedures may be considered in obese patients after successful weight loss. Apronectomy is usually advocated to remove an overhang of abdominal skin, especially if infected or ulcerated. This operation is of no value for long-term weight reduction if food intake remains unrestricted.

Treatment of additional risk factors

m

e. co m

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704 • Nutritional factors in disease

 

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re e

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co

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fre

m

eb

oo

ks

ok s

eb o

m

co

e.

ok s

re

sf re

sf

•

Severe

ok

Moderate

ks

sf

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eb

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Weight loss Thirst, craving for food, weakness and feeling cold Nocturia, amenorrhoea or impotence Lax, pale, dry skin with loss of turgor and, occasionally, pigmented patches Cold and cyanosed extremities, pressure sores Hair thinning or loss (except in adolescents) Muscle-wasting, best demonstrated by the loss of the temporalis and periscapular muscles and reduced mid-arm circumference Loss of subcutaneous fat, reflected in reduced skinfold thickness and mid-arm circumference Hypothermia, bradycardia, hypotension and small heart Oedema, which may be present without hypoalbuminaemia (‘famine oedema’) Distended abdomen with diarrhoea Diminished tendon jerks Apathy, loss of initiative, depression, introversion, aggression if food is nearby Susceptibility to infections (Box 19.13)

m e. co

Mild

ok

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• • •

19.12  Clinical features of severe under-nutrition in adults

 

m

ks fre

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eb

m

Under-nutrition

m

Marginal

 2 months • Infants fed exclusively on boiled milk

m

m

eb

oo

Increased requirement • Trauma, surgery, burns, infections • Smoking • Drugs (glucocorticoids, aspirin, indometacin, tetracycline)

oo ks

Precipitants

inadequate dietary intake of minerals or excessive loss from the body. Toxic effects have also been observed from selfmedication and disordered absorption or excretion. Examples of clinical toxicity include excess of iron (haemochromatosis or haemosiderosis), fluoride (fluorosis; p. 149), copper (Wilson’s disease) and selenium (selenosis, seen in parts of China). For most minerals, the available biochemical markers do not accurately reflect dietary intake and dietary assessment is required.

fre

19.33  Scurvy – vitamin C deficiency

ks fre  

fre e.

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due to scurvy. J New Zeal Med Assoc 2007; 120:62. Reproduced with permission.

ok s

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Fig. 19.14  Scurvy. A Gingival swelling and bleeding. B Perifollicular hyperkeratosis. A and B, From Ho V, Prinsloo P, Ombiga J. Persistent anaemia

fre e. c

Most foods contain phosphorus Marmite and dry-roasted peanuts Milk, cereal products, bread and meat

550 mg2

Magnesium

Whole grains, nuts

Unprocessed and wholegrain foods

300 mg men 270 mg women2

Iron

Liver, red meat (haem iron)

Non-haem iron from vegetables, wholemeal bread

8.7 mg 14.8 mg women  10 ppm fluoride. It can also occur in workers handling cryolite (aluminium sodium fluoride), used in smelting aluminium. Fluoride poisoning is described on page 149. Pitting of teeth is a result of too much fluoride as a child.

oo eb

m

Other essential inorganic nutrients

eb

eb o

m

m

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The family of seleno-enzymes includes glutathione peroxidase, which helps prevent free radical damage to cells, and mono­ deiodinase, which converts thyroxine to triiodothyronine (p. 634). North American soil has a higher selenium content than European and Asian soil, and the decreasing reliance of Europe on imported American food in recent decades has resulted in a decline in dietary selenium intake. Selenium deficiency can cause hypothyroidism, cardiomyopathy in children (Keshan’s disease) and myopathy in adults. Excess selenium can cause heart disease.

that daily salt intakes are kept well below 6 g. The roles of sodium, potassium and magnesium, along with the disease states associated with abnormal intakes or disordered metabolism, are discussed in Chapter 14.

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Selenium

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718 • Nutritional factors in disease

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Complications of diabetes 755 Diabetic retinopathy 757 Diabetic nephropathy 757 Diabetic neuropathy 758 The diabetic foot 761

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Presenting problems in diabetes mellitus 734 Hyperglycaemia 734 Presentation with the complications of diabetes 735 Diabetes emergencies 735 Diabetic ketoacidosis 735 Hyperglycaemic hyperosmolar state 738 Hypoglycaemia 738

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Aetiology and pathogenesis of diabetes 728

Management of diabetes 741 Patient education, diet and lifestyle 743 Drugs to reduce hyperglycaemia 745 Insulin therapy 748 Transplantation 752 Management of diabetes in special situations 752

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Investigations 725 Establishing the diagnosis of diabetes 727

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Functional anatomy and physiology 723

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20 

Diabetes mellitus

Clinical examination of the patient with diabetes 720

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ER Pearson RJ McCrimmon

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Neuropathic foot ulcer

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Observation • Weight loss in insulin deficiency • Obesity in type 2 diabetes • Mucosal candidiasis • Dehydration– dry mouth, ↓tissue turgor • Air hunger– Kussmaul breathing in ketoacidosis

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11 Feet (see opposite) Inspection Peripheral pulses Sensation

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1 Hands (see opposite)

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Necrobiosis lipoidica

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3 Blood pressure

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10 Legs Muscle-wasting Sensory abnormality Hair loss Tendon reflexes

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4

‘Prayer sign’

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Acanthosis nigricans in insulin resistance

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9 Abdomen Hepatomegaly (fatty infiltration of liver)

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5

2 Skin Bullae Pigmentation Granuloma annulare Vitiligo

8 Insulin injection sites (see opposite)

Exudative maculopathy

4 Axillae

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5 Neck Carotid pulse Bruits Thyroid enlargement

7 Eyes (see opposite) Visual acuity Cataract/lens opacity Fundoscopy

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6 Head Xanthelasma Cranial nerve palsy/eye movements/ptosis

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Clinical examination of the patient with diabetes

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720 • Diabetes mellitus

Charcot neuroarthropathy

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Insets (Acanthosis nigricans) From Lim E (ed.). Medicine and surgery: an integrated textbook. Edinburgh: Elsevier Ltd; 2007. ( Exudative maculopathy) Courtesy of Dr A.W. Patrick and Dr I.W. Campbell.

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20

Monofilaments. The monofilament is applied gently until slightly deformed at five points on each foot. Callus should be avoided as sensation is reduced. If the patient feels fewer than 8 out of 10 touches, the risk of foot ulceration is increased 5–10-fold.

Lipohypertrophy of the upper arm.

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• Ankle reflexes are lost in typical sensorimotor neuropathy • Test plantar and ankle reflexes

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Reflexes

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• This is abnormal in stocking distribution in typical peripheral sensorimotor neuropathy • Testing light touch with monofilaments is sufficient for risk assessment; test other sensation modalities (vibration, pain, proprioception) only when neuropathy is being evaluated

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• Bruising • Subcutaneous fat deposition (lipohypertrophy) • Subcutaneous fat loss (lipoatrophy; associated with injection of unpurified animal insulins – now rare) • Erythema, infection (rare)

Proliferative retinopathy. Courtesy of Dr A.W. Patrick and Dr I.W. Campbell.

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Sensation

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Main areas used

Inspection

Background retinopathy. Courtesy of Dr A.W. Patrick and Dr I.W. Campbell.

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• Peripheral pulses, skin temperature and capillary refill may be abnormal

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Insulin injection sites

• Anterior abdominal wall • Upper thighs/buttocks • Upper outer arms

• Either use a three-field retinal camera or dilate pupils with a mydriatic (e.g. tropicamide) and examine with an ophthalmoscope in a darkened room • Note features of diabetic retinopathy (p. 1174), including photocoagulation scars from previous laser treatment

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• Look for evidence of callus formation on weight-bearing areas, clawing of the toes (in neuropathy), loss of the plantar arch, discoloration of the skin (ischaemia), localised infection and ulcers • Deformity may be present, especially in Charcot neuroarthropathy • Fungal infection may affect skin between toes, and nails

Circulation

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Lens opacification

Fundal examination

• Limited joint mobility (‘cheiroarthropathy’) causes painless stiffness. The inability to extend (to 180°) the metacarpophalangeal or interphalangeal joints of at least one finger bilaterally can be demonstrated in the ‘prayer sign’ • Dupuytren’s contracture (p. 1059) causes nodules or thickening of the skin and knuckle pads • Carpal tunnel syndrome (p. 1139) presents with wrist pain radiating into the hand • Trigger finger (flexor tenosynovitis) may be present • Muscle-wasting/sensory changes may be present in peripheral sensorimotor neuropathy, although this is more common in the lower limbs

Examination of the feet

Inspection

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• Check distance vision using Snellen chart at 6 m • Check near vision using standard reading chart • Note that visual acuity can alter reversibly with acute hyperglycaemia due to osmotic changes affecting the lens. Most patients with retinopathy do not have altered visual acuity, except after a vitreous haemorrhage or in some cases of maculopathy • Look for the red reflex using the ophthalmoscope held 30 cm from the eye

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Visual acuity

Examination of the hands

Several abnormalities are more common in diabetes:

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Examination of the eyes

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Diabetes can affect every system in the body. In routine clinical practice, exam­ ination of the patient with diabetes is focused on hands, blood pressure, axillae, neck, eyes, insulin injection sites and feet.

7 

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Clinical examination of the patient with diabetes • 721

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The incidence of diabetes is rising. Globally, it is estimated that 415 million people had diabetes in 2015 (10% of the world adult population), and this figure is expected to reach 642 million by 2040. This global pandemic principally involves type 2 diabetes; prevalence varies considerably around the world (Fig. 20.1), being associated with differences in genetic factors, as well as environmental ones such as greater longevity, obesity, unsatisfactory diet, sedentary lifestyle, increasing urbanisation and economic development. A pronounced rise in the prevalence of type 2 diabetes occurs in migrant populations to industrialised countries, as in Asian and Afro-Caribbean immigrants to the UK or USA. Type 2 diabetes is now seen in children and adolescents, particularly in some ethnic groups such as Hispanics, non-Hispanic blacks and Asian Indians. The incidence of type 1 diabetes is also increasing: between 1960 and 1996, 3% more children were diagnosed worldwide each year. It is generally more common in countries closer to the polar regions. Finland, for instance, has the highest rate of type 1 diagnosis per year at > 60 per 100 000 of the population, whereas in China, India and Venezuela the incidence is only 0.1 per 100 000. Type 1 diabetes is most common in Caucasians, and more people are diagnosed in the winter months. Diabetes is a major burden on health-care facilities in all countries. Globally, in 2015, diabetes caused 5 million deaths in those aged 20–79 years, and health-care expenditure attributed to diabetes was estimated to be at least 673 billion US dollars, or 12% of total health-care expenditure.

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Diabetes mellitus is a clinical syndrome characterised by an increase in plasma blood glucose (hyperglycaemia). It has many causes (see Box 20.9), most commonly type 1 or type 2 diabetes. Type 1 diabetes is generally considered to result from autoimmune destruction of insulin-producing cells (β cells) in the pancreas, leading to marked insulin deficiency, whereas type 2 diabetes is characterised by reduced sensitivity to the action of insulin and an inability to produce sufficient insulin to overcome this ‘insulin resistance’. Hyperglycaemia causes both acute and long-term problems. Acutely, high glucose and lack of insulin can result in marked symptoms, metabolic decompensation and hospitalisation. Chronic hyperglycaemia is responsible for diabetes-specific ‘microvascular’ complications affecting the eyes (retinopathy), kidneys (nephropathy) and feet (neuropathy). There is a continuous distribution of blood glucose in the population, with no clear division between people with normal values and those with abnormal ones. The diagnostic criteria for diabetes (a fasting plasma glucose of ≥ 7.0 mmol/L (126 mg/ dL) or glucose 2 hours after an oral glucose challenge of ≥ 11.1 mmol/L (200 mg/dL); p. 726) have been selected to identify a degree of hyperglycaemia that, if untreated, carries a significant risk of microvascular disease, and in particular diabetic retinopathy. Less severe hyperglycaemia is called ‘impaired glucose tolerance’. This is not associated with a substantial risk of microvascular disease, but is connected with an increased risk of large-vessel disease (e.g. atheroma leading to myocardial infarction) and with a greater risk of developing diabetes in future.

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722 • Diabetes mellitus

Fig. 20.1  Prevalence (%) of diabetes in those aged 20–79 years, 2015. Based on estimates from the International Diabetes Federation. IDF Diabetes

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Atlas, 7th edn. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org.

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Glycolysis

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Ca2+

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Oxidative phosphorylation

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HNF1α HNF4α

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Incretin-acting drugs

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Glucose

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Fig. 20.2  Pancreatic structure and endocrine function. A The normal adult pancreas contains about 1 million islets, which are scattered throughout the exocrine parenchyma. Histology is shown in Figure 20.6. B The core of each islet consists of β cells that produce insulin, and is surrounded by a cortex of endocrine cells that produce other hormones, including glucagon (α cells), somatostatin (δ cells) and pancreatic polypeptide (PP cells). C Schematic representation of the pancreatic β cell. (1) Glucose enters the cell via a glucose transporter (GLUT1 or GLUT2). (2) Glucose then enters glycolysis, and subsequent oxidative phosphorylation in the mitochondria results in a rise in intracellular adenosine triphosphate (ATP). (3) This ATP acts to close the KATP channel (which consists of four KIR6.2 subunits and four SUR1 subunits). This leads to membrane depolarisation. (4) The rise in membrane potential results in calcium influx due to opening of a voltage-gated calcium channel. This rise in intracellular calcium causes insulin secretory vesicles to fuse with the cell membrane, leading to insulin secretion. (5) Other stimuli, such as glucagon-like peptide-1 (GLP-1) or gastric inhibitory polypeptide (GIP), act on G-protein-coupled receptors to increase cyclic adenosine monophosphate (cAMP) and amplify the insulin secretion. Genetic defects in the β cell result in diabetes. The primary genes are glucokinase (the initial step in glycolysis) and HNF1α, HNF4α and HNF1β (nuclear transcription factors). Two groups of drugs act on the β cell to promote insulin secretion. Sulphonylureas act to close the KATP channel, causing membrane depolarisation, calcium influx and insulin secretion. Incretin-acting drugs either increase the concentration of endogenous GLP-1 and GIP (the dipeptidyl peptidase 4, or DPP-4, inhibitors) or act as directly on the GLP-1 receptor (GLP-1 receptor agonists). Both of these drug groups act to augment insulin secretion but only following an initial stimulus to insulin secretion through closure of β cell KATP channels by glucose (or sulphonylureas).

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B

Arteriole

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Ampulla of Vater

Lipolysis Lipoprotein lipase (muscle) Ketogenesis Fatty acid oxidation (liver)

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Protein metabolism Amino acid transport Protein synthesis

Gluconeogenesis Glycogenolysis

Duodenum Accessory ampulla

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Lipid metabolism Triglyceride synthesis Fatty acid synthesis (liver) Lipoprotein lipase activity (adipose tissue)

Decrease

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Carbohydrate metabolism Glucose transport (muscle, adipose tissue) Glucose phosphorylation Glycogen synthesis Glycolysis Pyruvate dehydrogenase activity Pentose phosphate shunt

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20.1  Metabolic actions of insulin

Increase

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Insulin is the primary regulator of glucose metabolism and storage (Box 20.1), and is secreted from pancreatic β cells into the portal circulation (Fig. 20.2). The pancreatic β cell is designed to regulate blood glucose concentrations tightly by coupling glucose and other nutrient stimulus with insulin secretion (Fig. 20.2). Entry of glucose into the pancreatic β cell is by facilitated diffusion

down its concentration gradient through cell membrane glucose transporters (GLUTs). Glucose is then metabolised by glycolysis and oxidative phosphorylation. The first step of the glycolytic pathway, the conversion of glucose to glucose-6-phosphate, is catalysed by the enzyme glucokinase (GK). Glucokinase has a low affinity for glucose and so its activity under normal physiological conditions varies markedly, according to the concentration of glucose. This makes it a very effective glucose sensor in the β cell. In what is considered a classical direct or triggering pathway, glucose metabolism results in increased intracellular adenosine triphosphate (ATP) and reduced adenosine diphosphate

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Regulation of insulin secretion

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Functional anatomy and physiology

Functional anatomy and physiology • 723

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Blood glucose is tightly regulated and maintained within a narrow range. This is essential for ensuring a continuous supply of glucose to the central nervous system. The brain has little capacity to store energy in the form of glycogen or triglyceride, and the blood–brain barrier is largely impermeable to fatty acids, so the brain depends on the liver for a constant supply of glucose for oxidation and hence generation of ATP. Glucose homeostasis is achieved through the coordinated actions of multiple organs, but mainly reflects a balance between the entry of glucose into the circulation from the liver, supplemented by intestinal absorption of glucose after meals, and the uptake of glucose by peripheral tissues, particularly skeletal muscle and brain. After ingestion of a meal containing carbohydrate, normal blood glucose levels are maintained by: • suppression of hepatic glucose production • stimulation of hepatic glucose uptake • stimulation of glucose uptake by peripheral tissues (Fig. 20.5).

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The post-prandial rise in portal vein insulin and glucose, together with a fall in portal glucagon concentrations, suppresses hepatic glucose production and results in net hepatic glucose uptake. Depending on the size of the carbohydrate load, around one-quarter to one-third of ingested glucose is taken up in the liver. In addition, insulin stimulates glucose uptake in skeletal muscle and fat, mediated by the glucose transporter GLUT4.

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Blood glucose homeostasis

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(ADP), which causes closure of an ATP-sensitive potassium channel (KATP). The resulting membrane depolarisation of the β cell results in insulin secretion due to triggering of calcium release by voltage-sensitive calcium channels. In addition to this pathway, the amount of insulin released can be amplified or potentiated by the background blood glucose, other nutrients and peptides, and by neuronal control via the sympathetic and parasympathetic nervous system. A good example of this potentiation of insulin release is seen with the secretion of two gut peptides following ingestion of food. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are released from gastrointestinal L cells and K cells, respectively, following a meal, and act via receptors on the pancreatic β cells to augment insulin secretion. Thus, for a given glucose stimulus to the β cell, there is greater insulin secretion with oral glucose administration (where the gut peptides are released) compared to intravenous glucose administration (which does not stimulate gut peptide release). This enhanced insulin secretion following oral administration of glucose is termed the ‘incretin’ effect (Fig. 20.3), and GLP-1 and GIP are known as incretin hormones. Insulin is synthesised as a pro-hormone (pro-insulin) that consists of an α and a β chain, which are linked by C-peptide (Fig. 20.4). The C-peptide is cleaved by β-cell peptidases to create insulin (which now consists of the α and β chains) and free C-peptide. Insulin secretion in response to a glucose stimulus

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Pancreatic islets also contain other endocrine cells such as α cells that secrete the peptide hormone glucagon, and δ cells that produce somatostatin (see Fig. 20.2B). Alpha cells make up about 20% of the human islet cell population. Glucagon has opposite effects to insulin and acts on the liver (and kidney) to stimulate glycogenolysis, leading to increased hepatic glucose production. Regulation of glucagon secretion by the α cell is complex, but β-cell insulin secretion, co-secreted zinc and γ-aminobutyric acid (GABA), as well as somatostatin from δ cells, are thought to have major regulatory roles. This means that insulin and glucagon are tightly, and reciprocally, regulated, such that the ratio of insulin to glucagon in the portal vein is a major determinant of hepatic glucose production. Glucagon is also critically important to the body’s defence against hypoglycaemia (p. 738).

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Insulin

After intravenous glucose

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Regulation of glucagon secretion

glucose. A An acute first phase of insulin secretion occurs in response to an elevated blood glucose, followed by a sustained second phase. B The incretin effect describes the observation that insulin secretion is greater when glucose is given by mouth than when glucose is administered intravenously to achieve the same rise in blood glucose concentrations. The additional stimulus to insulin secretion is mediated by release of peptides from the gut and these actions are exploited in incretin-based therapies (p. 747).

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classically occurs in two phases (see Fig. 20.3). The rapid first phase represents the secretion of pre-formed insulin from granules within the β cells, while the more prolonged second phase is a consequence of newly synthesised insulin.

After oral glucose

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Time

Fig. 20.3  Insulin secretion in response to intravenous or oral

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C-peptide

Fig. 20.4  Processing of pro-insulin into insulin and C-peptide. Pro-insulin in the pancreatic β cell is cleaved to release insulin and equimolar amounts of inert C-peptide (connecting peptide). Measurement of C-peptide can be used to assess endogenous insulin secretory capacity.

The incretin effect

B

Pro-insulin

2nd phase

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Insulin

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Basal secretion

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1st phase

Pancreatic β cell

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Glucose stimulus

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Insulin secretion

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724 • Diabetes mellitus

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Glucose

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FFAs + Glycerol

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Glycerol

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Triglycerides

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GLUT4

Oxidation

FFAs

Ketogenesis

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Ketone bodies

Glycogen

Glucose

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Glucose

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Oxidation

Glycogen

Gluconeogenesis Oxidation

Proteolysis

Lactate Pyruvate

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Amino acids

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Food

Liver

FFAs

Investigations • 725

Adipose tissue

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Testing the urine for glucose with dipsticks is a common screening procedure for detecting diabetes. If possible, testing should be performed on urine passed 1–2 hours after a meal to maximise sensitivity. Glycosuria always warrants further assessment by blood testing (see below). The greatest disadvantage of urine glucose measurement is the individual variation in renal threshold for glucose. The most frequent cause of glycosuria is a low renal threshold, which is common during pregnancy and in young people; the resulting ‘renal glycosuria’ is a benign condition unrelated to diabetes. Another disadvantage is that some drugs (such as β-lactam antibiotics, levodopa and salicylates) may interfere with urine glucose tests.

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Urine glucose

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Investigations

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Adipocytes (and the liver) synthesise triglyceride from nonesterified (‘free’) fatty acids (FFAs) and glycerol. Insulin is the major regulator not only of glucose metabolism but also of fatty acid metabolism. High insulin levels after meals promote triglyceride accumulation. In contrast, in the fasting state, low insulin levels permit lipolysis and the release into the circulation of FFAs (and glycerol), which can be oxidised by many tissues. Their partial oxidation in the liver provides energy to drive gluconeogenesis and also produces ketone bodies (acetoacetate, which can be reduced to 3-hydroxybutyrate or decarboxylated to acetone), which are generated in hepatocyte mitochondria. Ketone bodies are organic acids that, when formed in small amounts, are oxidised and utilised as metabolic fuel. However, the rate of

20

utilisation of ketone bodies by peripheral tissues is limited, and when the rate of production by the liver exceeds their removal, hyperketonaemia results. This occurs physiologically during starvation, when low insulin levels and high catecholamine levels increase lipolysis and delivery of FFAs to the liver.

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When intestinal glucose absorption declines between meals, portal vein insulin and glucose concentrations fall while glucagon levels rise. This leads to increased hepatic glucose output via gluconeogenesis and glycogen breakdown. The liver now resumes net glucose production and glucose homeostasis is maintained. The main substrates for gluconeogenesis are glycerol and amino acids, as shown in Figure 20.5.

Fat metabolism

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In response to a rise in blood glucose, e.g. after a meal, insulin is released, suppressing gluconeogenesis and promoting glycogen synthesis and storage. Insulin promotes the peripheral uptake of glucose, particularly in skeletal muscle, and encourages storage (as muscle glycogen). It also promotes protein synthesis and lipogenesis, and suppresses lipolysis. The release of intermediate metabolites, including amino acids (glutamine, alanine), 3-carbon intermediates in oxidation (lactate, pyruvate) and free fatty acids (FFAs), is controlled by insulin. In the absence of insulin, e.g. during fasting, these processes are reversed and favour gluconeogenesis in liver from glycogen, glycerol, amino acids and other 3-carbon precursors.

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Fig. 20.5  Major metabolic pathways of fuel metabolism and the actions of insulin. ⊕ indicates stimulation and ⊖ indicates suppression by insulin.

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> 3.0 mmol/L

Severe ketosis; in the presence of high glucose (> 10 mmol/L) suggests presence of diabetic ketoacidosis; seek urgent medical help

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*To convert to mg/dL, multiply values by 18.

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With high blood glucose (> 10 mmol/L), there is a high risk of diabetic ketoacidosis; seek medical advice

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1.5–3.0 mmol/L

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Suggests metabolic control may be deteriorating; the patient should continue to monitor and seek medical advice if sustained/progressive

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Normal; no action required

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Interpretation

 600 U/L

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• • • • • • • • •

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Endometriosis

21.78  Glasgow criteria for prognosis in acute pancreatitis*

 

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Other disorders

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abdominal mass, due to omental infiltration, and with ascites. The prognosis is extremely poor.

Diseases of the pancreas • 837

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Gastric or duodenal erosions

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Splenic or portal vein thrombosis Erosion by pancreatic pseudocyst Compression by pancreatic mass Compression of common bile duct

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‘pseudocysts’ are common and usually asymptomatic, resolving as the pancreatitis recovers. Pseudocysts greater than 6 cm in diameter seldom disappear spontaneously and can cause constant abdominal pain and compress or erode surrounding structures, including blood vessels, to form pseudoaneurysms. Large pseudocysts can be detected clinically as a palpable abdominal mass. Pancreatic ascites occurs when fluid leaks from a disrupted pancreatic duct into the peritoneal cavity. Leakage into the thoracic cavity can result in a pleural effusion or a pleuro-pancreatic fistula.

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Gastrointestinal Upper gastrointestinal bleeding Variceal haemorrhage Erosion into colon Duodenal obstruction Obstructive jaundice

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Pseudocyst Pancreatic ascites or pleural effusion

(Grey Turner’s sign) or the periumbilical region (Cullen’s sign) is a feature of severe pancreatitis with haemorrhage. The differential diagnosis includes a perforated viscus, acute cholecystitis and myocardial infarction. Various complications may occur and these are listed in Box 21.81. A collection of fluid and debris may develop in the lesser sac, following inflammatory rupture of the pancreatic duct; this is known as a pancreatic fluid collection. It is initially contained within a poorly defined, fragile wall of granulation tissue, which matures over a 6-week period to form a fibrous capsule (Fig. 21.65). Such

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Abscess

Non-viable pancreatic tissue and peripancreatic tissue death; frequently infected Circumscribed collection of pus close to the pancreas and containing little or no pancreatic necrotic tissue Disruption of pancreatic ducts Disruption of pancreatic ducts

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Reduced serum albumin concentration Pancreatic Necrosis

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(ERCP = endoscopic retrograde cholangiopancreatography)

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Hypocalcaemia

• Post-surgical (abdominal, cardiopulmonary bypass) • Trauma • Drugs (azathioprine/mercaptopurine, thiazide diuretics, sodium valproate) • Metabolic (hypercalcaemia, hypertriglyceridaemia) • Pancreas divisum (p. 842) • Sphincter of Oddi dysfunction • Infection (mumps, Coxsackie virus) • Hereditary factors • Renal failure • Organ transplantation (kidney, liver) • Severe hypothermia • Petrochemical exposure

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Increased vascular permeability from cytokine, platelet-aggregating factor and kinin release Acute respiratory distress syndrome (ARDS) due to microthrombi in pulmonary vessels Disruption of islets of Langerhans with altered insulin/glucagon release Sequestration of calcium in fat necrosis, fall in ionised calcium Increased capillary permeability

Hyperglycaemia

Gallstones Alcohol Idiopathic causes Post-ERCP

Cause

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Complication

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21.80  Causes of acute pancreatitis

Rare

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21.81  Complications of acute pancreatitis

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Systemic Systemic inflammatory response syndrome (SIRS) Hypoxia

Common (90% of cases) • • • •

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Pancreatic secretory trypsin inhibitors

Acute pancreatitis

 

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pseudocyst (C) compressing the stomach (S). The pancreas is atrophic and calcified (arrows).

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Activated proteolytic enzymes

Fig. 21.65  Computed tomogram showing large pancreatic

Fig. 21.64  Pathophysiology of acute pancreatitis.

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Reflux of infected bile or duodenal contents into pancreatic duct (sphincter of Oddi dysfunction)

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Hyperstimulation of pancreas (alcohol, triglycerides)

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C

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Pro-enzymes

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Pancreatic duct obstruction (common bile duct stones, tumours)

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Defective intracellular transport and secretion of pancreatic zymogens

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838 • Gastroenterology

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Pathophysiology

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Around 80% of cases in Western countries result from alcohol misuse. In southern India, severe chronic calcific pancreatitis

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21

Chronic pancreatitis is a chronic inflammatory disease char­ acterised by fibrosis and destruction of exocrine pancreatic tissue. Diabetes mellitus occurs in advanced cases because the islets of Langerhans are involved (p. 733).

pancreas during contrast-enhanced computed tomography indicates necrosis (arrow). The presence of gas suggests that infection has occurred.

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Chronic pancreatitis

Fig. 21.66  Pancreatic necrosis. Lack of vascular enhancement of the

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Opiate analgesics should be given to treat pain and hypovolaemia should be corrected using normal saline or other crystalloids. All severe cases should be managed in a high-dependency or intensive care unit. A central venous line and urinary catheter should be inserted to monitor patients with shock. Oxygen should be given to hypoxic patients, and those who develop systemic inflammatory response syndrome (SIRS) may require ventilatory support. Hyperglycaemia should be corrected using insulin and hypocalcaemia by intravenous calcium injection. Nasogastric aspiration is required only if paralytic ileus is present. Enteral feeding, if tolerated, should be started at an early stage in patients with severe pancreatitis because they are in a severely catabolic state and need nutritional support. Enteral feeding decreases endotoxaemia and so may reduce systemic complications. Nasogastric feeding is just as effective as feeding by the nasojejunal route. Prophylaxis of thromboembolism with subcutaneous low-molecular-weight heparin is also advisable. The use of prophylactic, broad-spectrum intravenous antibiotics to prevent infection of pancreatic necrosis is not indicated, but infected necrosis is treated with antibiotics that penetrate necrotic tissue, e.g. carbapenems or quinolones, and metronidazole. Patients who present with cholangitis or jaundice in association with severe acute pancreatitis should undergo urgent ERCP to diagnose and treat choledocholithiasis. In less severe cases of gallstone pancreatitis, biliary imaging (using MRCP or EUS) can be carried out after the acute phase has resolved. If the liver function tests return to normal and ultrasound has not demonstrated a dilated biliary tree, laparoscopic cholecystectomy with an on-table cholangiogram is appropriate because any common bile duct stones have probably passed. When the operative cholangiogram detects residual common bile duct stones, these should be removed by laparoscopic exploration of the duct or by post-operative ERCP. Cholecystectomy should be undertaken within 2 weeks of resolution of pancreatitis – and preferably during the same admission – to prevent further potentially fatal attacks of pancreatitis. Patients with infected pancreatic necrosis or pancreatic abscess require urgent endoscopic drainage or minimally invasive retroperitoneal pancreatic (MIRP) necrosectomy to debride all cavities of necrotic material. Pancreatic pseudocysts can be treated by drainage into the stomach or duodenum. This is usually performed after an interval of at least 6 weeks, once a pseudocapsule has matured, by surgical or endoscopic cystogastrostomy.

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Management comprises several related steps: • establishing the diagnosis and disease severity • early resuscitation, according to whether the disease is mild or severe • detection and treatment of complications • treatment of the underlying cause.

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Management

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The diagnosis is based on raised serum amylase or lipase concentrations and ultrasound or CT evidence of pancreatic swelling. Plain X-rays should be taken to exclude other diagnoses, such as perforation or obstruction, and to identify pulmonary complications. Amylase is efficiently excreted by the kidneys and concentrations may have returned to normal if measured 24–48 hours after the onset of pancreatitis. A persistently elevated serum amylase concentration suggests pseudocyst formation. Peritoneal amylase concentrations are massively elevated in pancreatic ascites. Serum amylase concentrations are also elevated (but less so) in intestinal ischaemia, perforated peptic ulcer and ruptured ovarian cyst, while the salivary isoenzyme of amylase is elevated in parotitis. If available, serum lipase measurements are preferable to amylase, as they have greater diagnostic accuracy for acute pancreatitis. Ultrasound scanning can confirm the diagnosis, although in the earlier stages the gland may not be grossly swollen. The ultrasound scan is also useful because it may show gallstones, biliary obstruction or pseudocyst formation. Contrast-enhanced pancreatic CT performed 6–10 days after admission can be useful in assessing viability of the pancreas if persisting organ failure, sepsis or clinical deterioration is present, since these features may indicate that pancreatic necrosis has occurred. Necrotising pancreatitis is associated with decreased pancreatic enhancement on CT, following intravenous injection of contrast material. The presence of gas within necrotic material (Fig. 21.66) suggests infection and impending abscess formation, in which case percutaneous aspiration of material for bacterial culture should be carried out and appropriate antibiotics prescribed. Involvement of the colon, blood vessels and other adjacent structures by the inflammatory process is best seen by CT. Certain investigations stratify the severity of acute pancreatitis and have important prognostic value at the time of presentation (see Boxes 21.78 and 21.79). In addition, serial assessment of CRP is a useful indicator of progress. A peak CRP of > 210 mg/L in the first 4 days predicts severe acute pancreatitis with 80% accuracy. It is worth noting that the serum amylase concentration has no prognostic value.

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Investigations

Diseases of the pancreas • 839

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Autoimmune

• SPINK-1 mutation • Cystic fibrosis

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• Hereditary pancreatitis (cationic trypsinogen mutation)

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• Early-/late-onset types

Genetic

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Investigations (Box 21.84 and Fig. 21.68) are carried out to: • make a diagnosis of chronic pancreatitis • define pancreatic function • demonstrate anatomical abnormalities prior to surgical intervention.

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• Tropical

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Investigations

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Idiopathic

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• Hypercalcaemia • Chronic kidney disease

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21.82  Causes of chronic pancreatitis*

Toxic–metabolic

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Chronic pancreatitis predominantly affects middle-aged alcoholic men. Almost all present with abdominal pain. In 50%, this occurs as episodes of ‘acute pancreatitis’, although each attack results in a degree of permanent pancreatic damage. Relentless, slowly progressive chronic pain without acute exacerbations affects 35% of patients, while the remainder have no pain but

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Clinical features

present with diarrhoea. Pain is due to a combination of increased pressure within the pancreatic ducts and direct involvement of peripancreatic nerves by the inflammatory process. Pain may be relieved by leaning forwards or by drinking alcohol. Approximately one-fifth of patients chronically consume opiate analgesics. Weight loss is common and results from a combination of anorexia, avoidance of food because of post-prandial pain, malabsorption and/or diabetes. Steatorrhoea occurs when more than 90% of the exocrine tissue has been destroyed; protein malabsorption develops only in the most advanced cases. Overall, 30% of patients have (secondary) diabetes but this figure rises to 70% in those with chronic calcific pancreatitis. Physical examination reveals a thin, malnourished patient with epigastric tenderness. Skin pigmentation over the abdomen and back is common and results from chronic use of a hot water bottle (erythema ab igne). Many patients have features of other alcohol- and smoking-related diseases. Complications are listed in Box 21.83.

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occurs in non-alcoholics, possibly as a result of malnutrition, deficiency of trace elements and micronutrients, and cassava consumption. Other causes are listed in Box 21.82. The pathophysiology of chronic pancreatitis is shown in Figure 21.67.

 

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840 • Gastroenterology

Recurrent acute pancreatitis

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pancreatitis. Alcohol and other risk factors may trigger acute pancreatitis through multiple mechanisms. The first (or ‘sentinel’) episode of acute pancreatitis initiates an inflammatory response involving T-helper (Th) cells. Ongoing exposure to alcohol drives further inflammation but this is modified by regulatory T cells (Treg) with subsequent fibrosis, via activation of pancreatic stellate cells. A cycle of inflammation and fibrosis ensues, with development of chronic pancreatitis. Alcohol is the most relevant risk factor, as it is involved at multiple steps.

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Chronic pancreatitis

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Recurrent acute pancreatitis

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Acinus

Acute pancreatitis

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Fig. 21.67  Pathophysiology of chronic

Ductule

Clinical course

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Duct obstruction

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Treg

Normal

Obstructive

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Necrosis – fibrosis

Th

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Toxic – metabolic

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Oxidative stress

Genetic

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Mechanisms

Idiopathic

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Alcohol Smoking

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• Pancreas divisum • Sphincter of Oddi stenosis

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• Pseudocysts and pancreatic ascites, which occur in both acute and chronic pancreatitis • Obstructive jaundice due to benign stricture of the common bile duct as it passes through the diseased pancreas • Duodenal stenosis • Portal or splenic vein thrombosis leading to segmental portal hypertension and gastric varices • Peptic ulcer

*These can be memorised by the mnemonic ‘TIGARO’. Gallstones do not cause chronic pancreatitis but may be observed as an incidental finding.

Aetiology

21.83  Complications of chronic pancreatitis

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Obstructive

• Ductal adenocarcinoma • Intraductal papillary mucinous neoplasia

 

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Recurrent and severe acute pancreatitis

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• In isolation or as part of multi-organ problem

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Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that can mimic cancer but which responds to glucocorticoids. It is characterised by abdominal pain, weight loss or obstructive jaundice, without acute attacks of pancreatitis. Blood tests reveal increased serum IgG or IgG4 and the presence of other autoantibodies. Imaging shows a diffusely enlarged pancreas, narrowing of the pancreatic duct and stricturing of the lower bile duct. AIP may occur alone or with other autoimmune disorders, such as Sjögren’s syndrome, primary sclerosing cholangitis or IBD. The response to glucocorticoids is usually excellent but some patients require azathioprine.

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Autoimmune pancreatitis

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Alcohol avoidance is crucial in halting progression of the disease and reducing pain.

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Alcohol misuse

21

Surgical or endoscopic therapy may be necessary for the management of pseudocysts, pancreatic ascites, common bile duct or duodenal stricture and the consequences of portal hypertension. Many patients with chronic pancreatitis also require treatment for other alcohol- and smokingrelated diseases and for the consequences of self-neglect and malnutrition.

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Management

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Management of complications

showing a grossly dilated and irregular duct with a calcified stone (arrow A). Note the calcification in the head of the gland (arrow B). B Magnetic resonance cholangiopancreatogram of the same patient showing marked ductal dilatation with abnormal dilated side branches (arrows A). A small cyst is also present (arrow B).

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This is treated by dietary fat restriction (with supplementary medium-chain triglyceride therapy in malnourished patients) and oral pancreatic enzyme supplements. A PPI is added to optimise duodenal pH for pancreatic enzyme activity.

Fig. 21.68  Imaging in chronic pancreatitis. A Computed tomogram

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Malabsorption

A

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A range of analgesic drugs, particularly NSAIDs, are valuable but the severe and unremitting nature of the pain often leads to opiate use with the risk of addiction. Analgesics, such as pregabalin and tricyclic antidepressants at a low dose, may be effective. Oral pancreatic enzyme supplements suppress pancreatic secretion and their regular use reduces analgesic consumption in some patients. Patients who are abstinent from alcohol and who have severe chronic pain that is resistant to conservative measures should be considered for surgical or endoscopic pancreatic therapy (Box 21.85). Coeliac plexus neurolysis sometimes produces long-lasting pain relief, although relapse occurs in the majority of cases. In some patients, MRCP does not show a surgically or endoscopically correctable abnormality and, in these individuals, the only surgical approach is total pancreatectomy. Unfortunately, even after this operation, some continue to experience pain. Moreover, the procedure causes diabetes, which may be difficult to control, with a high risk of hypoglycaemia (since both insulin and glucagon are absent) and significant morbidity and mortality.

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B

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Pain relief

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• Partial pancreatic resection, preserving the duodenum • Pancreatico-jejunostomy

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• Magnetic resonance cholangiopancreatography

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Surgical methods

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Tests to demonstrate anatomy prior to surgery

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• Dilatation or stenting of pancreatic duct strictures • Removal of calculi (mechanical or shock-wave lithotripsy) • Drainage of pseudocysts

Tests to define pancreatic function

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21.85  Intervention in chronic pancreatitis

Endoscopic therapy

• Ultrasound • Computed tomography (may show atrophy, calcification or ductal dilatation) • Abdominal X-ray (may show calcification) • Magnetic resonance cholangiopancreatography • Endoscopic ultrasound • Collection of pure pancreatic juice after secretin injection (gold standard but invasive and seldom used) • Pancreolauryl test (see Box 21.12, p. 777) • Faecal pancreatic elastase

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Tests to establish the diagnosis

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21.84  Investigations in chronic pancreatitis

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Diseases of the pancreas • 841

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Surgical resection is the only method of effecting cure, and 5-year survival in patients undergoing a complete resection is around 12%. Clinical trials have demonstrated improved survival (21–29%) with adjuvant chemotherapy using gemcitabine. Unfortunately, only 10–15% of tumours are resectable for cure, since most are locally advanced at the time of diagnosis. For the great majority of patients, treatment is palliative. Chemotherapy with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) improves median survival to 11 months. Pain relief can be achieved using analgesics but, in some patients, coeliac plexus neurolysis may be required. Jaundice can be relieved by choledochojejunostomy in fit patients, whereas percutaneous or endoscopic stenting is preferable in the elderly and those with very advanced disease. Ampullary or periampullary adenocarcinomas are rare neoplasms that arise from the ampulla of Vater or adjacent duodenum. They are often polypoid and may ulcerate; they frequently infiltrate the duodenum but behave less aggressively than pancreatic adenocarcinoma. Around 25% of patients undergoing resection

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Some 90% of pancreatic neoplasms are adenocarcinomas that arise from the pancreatic ducts. These tumours involve local structures and metastasise to regional lymph nodes at an early stage. Most patients have advanced disease at the time of presentation. Neuro-endocrine tumours also arise in the pancreas but tend to grow more slowly and have a better prognosis; these are discussed in detail on page 678. Pancreatic adenocarcinoma affects 10–15 per 100 000 in Western populations, rising to 100 per 100 000 in those over the age of 70. Men are affected twice

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Management

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Adenocarcinoma of the pancreas

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The diagnosis is usually made by ultrasound and contrastenhanced CT (Fig. 21.70). Diagnosis in non-jaundiced patients is often delayed because presenting symptoms are relatively non-specific. Fit patients with small, localised tumours should undergo staging to define operability. EUS or laparoscopy with laparoscopic ultrasound will define tumour size, involvement of blood vessels and metastatic spread. In patients unsuitable for surgery because of advanced disease, frailty or comorbidity, EUS- or CT-guided cytology or biopsy can be used to confirm the diagnosis (Fig. 21.70). MRCP and ERCP are sensitive methods of diagnosing pancreatic cancer and are valuable when the diagnosis is in doubt, although differentiation between cancer and localised chronic pancreatitis can be difficult. The main role of ERCP is to insert a stent into the common bile duct to relieve obstructive jaundice in inoperable patients.

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Tumours of the pancreas

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Investigations

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Mucus-rich plugs within intestinal contents can obstruct the small or large intestine of a newborn child. Meconium ileus is treated by the mucolytic agent N-acetylcysteine, given either orally, by Gastrografin enema or by gut lavage using polyethylene glycol. In resistant cases of meconium ileus, surgical resection may be necessary.

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Many patients are asymptomatic until an advanced stage, when they present with central abdominal pain, weight loss and obstructive jaundice (Fig. 21.69). The pain results from invasion of the coeliac plexus and is characteristically incessant and gnawing. It often radiates from the upper abdomen through to the back and may be eased a little by bending forwards. Almost all patients lose weight and many are cachectic. Around 60% of tumours arise from the head of the pancreas, and involvement of the common bile duct results in the development of obstructive jaundice, often with severe pruritus. A few patients present with diarrhoea, vomiting from duodenal obstruction, diabetes mellitus, recurrent venous thrombosis, acute pancreatitis or depression. Physical examination reveals clear evidence of weight loss. An abdominal mass due to the tumour itself, a palpable gallbladder or hepatic metastasis is commonly found. A palpable gallbladder in a jaundiced patient is usually the consequence of distal biliary obstruction by a pancreatic cancer (Courvoisier’s sign).

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Meconium ileus

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Clinical features

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This disease is considered in detail on page 580. The major gastrointestinal manifestations are pancreatic insufficiency and meconium ileus. Peptic ulcer and hepatobiliary disease may also occur. In cystic fibrosis, pancreatic secretions are protein- and mucus-rich. The resultant viscous juice forms plugs that obstruct the pancreatic ductules, leading to progressive destruction of acinar cells. Steatorrhoea is universal and the large-volume bulky stools predispose to rectal prolapse. Malnutrition is compounded by the metabolic demands of respiratory failure and by diabetes, which develops in 40% of patients by adolescence. Nutritional counselling and supervision are important to ensure intake of high-energy foods, providing 120–150% of the recommended intake for normal subjects. Fats are an important calorie source and, despite the presence of steatorrhoea, fat intake should not be restricted. Supplementary fat-soluble vitamins are also necessary. High-dose oral pancreatic enzymes are required, in doses sufficient to control steatorrhoea and stool frequency. A PPI aids fat digestion by producing an optimal duodenal pH.

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Cystic fibrosis

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In this congenital anomaly, the pancreas encircles the second/ third part of the duodenum, leading to gastric outlet obstruction. Annular pancreas is associated with malrotation of the intestine, atresias and cardiac anomalies.

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This is due to failure of the primitive dorsal and ventral ducts to fuse during embryonic development of the pancreas. As a consequence, most of the pancreatic drainage occurs through the smaller accessory ampulla rather than through the major ampulla. The condition occurs in 7–10% of the normal population and is usually asymptomatic, but some patients develop acute pancreatitis, chronic pancreatitis or atypical abdominal pain.

Annular pancreas

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as often as women. The disease is associated with increasing age, smoking and chronic pancreatitis. Between 5% and 10% of patients have a genetic predisposition: hereditary pancreatitis, HNPCC and familial atypical mole multiple melanoma syndrome (FAMMM). Overall survival is only 3–5%, with a median survival of 6–10 months for those with locally advanced disease and 3–5 months if metastases are present.

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Congenital abnormalities affecting the pancreas Pancreas divisum

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842 • Gastroenterology

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Venous thrombosis (‘thrombophlebitis migrans’)

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Sister Joseph’s nodule (tumour spread to umbilicus via umbilical vein)

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Pancreatic tumour mass

Erythema ab igne

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Fig. 21.69  Features of pancreatic cancer.

Fig. 21.70  Carcinoma of the pancreas. A A computed tomogram showing a large, necrotic mass encasing the coeliac axis (arrows). B Endoscopic

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ultrasound was subsequently performed to enhance staging and to obtain a fine needle aspiration biopsy, which confirmed pancreatic ductal adenocarcinoma.

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Dilated pancreatic duct

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Scratch marks (obstructive jaundice)

Cancer

Lymph node spread at early stage

Palpable gallbladder (Courvoisier’s sign)

Hepatomegaly (extrahepatic biliary obstruction/secondary deposits)

Obstructed common bile duct and dilated gallbladder

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Lymphadenopathy

Metastases common

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Vomiting from duodenal obstruction

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Jaundice Cachexia Depression

Diseases of the pancreas • 843

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bsg.org.uk British Society of Gastroenterology. crohnsandcolitis.org.uk Crohn’s and Colitis UK. coeliac.org.uk Coeliac UK. ecco-ibd.eu European Crohn’s and Colitis Organisation. gastro.org American Gastroenterological Association and American Digestive Health Foundation. isg.org.in Indian Society of Gastroenterology.

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Websites

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Canard JM, Letard J-C, Palazzo L, et al. Gastrointestinal endoscopy in practice. Edinburgh: Churchill Livingstone; 2011. Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and liver disease, 10th edn. Philadelphia: Elsevier Saunders; 2015.

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Books and journal articles

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Further information

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or to monitor depends on age and fitness of the patient and location, size and evolution of lesions.

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Cystic neoplasms of the pancreas are increasingly being seen with widespread use of CT. These are a heterogeneous group; serous cystadenomas rarely, if ever, become malignant and do not require surgery. Mucinous cysts occur more often in women, are usually in the pancreatic tail and display a spectrum of behaviour from benign to frankly malignant. Aspiration of the cyst contents for cytology and measurement of CEA and amylase concentrations in fluid obtained at EUS can help determine whether a lesion is mucinous or not. In fit patients, all mucinous lesions should be resected. A variant, called intraductal papillary mucinous neoplasia (IPMN), is often discovered coincidentally on CT, frequently in elderly men. This may affect the main pancreatic duct with marked dilatation and plugs of mucus, or may involve a side branch. The histology varies from villous adenomatous change to dysplasia or carcinoma. Since IPMN is a pre-malignant but indolent condition, the decision to resect

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of ampullary or periampullary tumours survive for 5 years, in contrast to patients with pancreatic ductal cancer.

Incidental pancreatic mass

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844 • Gastroenterology

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Cholestatic and biliary disease 902 Chemical cholestasis 902 Benign recurrent intrahepatic cholestasis 902 Intrahepatic biliary disease 902 Extrahepatic biliary disease 902 Secondary biliary cirrhosis 903 Gallstones 903 Cholecystitis 905 Choledocholithiasis 906 Tumours of the gallbladder and bile duct 907 Miscellaneous biliary disorders 908

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Autoimmune liver and biliary disease 885 Autoimmune hepatitis 886 Primary biliary cholangitis 887 Primary sclerosing cholangitis 888 IgG4-associated cholangitis 890

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Liver transplantation 900 Indications and contraindications 900 Complications 901 Prognosis 901

Non-alcoholic fatty liver disease 882

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Vascular liver disease 898 Hepatic arterial disease 898 Portal venous disease 898 Hepatic venous disease 898

Pregnancy and the liver 899 Intercurrent and pre-existing liver disease 900 Pregnancy-associated liver disease 900

Alcoholic liver disease 880

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Portal hypertension 868

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Drugs and the liver 893 Drug-induced liver injury 894

Inherited liver diseases 895 Haemochromatosis 895 Wilson’s disease 896 Alpha1-antitrypsin deficiency 897 Gilbert’s syndrome 897

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Cirrhosis 866

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Liver tumours and other focal liver lesions 890 Primary malignant tumours 890 Secondary malignant tumours 892 Benign tumours 893

Investigation of liver and hepatobiliary disease 852 Liver blood biochemistry 852 Haematological tests 853 Immunological tests 853 Imaging 853 Histological examination 855 Non-invasive markers of hepatic fibrosis 855

Presenting problems in liver disease 855 Acute liver failure 856 Abnormal liver function tests 859 Jaundice 860 Hepatomegaly 862 Ascites 862 Hepatic encephalopathy 864 Variceal bleeding 865

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Functional anatomy and physiology 848 Applied anatomy 848 Hepatic function 850

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Hepatology

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Clinical examination of the abdomen for liver and biliary disease 846

Infections and the liver 871 Viral hepatitis 871 HIV infection and the liver 879 Liver abscess 879

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QM Anstee DEJ Jones

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3 Chest Loss of body hair

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2 Face Jaundice Spider naevi Parotid swelling

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Clinical examination of the abdomen for liver and biliary disease

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846 • Hepatology

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6 Legs Bruising Oedema

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Insets (Spider naevi) From Hayes P, Simpson K. Gastroenterology and liver disease. Edinburgh: Churchill Livingstone, Elsevier Ltd; 1995; (Aspiration) Strachan M. Davidson’s Clinical cases. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2008; (Palmar erythema) Goldman L, Schafter AI. Goldman’s Cecil medicine, 24th edn. Philadelphia: WB Saunders, Elsevier Inc.; 2012.

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5 Abdomen: palpation/ percussion/auscultation Hepatomegaly Splenomegaly Ascites Palpable gallbladder Hepatic bruit (rare) Tumour

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Dilated abdominal wall veins (caput medusae)

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Aspiration of ascitic fluid

Observation • Unkempt • Smell of alcohol or fetor hepaticus • Encephalopathy • Weight loss • Scratch marks from itching

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4 Abdomen: inspection Scars Distension Veins Testicular atrophy

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1 Hands Clubbing Dupuytren’s contracture Leuconychia Bruising Flapping tremor (hepatic encephalopathy)

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Spider naevi

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Xanthelasma and jaundiced sclera in a patient with chronic cholestasis

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Gynaecomastia

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Constructional apraxia. Drawing stars and clocks may reveal marked abnormality.

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• Start in the right iliac fossa. • Progress up the abdomen 2 cm with each breath (through open mouth). • Confirm the lower border of the liver by percussion. • Detect if smooth or irregular, tender or non-tender; ascertain the shape. • Identify the upper border by percussion.

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5  Assessment of liver size Clinical assessment of hepatomegaly is important in diagnosing liver disease.

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Number connection test. These 25 numbered circles can normally be joined together within 30 secs. Serial observations may provide useful information, as long as the position of the numbers is varied to avoid the patient learning their pattern.

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Congestive heart failure

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Hepatomegaly Splenomegaly Spider naevi Generalised oedema Peripheral oedema Elevated jugular venous pressure

Renal failure (including nephrotic syndrome)

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Transudative (low protein) Cirrhosis

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Associated clinical findings

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Weight loss ± hepatomegaly Weight loss ± fever

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Exudative (high protein) Carcinoma Tuberculosis

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Causes

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• Detection of a liver-related autoantibody

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Ascites

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Serological abnormality

• Liver enzyme abnormality detected during health screening or drug monitoring

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• Observation of an unexpected structural lesion (liver mass most usually) following ultrasound, computed tomography or other imaging assessment undertaken for reasons unrelated to the liver

Biochemical abnormality

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Radiological abnormality

It is important to note that patients with liver disease can present silently following detection of abnormality on screening investigation. This occurs frequently in practice in three settings:

Flapping tremor. Jerky forward movements every 5–10 secs, when arms are outstretched and hands are dorsiflexed, suggest hepatic encephalopathy. The movements are coarser than those seen in tremor.

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Silent presentation of liver disease

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• Effects of aetiological agent, e.g. intoxication, withdrawal, cognitive impairment versus • Effects of liver injury from agent, e.g. encephalopathy

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Ongoing presence of aetiological factors (e.g. alcohol)

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• Jaundice (failure of bilirubin clearance) • Encephalopathy (failure of clearance of by-products of metabolism) • Bleeding (impaired liver synthesis of clotting factors) • Hypoglycaemia

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Catabolic status (± poor nutrition) • Skin thinning (‘paper-money skin’) • Loss of muscle bulk • Leuconychia Impaired albumin synthesis • Reduced oncotic pressure (contributes to ascites) Reduced aldosterone clearance • Na+ retention (contributes to ascites) Reduced oestrogen clearance • Mild feminisation of males (loss of body hair, gynaecomastia)

Impairment of liver function and its metabolic sequelae

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Effects of chronic liver injury (> 6 months)

These represent the combined effects of:

Assessment of encephalopathy

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Presenting clinical features of liver disease

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History and significance of abdominal signs

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Clinical examination of the abdomen for liver and biliary disease • 847

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Sphincter of Oddi

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Zone 1 (perivenous) Good O2 supply Gluconeogenesis Bile salt formation

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Pancreatic duct

Zone 2

Cholangiole Zone 3 (pericentral) Mono-oxygenation Glycolysis Lipolysis Glucuronidation

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Pancreas

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Bile duct

Central vein

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Hepatic artery

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Duodenum

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Portal vein

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Common bile duct

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C Hepatic acinus

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Portal vein Hepatic artery Bile duct

Common hepatic duct

Gallbladder Cystic duct

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Hepatic lobule

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Right Left hepatic duct hepatic duct

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Fig. 22.1  Liver blood supply.

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Hepatocytes comprise 80% of liver cells. The remaining 20% are the endothelial cells lining the sinusoids, epithelial cells lining the intrahepatic bile ducts, cells of the immune system (including macrophages (Kupffer cells) and unique populations of atypical lymphocytes), and a key population of non-parenchymal cells called stellate or Ito cells.

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Left hemiliver (LHL) Portal vein Hepatic vein

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Right hemiliver (RHL)

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Liver cells

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Inferior vena cava

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The liver weighs 1.2–1.5 kg and has multiple functions, including key roles in metabolism, control of infection, and elimination of toxins and by-products of metabolism. It is classically divided into left and right lobes by the falciform ligament, but a more useful functional division is into the right and left hemilivers, based on blood supply (Fig. 22.1). These are further divided into eight segments, according to subdivisions of the hepatic and portal veins. Each segment has its own branch of the hepatic artery and

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Normal liver structure and blood supply

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Applied anatomy

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biliary tree. The segmental anatomy of the liver has an important influence on imaging and treatment of liver tumours, given the increasing use of surgical resection. A liver segment is made up of multiple smaller units known as lobules, comprised of a central vein, radiating sinusoids separated from each other by single liver cell (hepatocyte) plates, and peripheral portal tracts. The functional unit of the liver is the hepatic acinus (Fig. 22.2). Blood flows into the acinus via a single branch of the portal vein and hepatic artery situated centrally in the portal tracts. Blood flows outwards along the hepatic sinusoids into one of several tributaries of the hepatic vein at the periphery of the acinus. Bile, formed by active and passive excretion by hepatocytes into channels called cholangioles, which lie between them, flows in the opposite direction from the periphery of the acinus. The cholangioles converge in interlobular bile ducts in the portal tracts. The hepatocytes in each acinus lie in three zones, depending on their position relative to the portal tract. Those in zone 1 are closest to the terminal branches of the portal vein and hepatic artery, and are richly supplied with oxygenated blood, and with blood containing the highest concentration of nutrients and toxins. Conversely, hepatocytes in zone 3 are furthest from the portal tracts and closest to the hepatic veins, and are therefore relatively hypoxic and exposed to lower concentrations of nutrients and toxins compared to zone 1. The different perfusion and toxin exposure patterns, and thus vulnerability, of hepatocytes in the different zones contribute to the often patchy nature of liver injury.

Functional anatomy and physiology

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848 • Hepatology

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C Hepatic acinus.

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Fig. 22.2  Liver structure and microstructure. A Liver anatomy showing relationship with pancreas, bile duct and duodenum. B Hepatic lobule.

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T cell

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NK cell

to the hepatocytes. Individual hepatocytes are separated from the leaky sinusoids by the space of Disse, which contains stellate cells that store vitamin A and play an important part in regulating liver blood flow. They may also be immunologically active and play a role in the liver’s contribution to defence against pathogens. The key role of stellate cells in terms of pathology is in the development of hepatic fibrosis, the precursor of cirrhosis. They undergo activation in response to cytokines produced following liver injury, differentiating into myofibroblasts, which are the major producers of the collagen-rich matrix that forms fibrous tissue (Fig. 22.4).

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Space of Disse Endothelial cell Hepatocyte

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Endothelial cells line the sinusoids (Fig. 22.3), a network of capillary vessels that differ from other capillary beds in the body, in that there is no basement membrane. The endothelial cells have gaps between them (fenestrae) of about 0.1 micron in diameter, allowing free flow of fluid and particulate matter

Functional anatomy and physiology • 849

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TGF-β1

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Initiation

Cytokine production (IL-10)

PDGF

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Vasoconstriction (ET1)

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Chemotaxis

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Injured hepatocyte

Fibrogenesis (TGF-β1) Matrix degeneration (MMP2, TIMP1+ 2)

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Activated Kupffer cell

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Hepatocytes provide the driving force for bile flow by creating osmotic gradients of bile acids, which form micelles in bile (bile

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= natural killer cell; PMN cell = polymorphonuclear leucocyte; T cell = T lymphocyte).

Biliary system and gallbladder

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Fig. 22.3  Non-parenchymal liver cells. (B cell = B lymphocyte; NK cell

Fig. 22.4  Pathogenic mechanisms in hepatic fibrosis. Stellate cell activation occurs under the influence of cytokines released by other cell types in the

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liver, including hepatocytes, Kupffer cells (tissue macrophages), platelets and lymphocytes. Once stellate cells become activated, they can perpetuate their own activation by synthesis of transforming growth factor beta (TGF-β1), and platelet-derived growth factor (PDGF) through autocrine loops. Activated stellate cells produce TGF-β1, stimulating the production of collagen matrix, as well as inhibitors of collagen breakdown. The inhibitors of collagen breakdown, matrix metalloproteinase 2 and 9 (MMP2 and MMP9), are inactivated in turn by tissue inhibitors TIMP1 and TIMP2, which are increased in fibrosis. Inflammation also contributes to fibrosis, with the cytokine profile produced by Th2 lymphocytes, such as interleukin-6 and 13 (IL-6 and IL-13). Activated stellate cells also produce endothelin 1 (ET1), which may contribute to portal hypertension. (EGF = epidermal growth factor; IGF1 = insulin-like growth factor 1; ROS = reactive oxygen species)

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PMN cell

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The liver is unique as an organ, as it has dual perfusion: it receives a majority of its supply via the portal vein, which drains blood from the gut via the splanchnic circulation and is the principal route for nutrient trafficking to the liver, and a minority from the hepatic artery. The portal venous contribution is 50–90%. The dual perfusion system, and the variable contribution from portal vein and hepatic artery, can have important effects on the clinical expression of liver ischaemia (which typically exhibits a less dramatic pattern than ischaemia in other organs, a fact that can sometimes lead to it being missed clinically), and can raise practical challenges in liver transplant surgery.

B cell

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Sinusoid lumen

Stellate cell

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Blood supply

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Clotting factors

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The liver produces key proteins that are involved in the coagulation cascade. Many of these coagulation factors (II, VII, IX and X) are post-translationally modified by vitamin K-dependent enzymes, and their synthesis is impaired in vitamin K deficiency (p. 918). Reduced clotting factor synthesis is an important and easily accessible biomarker of liver function in the setting of liver injury. Prothrombin time (PT; or the International Normalised Ratio, INR) is therefore one of the most important clinical tools available for the assessment of hepatocyte function. Note that the deranged PT or INR seen in liver disease may not directly equate to increased bleeding risk, as these tests do not capture the concurrent reduced synthesis of anticoagulant factors, including protein C and protein S. In general, therefore, correction of PT using blood products before minor invasive procedures should be guided by clinical risk rather than the absolute value of the PT.

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Bilirubin metabolism and bile

The liver plays a central role in the metabolism of bilirubin and is responsible for the production of bile (Fig. 22.6). Between 425 and 510 mmol (250–300 mg) of unconjugated bilirubin is produced from the catabolism of haem daily. Bilirubin in the

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converted to glycerol and fatty acids, thus preventing hyperglycaemia. During fasting, glucose is synthesised (gluconeogenesis) or released from glycogen in the liver, thereby preventing hypoglycaemia (p. 724). • The liver plays a central role in lipid metabolism, producing very low-density lipoproteins and further metabolising low- and high-density lipoproteins (see Fig. 14.13, p. 372). Dysregulation of lipid metabolism is thought to have a critical role in the pathogenesis of NAFLD. Lipids are now recognised to play a key part in the pathogenesis of hepatitis C, facilitating viral entry into hepatocytes.

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Excretion Bile salts Bilirubin Drugs Phospholipid Cholesterol

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Immune functions Local cells (Kupffer cells) Innate factors (defensins etc.)

Fig. 22.5  Important liver functions.

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The liver plays a central role in carbohydrate, lipid and amino acid metabolism, and is also involved in metabolising drugs and environmental toxins (Fig. 22.5). An important and increasingly recognised role for the liver is in the integration of metabolic pathways, regulating the response of the body to feeding and starvation. Abnormality in metabolic pathways and their regulation can play an important role both in liver disease (e.g. non-alcoholic fatty liver disease, NAFLD) and in diseases that are not conventionally regarded as diseases of the liver (such as type 2 diabetes and inborn errors of metabolism). Hepatocytes have specific pathways to handle each of the nutrients absorbed from the gut and carried to the liver via the portal vein: • Amino acids from dietary proteins are used for synthesis of plasma proteins, including albumin. The liver produces 8–14 g of albumin per day, and this plays a critical role in maintaining oncotic pressure in the vascular space and in the transport of small molecules like bilirubin, hormones and drugs throughout the body. Amino acids that are not required for the production of new proteins are broken down, with the amino group being converted ultimately to urea. • Following a meal, more than half of the glucose absorbed is taken up by the liver and stored as glycogen or

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Storage Iron Copper Vitamins A, D and B12

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Carbohydrate, amino acid and lipid metabolism

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Protein synthesis Albumin Coagulation factors Complement factors Haptoglobin Caeruloplasmin Transferrin Protease inhibitors, e.g. α1-antitrypsin

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Nutrient metabolism Carbohydrate Protein Lipids

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acid-dependent bile flow), and of sodium (bile acid-independent bile flow). Bile is secreted by hepatocytes and flows from cholangioles to the biliary canaliculi. The canaliculi join to form larger intrahepatic bile ducts, which in turn merge to form the right and left hepatic ducts. These ducts join as they emerge from the liver to form the common hepatic duct, which becomes the common bile duct after joining the cystic duct (see Fig. 22.2). The common bile duct is approximately 5 cm long and 4–6 mm wide. The distal portion of the duct passes through the head of the pancreas and usually joins the pancreatic duct before entering the duodenum through the ampullary sphincter (sphincter of Oddi). It should be noted, though, that the anatomy of the lower common bile duct can vary widely. Common bile duct pressure is maintained by rhythmic contraction and relaxation of the sphincter of Oddi; this pressure exceeds gallbladder pressure in the fasting state, so that bile normally flows into the gallbladder, where it is concentrated 10-fold by resorption of water and electrolytes. The gallbladder is a pear-shaped sac typically lying under the right hemiliver, with its fundus located anteriorly behind the tip of the 9th costal cartilage. Anatomical variation is common and should be considered when assessing patients clinically and radiologically. The function of the gallbladder is to concentrate, and provide a reservoir for, bile. Gallbladder tone is maintained by vagal activity, and cholecystokinin released from the duodenal mucosa during feeding causes gallbladder contraction and reduces sphincter pressure, so that bile flows into the duodenum. The body and neck of the gallbladder pass posteromedially towards the porta hepatis, and the cystic duct then joins it to the common hepatic duct. The cystic duct mucosa has prominent crescentic folds (valves of Heister), giving it a beaded appearance on cholangiography.

Hepatic function

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850 • Hepatology

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Approximately 9% of the normal liver is composed of immune cells (see Fig. 22.3). Cells of the innate immune system include Kupffer cells derived from blood monocytes, the liver macrophages and natural killer (NK) cells, as well as ‘classical’ B and T cells of the adaptive immune response (p. 67). An additional type of atypical lymphocyte, with phenotypic features of both T cells and NK cells, is thought to play an important role in host defence through linking of innate and adaptive immunity. The enrichment of such cells in the liver reflects the unique importance of the liver in preventing microorganisms from the gut from entering the systemic circulation. Kupffer cells constitute the largest single mass of tissue-resident macrophages in the body and account for 80% of the phagocytic capacity of this system. They remove aged and damaged red blood cells, bacteria, viruses, antigen–antibody complexes and endotoxin. They also produce a wide variety of inflammatory mediators that can act locally or may be released into the systemic circulation. The immunological environment of the liver is unique in that antigens presented within it tend to induce immunological tolerance. This is of importance in liver transplantation, where classical major histocompatibility (MHC) barriers may be crossed, and also in chronic viral infections, when immune responses may be attenuated. The mechanisms that underlie this phenomenon have not been fully defined.

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fat-soluble vitamins, as occurs in biliary obstruction, results in a coagulopathy. The liver also stores minerals such as iron, in ferritin and haemosiderin, and copper, which is excreted in bile.

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Vitamins A, D and B12 are stored by the liver in large amounts, while others, such as vitamin K and folate, are stored in smaller amounts and disappear rapidly if dietary intake is reduced. The liver is also able to metabolise vitamins to more active compounds, e.g. 7-dehydrocholesterol to 25(OH) vitamin D. Vitamin K is a fat-soluble vitamin and so the inability to absorb

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Storage of vitamins and minerals

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membrane, sodium taurocholate co-transporting polypeptide (NTCP) mediates uptake of conjugated bile acids from portal blood. At the canalicular membrane, these bile acids are secreted via the bile salt export pump (BSEP) into bile. Multidrug resistance protein 3 (MDR3), also situated on the canalicular membrane, transports phospholipid to the outer side of the membrane. This solubilises bile acids, forming micelles and protecting bile duct membranes from bile salt damage. Familial intrahepatic cholestasis 1 (FIC1) moves phosphatidylserine from the inside to the outside of the canalicular membrane; mutations result in familial cholestasis syndrome in childhood. MDR2 (multidrug resistance 2) regulates transport of glutathione. Multidrug resistance protein 2 (MRP2) transports bilirubin and is induced by rifampicin. Organic anion transporter protein (OATP) transports bilirubin and organic anions.

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blood is normally almost all unconjugated and, because it is not water-soluble, is bound to albumin and does not pass into the urine. Unconjugated bilirubin is taken up by hepatocytes at the sinusoidal membrane, where it is conjugated in the endoplasmic reticulum by UDP-glucuronyl transferase, producing bilirubin mono- and diglucuronide. Impaired conjugation by this enzyme is a cause of inherited hyperbilirubinaemias (see Box 22.17). These bilirubin conjugates are water-soluble and are exported into the bile canaliculi by specific carriers on the hepatocyte membranes. The conjugated bilirubin is excreted in the bile and passes into the duodenal lumen. Once in the intestine, conjugated bilirubin is metabolised by colonic bacteria to form stercobilinogen, which may be further oxidised to stercobilin. Both stercobilinogen and stercobilin are then excreted in the stool, contributing to its brown colour. Biliary obstruction results in reduced stercobilinogen in the stool, and the stools become pale. A small amount of stercobilinogen (4 mg/day) is absorbed from the bowel, passes through the liver and is excreted in the urine, where it is known as urobilinogen or, following further oxidisation, urobilin. The liver secretes 1–2 L of bile daily. Bile contains bile acids (formed from cholesterol), phospholipids, bilirubin and cholesterol. Several biliary transporter proteins have been identified (Fig. 22.7). Mutations in genes encoding these proteins have been identified in inherited intrahepatic biliary diseases presenting in childhood, and in adult-onset disease such as intrahepatic cholestasis of pregnancy and gallstone formation.

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Fig. 22.6  Pathway of bilirubin excretion.

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Fig. 22.7  Biliary transporter proteins. On the hepatocyte basolateral

Stercobilinogen (100 –200 mg/day)

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Large intestine

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Hepatocytes

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Bilirubin (unconjugated)

Functional anatomy and physiology • 851

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Other widely available biochemical tests may become altered in patients with liver disease: • Hyponatraemia occurs in severe liver disease due to increased production of vasopressin (antidiuretic hormone,

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Other biochemical tests

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• Detect hepatic abnormality • Measure the severity of liver damage • Detect the pattern of liver function test abnormality: hepatitic or obstructive/cholestatic • Identify the specific cause • Investigate possible complications

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22.1  Aims of investigations in patients with suspected liver disease

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Alkaline phosphatase (ALP) is the collective name given to several different enzymes that hydrolyse phosphate esters at alkaline pH. These enzymes are widely distributed in the body but the main sites of production are the liver, gastrointestinal tract, bone, placenta and kidney. ALPs are post-translationally modified, resulting in the production of several different isoenzymes, which differ in abundance in different tissues. ALP enzymes in the liver are located in cell membranes of the hepatic sinusoids and the biliary canaliculi. Accordingly, levels rise with intrahepatic and extrahepatic biliary obstruction and with sinusoidal obstruction, as occurs in infiltrative liver disease. Gamma-glutamyl transferase (GGT) is a microsomal enzyme found in many cells and tissues of the body. The highest concentrations are located in the liver, where it is produced by hepatocytes and by the epithelium lining small bile ducts. The function of GGT is to transfer glutamyl groups from γ-glutamyl peptides to other peptides and amino acids. The pattern of a modest increase in aminotransferase activity and large increases in ALP and GGT activity favours biliary obstruction and is commonly described as ‘cholestatic’ or ‘obstructive’ (Box 22.2). Isolated elevation of the serum GGT is relatively common and may occur during ingestion of microsomal enzyme-inducing drugs, including alcohol (Box 22.3), but also in NAFLD.

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Alkaline phosphatase and γ-glutamyl transferase

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Liver blood biochemistry (LFTs) includes the measurement of serum bilirubin, aminotransferases, alkaline phosphatase, γ-glutamyl transferase and albumin. Most analytes measured by LFTs are not truly ‘function’ tests but instead, given that they are released by injured hepatocytes, provide biochemical evidence of liver cell damage. Liver function per se is best assessed by the serum albumin, PT and bilirubin because of the role played by the liver in synthesis of albumin and clotting factors and in clearance of bilirubin. Although LFT abnormalities are often non-specific, the patterns are frequently helpful in directing further investigations. In addition, levels of bilirubin and albumin and the PT are related to clinical outcome in patients with severe liver disease, reflected by their use in several prognostic scores: the Child–Pugh and MELD scores in cirrhosis (see Boxes 22.29 and 22.30, pp. 867 and 868), the Glasgow score in alcoholic hepatitis (see Box 22.47, p. 882) and the King’s College Hospital criteria for liver transplantation in acute liver failure (see Box 22.11, p. 858). These established predictive models, together with emerging disease-specific scoring systems in conditions such as non-alcoholic steatohepatitis (the NASH fibrosis score) and primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis; the UK-PBC risk score), systematise the approach to assessing abnormal LFTs and can be important for the targeting of more expensive and/or invasive confirmatory diagnostic tests.

 

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are located in the cytoplasm of the hepatocyte; AST is also located in the hepatocyte mitochondria. Although both transaminase enzymes are widely distributed, expression of ALT outside the liver is relatively low and this enzyme is therefore considered more specific for hepatocellular damage. Large increases of aminotransferase activity favour hepatocellular damage, and this pattern of LFT abnormality is known as ‘hepatitic’.

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Liver blood biochemistry

m

Alanine aminotransferase and aspartate aminotransferase

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When planning investigations, it is important to be clear as to which of these goals is being addressed. Suspicion of the presence of liver disease is normally based on blood biochemistry abnormality (‘liver function tests’, or ‘LFTs’). Aetiology is typically established through a combination of history, specific blood tests and, where appropriate, imaging and liver biopsy. Staging of disease (in essence, the identification of cirrhosis) is largely histological, although there is increasing interest in noninvasive approaches, including novel imaging modalities, serum markers of fibrosis and the use of predictive scoring systems. The aims of investigation in patients with suspected liver disease are shown in Box 22.1.

The degree of elevation of bilirubin can reflect the degree of liver damage. A raised bilirubin often occurs earlier in the natural history of biliary disease (e.g. PBC) than in disease of the liver parenchyma (e.g. cirrhosis), where the hepatocytes are primarily involved. Swelling of the liver within its capsule in inflammation can, however, sometimes impair bile flow and cause an elevation of bilirubin level that is disproportionate to the degree of liver injury. Caution is therefore needed in interpreting the level of liver injury purely on the basis of bilirubin elevation. Serum albumin levels are often low in patients with liver disease. This is due to a change in the volume of distribution of albumin, and to reduced synthesis. Since the plasma half-life of albumin is about 2 weeks, albumin levels may be normal in acute liver failure but are almost always reduced in chronic liver failure.

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Investigations play an important role in the management of liver disease in three settings: • identifying the presence of liver disease • establishing the aetiology • understanding disease severity (in particular, identification of cirrhosis with its complications).

Bilirubin and albumin

m

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Investigation of liver and hepatobiliary disease

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852 • Hepatology

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↑

↑

Alcohol/enzyme-inducing drugs

N/↑

↑↑

N

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Ultrasound

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Several imaging techniques can be used to determine the site and general nature of structural lesions in the liver and biliary tree. In general, however, imaging techniques are unable to identify hepatic inflammation and have poor sensitivity for liver fibrosis unless advanced cirrhosis with portal hypertension is present.

m

m

m

m

Ultrasound is non-invasive and most commonly used as a ‘first-line’ test to identify gallstones, biliary obstruction (Fig. 22.8) or thrombosis in the hepatic vasculature. Ultrasound is good for the identification of splenomegaly and abnormalities in liver texture but is less effective at identifying diffuse parenchymal disease. Focal lesions, such as tumours, may not be detected if they are less than 2 cm in diameter and have similar echogenicity to normal liver tissue. Bubble-based contrast media are now used routinely and can enhance discriminant capability. Doppler ultrasound allows blood flow in the hepatic artery, portal vein

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Immunoglobulins Ferritin α1-antitrypsin Caeruloplasmin

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• • • •

Imaging

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22.4  Chronic liver disease screen

• Hepatitis B surface antigen • Hepatitis C antibody • Liver autoantibodies (antinuclear antibody, smooth muscle antibody, antimitochondrial antibody)

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A variety of tests are available to evaluate the aetiology of hepatic disease (Boxes 22.4 and 22.5). The presence of liverrelated autoantibodies can be suggestive of the presence of autoimmune liver disease (although false-positive results can occur in non-autoimmune inflammatory disease such as NAFLD). Elevation in overall serum immunoglobulin levels can also indicate autoimmunity (immunoglobulin G (IgG) and IgM). Elevated serum IgA can be seen, often in more advanced alcoholic liver disease and NAFLD, although the association is not specific.

 

The peripheral blood count is often abnormal and can give a clue to the underlying diagnosis: • A normochromic normocytic anaemia may reflect recent gastrointestinal haemorrhage, whereas chronic blood loss is characterised by a hypochromic microcytic anaemia secondary to iron deficiency. A high erythrocyte mean cell volume (macrocytosis) is associated with alcohol misuse, but target cells in any jaundiced patient also result in a macrocytosis. Macrocytosis can persist for a long period of time after alcohol cessation, making it a poor marker of ongoing consumption. • Leucopenia may complicate portal hypertension and hypersplenism, whereas leucocytosis may occur with cholangitis, alcoholic hepatitis and hepatic abscesses. Atypical lymphocytes are seen in infectious mononucleosis, which may be complicated by an acute hepatitis. • Thrombocytopenia is common in cirrhosis and is due to reduced platelet production and increased breakdown because of hypersplenism. Thrombopoietin, required for platelet production, is produced in the liver and levels fall with worsening liver function. Thus platelet levels are usually more depressed than white cells and haemoglobin in the presence of hypersplenism in patients with cirrhosis.

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Immunological tests

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ADH; see Fig. 14.8, p. 359). Hyponatraemia can be a significant clinical problem in liver disease with aspects that are distinct from hyponatraemia of other causes. • Serum urea may be reduced in hepatic failure, whereas levels of urea may be increased following gastrointestinal haemorrhage. • When high levels of urea are accompanied by raised bilirubin, high serum creatinine and low urinary sodium, this suggests hepatorenal failure, which carries a grave prognosis. • Significantly elevated ferritin suggests haemochromatosis. Modest elevations can be seen in inflammatory disease, NAFLD and alcohol excess.

m

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• Griseofulvin • Rifampicin • Phenytoin

Haematological tests

m

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m

m

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22.3  Drugs that increase levels of γ-glutamyltransferase

 

• Barbiturates • Carbamazepine • Ethanol

These are often abnormal in patients with liver disease. The normal half-lives of the vitamin K-dependent coagulation factors in the blood are short (5–72 hours), and so changes in the PT occur relatively quickly following liver damage; these changes provide valuable prognostic information in patients with both acute and chronic liver failure. An increased PT is evidence of severe liver damage in chronic liver disease. Vitamin K does not reverse this deficiency if it is due to liver disease, but will correct the PT if the cause is vitamin K deficiency, as may occur with biliary obstruction due to non-absorption of fat-soluble vitamins.

m

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Coagulation tests

N = normal; ↑ mild elevation ( 5 times normal). (ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase)

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↑↑

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fre

↑

Hepatitis

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Biliary obstruction

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ALP

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GGT

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AST/ALT

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Pattern

• 853

A low platelet count is often an indicator of chronic liver disease, particularly in the context of hepatomegaly. Thrombocytosis is unusual in patients with liver disease but may occur in those with active gastrointestinal haemorrhage and, rarely, in hepatocellular carcinoma.

22.2  ‘Hepatitic’ and ‘cholestatic’/‘obstructive’ liver function tests

 

Blood count

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Investigation of liver and hepatobiliary disease

HCV-RNA

AMA

Liver biopsy

Other autoimmune diseases

ASMA, ANA, LKM, immunoglobulin

Haemochromatosis

Diabetes/joint pain

Transferrin saturation, ferritin

Wilson’s disease

Neurological signs; haemolysis

Caeruloplasmin

α1-antitrypsin

Lung disease

α1-antitrypsin level

Drug-induced liver disease

Drug/herbal remedy history

LFTs

Coeliac disease

Malabsorption

Tissue transglutaminase

Liver biopsy

fre e.

HFE gene test 24-hour urinary copper

α1-antitrypsin genotype

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Liver biopsy

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Hepatic angiography is seldom used nowadays as a diagnostic tool, since CT and MRI are both able to provide images of hepatic vasculature, but it still has a therapeutic role in the embolisation of vascular tumours, such as hepatocellular carcinoma. Hepatic venography is now rarely performed.

m

m

Cholangiography

Cholangiography can be undertaken by magnetic resonance cholangiopancreatography (MRCP; Fig. 22.10), endoscopy (endoscopic retrograde cholangiopancreatography, ERCP) or the percutaneous approach (percutaneous transhepatic

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Computed tomography (CT) detects smaller focal lesions in the liver, especially when combined with contrast injection (Fig. 22.9). Magnetic resonance imaging (MRI) can also be used to localise and confirm the aetiology of focal liver lesions, particularly primary and secondary tumours.

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is small and has an irregular outline (black arrow), the spleen is enlarged (long white arrow), fluid (ascites) is seen around the liver, and collateral vessels are present around the proximal stomach (short white arrow).

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Computed tomography and magnetic resonance imaging

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Fig. 22.9  Computed tomography in a patient with cirrhosis. The liver

and hepatic veins to be investigated. Endoscopic ultrasound provides high-resolution images of the pancreas, biliary tree and liver (see below and Fig. 22.46, p. 906).

sf

m

m

m e. co

fre ks oo eb m co m

S

acoustic shadow (S).

ok

eb

eb

eb

m

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m

oo

Duodenal biopsy

(ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMA = antimitochondrial antibody; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; HBeAb = antibody to hepatitis B e antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HFE = haemochromatosis (high iron/Fe); LKM = liver–kidney microsomal antibody; MCV = mean cell volume; MRCP = magnetic resonance cholangiopancreatography)

T

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ANCA

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Autoimmune hepatitis

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HCV antibody

Itching; raised ALP

MRCP

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Injection drug use; blood transfusion

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HBeAg, HBeAb HBV-DNA

Inflammatory bowel disease

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Random blood alcohol

m

HBsAg

Fig. 22.8  Ultrasound showing a stone in the gallbladder (A) with

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Injection drug use; blood transfusion

Additional tests

Liver biopsy

Primary sclerosing cholangitis

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LFTs

m

Chronic hepatitis B

LFTs AST > ALT; high MCV

Metabolic syndrome (central obesity, diabetes, hypertension)

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Non-alcoholic fatty liver disease (NAFLD)

Initial test

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History

Chronic hepatitis C

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Alcoholic liver disease

ok s

Clinical clue

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Diagnosis

Primary biliary cholangitis

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22.5  How to identify the cause of liver function test (LFT) abnormality

re

 

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854 • Hepatology

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Presenting problems in liver disease

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Liver injury may be either acute or chronic. The main causes are listed in Figure 22.11 and discussed in detail later in the chapter. In

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An ultrasound-guided liver biopsy can confirm the severity of liver damage and provide aetiological information. It is performed percutaneously with a Trucut or Menghini needle, usually through an intercostal space under local anaesthesia, or radiologically using a transjugular approach. Percutaneous liver biopsy is a relatively safe procedure if the conditions detailed in Box 22.6 are met, but carries a mortality of about 0.01%. The main complications are abdominal and/or shoulder pain, bleeding and biliary peritonitis. Biliary peritonitis is rare and usually occurs when a biopsy is performed in a patient with obstruction of a large bile duct. Liver biopsies can be carried out in patients with defective haemostasis if: • the defect is corrected with fresh frozen plasma and platelet transfusion • the biopsy is obtained by the transjugular route, or

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Non-invasive markers of liver fibrosis can reduce the need for liver biopsy to assess the extent of fibrosis in some settings. In general, they have high negative predictive value, being able to exclude the presence of advanced fibrosis, but a relatively low positive predictive value. It is important to note that many of these tests have been validated only in certain aetiologies of liver disease and therefore results cannot be extrapolated to all other liver diseases. Alcohol-related liver disease is particularly poorly served in this respect. Serological markers of hepatic fibrosis, such as α2-macroglobulin, haptoglobin and routine clinical biochemistry tests, are used in the Fibrotest®. The Enhanced Liver Fibrosis (ELF®) serological assay uses a combination of hyaluronic acid, procollagen peptide III (PIIINP) and tissue inhibitor of metalloproteinase 1 (TIMP1). These tests are good at differentiating severe fibrosis from mild scarring but are limited in their ability to detect subtle changes. A number of non-commercial scores based on standard biochemical and anthropometric indices have also been described that provide similar levels of sensitivity and specificity (e.g. the FIB4 score, which is based on age, ALT/AST ratio and platelet count). An alternative to serological markers is vibration-controlled transient elastography (Fibroscan®), in which ultrasound-based shock waves are sent through the liver to measure liver stiffness as a surrogate for hepatic fibrosis. Once again, this test is good at differentiating severe fibrosis from mild scarring, but it is limited in its ability to detect subtle changes and validity may be affected by obesity. Similar techniques, including magnetic resonance elastography, are promising but not yet widely available.

co

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Histological examination

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Non-invasive markers of hepatic fibrosis

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Endoscopic ultrasound (EUS; p. 774) is complementary to MRCP in the diagnostic evaluation of the extrahepatic biliary tree, ampulla of Vater and pancreas. With the ultrasonic probe in the duodenum, high-quality images are obtained, tissue sampling can be performed and, increasingly, therapeutic drainage of biliary obstruction can be performed. EUS has the advantage over ERCP of not exposing patients to the risk of pancreatitis, among other complications of bile duct cannulation.

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m

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In patients with potentially resectable malignancy, biopsy should be avoided due to the potential risk of tumour dissemination. Operative or laparoscopic liver biopsy may sometimes be valuable. Although the pathological features of liver disease are complex, with several features occurring together, liver disorders can be broadly classified histologically into fatty liver (steatosis), hepatitis (inflammation, ‘grade’) and cirrhosis (fibrosis, ‘stage’). The use of special histological stains can help in determining aetiology. The clinical features and prognosis of these changes are dependent on the underlying aetiology and are discussed in the relevant sections below.

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m

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fre

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Endoscopic ultrasound

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Cooperative patient Prothrombin time  80 × 109/L Exclusion of bile duct obstruction, localised skin infection, advanced chronic obstructive pulmonary disease, marked ascites and severe anaemia

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• • • •

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cholangiography, PTC). The latter does not allow the ampulla of Vater or pancreatic duct to be visualised. Endoscopic ultrasound can also provide high-quality biliary imaging safely (see below). MRCP is as good as ERCP at providing images of the biliary tree but is safer, and there is now little, if any, role for diagnostic ERCP. Both endoscopic and percutaneous approaches allow therapeutic interventions, such as the insertion of biliary stents across bile duct strictures. The percutaneous approach is used only if it is not possible to access the bile duct endoscopically.

m

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m

a biliary stricture due to cholangiocarcinoma in the distal common bile duct (arrow). The proximal common bile duct (CBD) is dilated but the pancreatic duct (PD) is normal.

m

22.6  Conditions required for safe percutaneous liver biopsy

 

• the procedure is conducted percutaneously under ultrasound control and the needle track is then plugged with procoagulant material.

Fig. 22.10  Magnetic resonance cholangiopancreatography showing

m

Presenting problems in liver disease • 855

Abnormal liver function tests

Abnormal liver function tests

Severe

Jaundice

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co

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2010

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2005

showing the rise in liver-related mortality. From Williams R, Aspinall R, Bellis M, et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Reprinted with permission from Elsevier (The Lancet 2014; 384:1953–1997).

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2000

Fig. 22.12  Standardised UK mortality rates

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1995

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1990 Year

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1985

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1980

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0 1970

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100

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200

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Disease Circulatory Ischaemic heart Cerebrovascular Neoplasms Respiratory Liver Endocrine or metabolic Diabetes

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Standardised mortality (% change)

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300

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often evidence of chronic liver disease at presentation, may present acutely with jaundice. In alcoholic liver disease this is due to superimposed alcoholic hepatitis. (NAFLD = non-alcoholic fatty liver disease; PBC = primary biliary cholangitis; PSC = primary sclerosing cholangitis)

400

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Acute liver failure is an uncommon but serious condition characterised by a relatively rapid progressive deterioration in liver function. The presence of encephalopathy is a cardinal feature, with mental changes progressing from delirium to coma. The syndrome was originally defined further as occurring within 8 weeks of onset of the precipitating illness, in the absence of evidence of pre-existing liver disease. This distinguishes it from instances in which hepatic encephalopathy represents a deterioration in chronic liver disease. Liver failure occurs when there is insufficient metabolic and synthetic function for the needs of the patient. Although the direct cause is usually acute loss of functional hepatocytes, this can occur in different settings, which have implications for outcome and treatment. In a patient whose liver was previously normal (fulminant liver failure), the level of injury needed to cause liver

Wilson’s disease a1-antitrypsin deficiency Cryptogenic (unknown)

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significantly increased risk, whereas decompensation can be a complication in all cases and the presence of portal hypertension with intra-abdominal varices can make abdominal surgery more hazardous. The possibility of undiagnosed liver disease should be borne in mind in all patients in at-risk groups undergoing significant surgery.

Fig. 22.11  Causes of acute and chronic liver injury. *Although there is

500

Chronic liver failure* Jaundice Ascites Hepatic encephalopathy Portal hypertension with variceal bleeding

*May not occur until several years after cirrhosis has presented.

PBC PSC

600

Acute liver failure

Acute liver failure

Alcoholic liver disease*

Autoimmune hepatitis*

Signs of cirrhosis ± portal hypertension

ks

Mild/moderate

oo

Chronic liver injury

Chronic liver injury

NAFLD Haemochromatosis

fre

Acute liver injury

ks

Severity

Very severe

Chronic viral hepatitis (B + C)

Drugs

22.7  Presentation of liver disease

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Acute liver injury Viral hepatitis (A, B, E)

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the UK, liver disease is the only one of the top causes of mortality that is steadily increasing (Fig. 22.12). Mortality rates have risen substantially over the last 30 years, with a near-fivefold increase in liver-related mortality in people younger than 65 years. The rate of increase is substantially higher in the UK than in other countries in Western Europe. • Acute liver injury may present with non-specific symptoms of fatigue and abnormal LFTs, or with jaundice and acute liver failure. • Chronic liver injury is defined as hepatic injury, inflammation and/or fibrosis occurring in the liver for more than 6 months. In the early stages, patients can be asymptomatic with fluctuating abnormal LFTs. With more severe liver damage, however, the presentation can be with jaundice, portal hypertension or other signs of cirrhosis and hepatic decompensation (Box 22.7). Patients with clinically silent chronic liver disease frequently present when abnormalities in liver function are observed on routine blood testing, or when clinical events, such as an intercurrent infection or surgical intervention, cause the liver to decompensate. Patients with compensated cirrhosis can undergo most forms of surgery without

e. co m

om

m

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856 • Hepatology

Cerebral disturbance (hepatic encephalopathy and/or cerebral oedema) is the cardinal manifestation of acute liver failure, but in the early stages this can be mild and episodic, and so its absence does not exclude a significant acute liver injury. The initial clinical features are often subtle and include reduced alertness and poor concentration, progressing through behavioural abnormalities, such as restlessness and aggressive outbursts, to drowsiness and coma (Box 22.9). Cerebral oedema may occur due to increased intracranial pressure, causing unequal or abnormally reacting pupils, fixed pupils, hypertensive episodes, bradycardia, hyperventilation, profuse sweating, local or general myoclonus, focal fits or decerebrate posturing. Papilloedema occurs rarely and is a late sign. More general symptoms include weakness, nausea and vomiting. Right hypochondrial discomfort is an occasional feature. The patient may be jaundiced but jaundice may not be present at the outset (e.g. in paracetamol overdose), and there are a number of exceptions, including Reye’s syndrome, in which jaundice is rare. Occasionally, death may occur in fulminant cases of acute liver failure before jaundice develops. Fetor hepaticus can be present. The liver is usually of normal size but later becomes smaller. Hepatomegaly is unusual and, in

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m

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eb

m

m

m

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fre e.

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Any cause of liver damage can produce acute liver failure, provided it is sufficiently severe (Fig. 22.13). Acute viral hepatitis is the most common cause worldwide, whereas paracetamol toxicity (p. 137) is the most frequent cause in the UK. Acute liver failure occurs occasionally with other drugs, or from Amanita phalloides (mushroom) poisoning, in pregnancy, in Wilson’s disease, following shock (p. 199) and, rarely, in extensive malignant disease of the liver. In 10% of cases, the cause of acute liver failure remains unknown and these patients are often labelled as having ‘non-A–E viral hepatitis’ or ‘cryptogenic’ acute liver failure.

oo eb

Clinical assessment

fre

fre e. c

ok s

eb o

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m

Pathophysiology

m

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m e. co

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failure, and thus the patient risk, is very high. In a patient with pre-existing chronic liver disease, the additional acute insult needed to precipitate liver failure is much less. It is critical, therefore, to understand whether liver failure is a true acute event or an acute deterioration on a background of pre-existing injury (which may itself not have been diagnosed). Although liver biopsy may ultimately be necessary, it is the presence or absence of the clinical features suggesting chronicity that guides the clinician. More recently, newer classifications have been developed to reflect differences in presentation and outcome of acute liver failure. One such classification divides acute liver failure into hyperacute, acute and subacute, according to the interval between onset of jaundice and encephalopathy (Box 22.8).

Presenting problems in liver disease • 857

22.9  How to assess clinical grade of hepatic encephalopathy

m Common causes

Grade 1

Poor concentration, slurred speech, slow mentation, disordered sleep rhythm

 0.5 cm, inflammation, oozing, bleeding, itch or altered sensation.

e. co

e. co

m

Detailed history-taking and examination are essential: • Change: Is the lump new or has there been a change in a pre-existing lesion? What is the nature of the change – size, colour, shape or surface change? Has change been rapid or slow? Are there other features – pain, itch, inflammation, bleeding or ulceration (definition of ‘ulcer’: an area from which the epidermis and at least the upper part of the dermis have been lost – see Fig. 29.9, p. 1223)? • Patient: What is the patient’s age? Are they fair-skinned and freckled? Has there been much sun exposure? Have they used sunbeds or lived in sunny climates? Have they used photoprotection? • Site: Is it on a sun-exposed or covered site? The scalp, face, upper limbs and back in men, and face, hands and lower legs in women, are the most chronically sunexposed sites. • Are there other similar lesions? These might include actinic keratoses (see Fig. 29.13, p. 1231) or basal cell papillomas (see Fig. 29.17, p. 1234). • Morphology: Tenderness, size, symmetry, regularity of border, colour, surface characteristics and the presence of features such as crust (definition: dried exudate of blood or serous fluid – see Fig. 29.19, p. 1235), scale (definition: a flake arising from the stratum corneum; any condition with a thickened stratum corneum can cause scaling – see Fig. 29.13, p. 1231) and ulceration must be assessed. Stretching the skin and using a magnifying lens can be helpful, such as for detecting the raised, pearled edge of a basal cell carcinoma (see Fig. 29.11, p. 1229). • Dermatoscopy: This can be used to detect the presence of abnormal vessels, such as in basal cell carcinoma or the characteristic keratin cysts in basal cell papillomas. It is invaluable for assessing pigmented and vascular lesions (Fig. 29.2).

eb oo ks

m

fre e.

fre

eb

The term lump or lesion is typically used to describe a papule or nodule, although sometimes may refer to a macule or plaque (p. 1211). A new or changing lump is one of the key dermatology presentations.

m

m

eb

oo

oo ks

Lumps and lesions

m

This is a common clinical scenario and one that it is critical to resolve correctly. • The precise nature of the change should be determined (as above). Listen to the patient and pay attention to subtle changes, as people know their skin well. • If the patient has other pigmented lesions, then these should be examined too, as they may be informative. For example, if the presenting lesion looks different from the others, then suspicion of melanoma is increased; conversely, if the patient has multiple basal cell papillomas, this may be reassuring – although do not be falsely reassured. • Is there a positive family history of melanoma? A suspicious naevus in a patient with a first-degree relative with melanoma probably warrants excision.

m

e. co

ks fre

The major presentations in dermatology are outlined below. Detail of the underlying disorders is mostly provided in the disease-specific sections further on in the chapter.

Clinical assessment

Is it a melanocytic naevus or a malignant melanoma?

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m

Presenting problems in skin disease

• Asymmetry • Border irregular • Colour irregular • Diameter > 0.5 cm • Elevation irregular (+ Loss of skin markings)

m

eb o

Imaging techniques are not typically required but X-rays, ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) may occasionally be indicated in specific situations, such as in metastatic melanoma or in a patient presenting with a diagnosis of cutaneous sarcoid.

m

m

eb

oo

ok s

Imaging

29.3  ABCDE features of malignant melanoma

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planus. These diverse examples emphasise the importance of considering an underlying systemic disease when assessing a patient with a dermatological presentation.

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om

m

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1216 • Dermatology

Herald patch

Macules and papules Erythema and scale Exfoliation

Possible mucosal involvement or erythroderma

fre

ks fre

e.

Well-defined Small, erythematous plaques Collarette of scale

Upper trunk and shoulders

Lichen planus (p. 1252)

Distal limbs Flexural aspect of wrists Lower back

Shiny, flat-topped, violaceous papules Wickham’s striae

White, lacy network on buccal mucosa Nail changes Scarring alopecia Köbner phenomenon

Tinea corporis (p. 1240)

Asymmetrical Often isolated lesions

Erythematous, often annular plaques Peripheral scale (sometimes pustules) Expansion with central clearing

Possible nail, scalp, groin involvement

Trunk and proximal limbs Palms and soles

Red macules and papules, which become ‘gun-metal’ grey

History of chancre Systemic symptoms, e.g. malaise and fever

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29

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m

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Hypo- and hyper-pigmented scaly patches

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Pityriasis versicolor (p. 1240)

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Widespread

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m

co

co

m

Nail pitting, onycholysis Scalp involvement Axillae and genital areas often affected Joint involvement Köbner phenomenon (p. 1252)

Drug eruption (p. 1265)

Secondary syphilis (p. 337)

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eb

m

om

.c re e sf

m

Shiny nails Infra-orbital crease ‘Dirty neck’ (grey–brown discoloration)

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m

co m

Well-defined Erythematous plaques Silvery scale

‘Fir tree’ pattern on trunk

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oo k

Extensor surfaces Lower back

Associated signs

Poorly defined erythema, scaling Vesicles Lichenification if chronic

eb

Psoriasis (p. 1247)

Morphology

m

Face and flexures

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ks eb co m

fre e. ks oo m

m e. co fre ks

Distribution

Atopic eczema (p. 1245)

eb

Diagnosis

oo

29.4  Causes and clinical features of common scaly rashes

ks f oo

A A changing lesion. B Dermatoscopy highlights the abnormal pigment network and other features suggestive of melanoma. Excision biopsy confirmed the diagnosis of superficial spreading malignant melanoma (Breslow thickness 0.8 mm). C Another changing lesion. D Dermatoscopy highlights the vascular lacunae of this benign angioma and the patient was reassured.

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eb m m e. co fre

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m

m e. co m fre

Fig. 29.2  Dermatoscopy.

oo ks

oo eb

m

m

oo

oo eb

eb o m m e. co

ks fre

D

Pityriasis rosea (p. 1251)

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e. co m

ks

ok s

ks f oo eb

m C

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B

re

A

Presenting problems in skin disease • 1217

ks

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m

Think of immunobullous causes Bullous pemphigoid, pemphigus, linear IgA disease, bullous lupus

ok s

ok

sf

re

m

Remember blisters in drug eruptions Fixed drug eruptions, erythema multiforme, vasculitis, TEN

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sf re

ok

oo

eb

m

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re e

Toxic epidermal necrolysis* Erythema multiforme Stevens–Johnson syndrome* Bullous pemphigoid Pemphigus* Epidermolysis bullosa acquisita Lupus erythematosus Porphyria cutanea tarda Pseudoporphyria Drug eruptions

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eb re

sf

Eczema herpeticum* Dermatitis herpetiformis Acute eczema

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m m

co

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ks fre

oo

*Usually with mucosal involvement too.

Systematic approach to the diagnosis of blistering diseases

Consider common diseases in which blisters are uncommon Peripheral oedema, cellulitis, allergic contact dermatitis, other eczemas

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m

co m

fre e.

ks

oo

Impetigo Cellulitis Stasis oedema Acute eczema Insect bites Fixed drug eruption

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ks

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eb

Bullous

Fig. 29.3  A systematic approach to the diagnosis of blistering diseases. (TEN = toxic epidermal necrolysis)

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Generalised

Herpes simplex Herpes zoster Impetigo Pompholyx

m m

co

e.

Localised

Vesicular

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co m

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ks f oo eb

m Exclude infection Herpes simplex, varicella zoster, Staphylococcus aureus

29.5  Causes of acquired blisters

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fre

fre

It is important to have a short differential diagnosis based on clinical assessment in order to direct investigations. For example, in psoriasis, no investigations may be needed and initial management with patient counselling and topical therapies may suffice. If the diagnosis is unclear, then a diagnostic skin biopsy and other targeted investigations based on the clinical picture may be required. An initial management plan should also be implemented. For example, in a child presenting with a rash that has features suggestive of impetigo, skin and nasal swabs should be performed and, once these have been taken, topical or systemic antibiotics should be introduced, depending on clinical extent of disease, and management should be adjusted accordingly, dependent on investigation findings and clinical course. In contrast, if a patient presents with a maculopapular rash shortly after introduction of a new drug, then drug withdrawal, diagnostic biopsy, full blood count, including eosinophil count, and liver and renal function tests, in parallel with topical emollients and glucocorticoids, may be indicated.

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ks

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fre

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Investigations and management

eb oo ks

A blister is a fluid-filled collection in the skin. The term vesicle is used for small lesions and bulla for larger lesions (p. 1211). Blistering occurs due to loss of cell adhesion within the epidermis or subepidermal region (see Fig. 29.1). The clinical presentation depends on the site or level of blistering within the skin, which in turn reflects the underlying cause (p. 1254). There are a limited number of conditions that present with blisters (Box 29.5): • Intact blisters are not often seen if the split is high in the epidermis (below the stratum corneum), as the blister roof is so fragile that it ruptures easily, leaving erosions (definition: an area of skin denuded by complete or partial loss of the epidermis). This occurs in pemphigus foliaceus, staphylococcal scalded skin syndrome (see Fig. 29.20, p. 1236) and bullous impetigo. • If the split is lower in the epidermis, then intact flaccid blisters and erosions may be seen, as occurs in pemphigus vulgaris and toxic epidermal necrolysis (see Fig. 29.41, p. 1254). • If the split is subepidermal, then tense-roofed blisters are seen. This occurs in bullous pemphigoid (see Fig. 29.42, p. 1256), epidermolysis bullosa acquisita and porphyria cutanea tarda (see Fig. 29.52, p. 1264). • If there are foci of separation at different levels of the epidermis, as in dermatitis (p. 1244), then multilocular bullae made up of coalescing vesicles can occur.

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e. co

ks fre

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m

The morphology of the rash and the characteristics of individual lesions are important (Box 29.4).

m

Blisters

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eb o

m

m

m

eb

oo

ok s

ks f

re

Important aspects of the history include: • Age at onset and duration of rash. Atopic eczema often starts in early childhood and psoriasis between 15 and 40 years, and both may be chronic. Infective or druginduced rashes are more likely to be of short duration and the latter to occur in relation to drug ingestion. Duration of individual lesions is also important, as in urticaria, for example. • Body site at onset and distribution. Flexural sites are more typically involved in atopic eczema, and extensor surfaces and scalp in psoriasis. Symmetry is often indicative of an endogenous disease, such as psoriasis, whereas asymmetry is more common with exogenous causes, such as contact dermatitis or infections like herpes zoster. • Itch. Eczema is usually extremely itchy and psoriasis may be less so. • Preceding illness and systemic symptoms. Guttate psoriasis may be precipitated by a β-haemolytic streptococcal throat infection; almost all patients with infectious mononucleosis (p. 241) treated with amoxicillin will develop an erythematous maculopapular eruption; a history of chancre at the site of inoculation may be elicited in a presentation of secondary syphilis; malaise and arthralgia are common in drug eruptions and vasculitis.

fre

fre e. c

Clinical assessment

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m

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1218 • Dermatology

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ks

eb

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co m

ks

eb

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ks oo

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ks oo 29

eb

Psychotherapy, anxiolytics, antidepressants

m

Unknown

m

m

Treatment of infection Local corticosteroids, UVB Anti-pityrosporal treatment UVB

Unknown

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co

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Treatment of infection

m ok s

Psychogenic

eb o

eb

fre

co

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ks fre

Seborrhoeic dermatitis Unknown

Malignancy

m

Increased infection risk, e.g. candidiasis, tinea

m

Infection, infestation Eosinophilic folliculitis

Iron replacement

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co

HIV infection

oo

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ks f

Unknown Unknown 5-HT-mediated

m

UVB Oral activated charcoal

Thyrotoxicosis Hypothyroidism Carcinoid syndrome (p. 678)

Treatment*

m

Unknown; uraemia contributes

Cause of pruritus

co

Naltrexone Colestyramine Rifampicin Sedative antihistamines UVB

Medical condition

e.

Central opioid effect Elevation in bile salts may contribute

oo eb

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sf

Liver disease

Endocrine disease Diabetes mellitus

fre e.

ks

oo

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Treatment*

m

Cause of pruritus

co m

Medical condition

Haematological disease Iron deficiency Anaemia Unknown (often Polycythaemia aquagenic pruritus) rubra vera Lymphoma Unknown Laukaemia Myeloma

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eb

eb

m

29.7  Secondary causes of pruritus

Renal failure

ok s

re sf ok

sf re ok

sf

re

*In addition to specific treatment of the primary condition and symptomatic treatments, such as emollients. (5-HT = 5-hydroxytryptamine, serotonin; UVB = ultraviolet B)

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m

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ks

eb m

m

• Pediculosis • Tinea infections

oo

eb oo ks

Localised pruritus • Eczemas • Lichen planus • Dermatitis herpetiformis

It is important to determine whether skin changes are primary (a process in the skin causing itch) or secondary (skin changes caused by rubbing and scratching because of itch). This requires a thorough history and examination, sometimes with investigations, to exclude systemic disease. Many common primary skin disorders are associated with itch (Box 29.6). If itch is not connected with primary skin disease, other causes should be considered (Box 29.7). These include liver diseases (mainly cholestatic diseases, such as primary biliary cirrhosis), malignancies (generalised itch may be the presenting feature

fre

• Urticarias • Xeroderma of old age • Psoriasis

m

m

e. co

fre

• Scabies • Eczemas • Pre-bullous pemphigoid

m

Clinical assessment

29.6  Primary skin diseases causing pruritus Generalised pruritus

eb

Itch describes the unpleasant sensation that leads to scratching or rubbing. The terms ‘itch’ and ‘pruritus’ are

m

eb

Itch

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m

eb

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fre

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m

Investigations and initial management will be guided by the clinical presentation and differential diagnosis, and are described in more detail under the specific diseases. For example, an initial approach may include directed investigations, such as incisional diagnostic skin biopsy for histology and direct immunofluorescence, indirect immunofluorescence and other targeted blood tests or skin swabs. Management should be based on the likely diagnosis and begin in parallel with investigations, until the diagnosis is confirmed.

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Investigations and management

synonymous; however, ‘pruritus’ is often used when itch is generalised. Itch can arise from primary cutaneous disease or be secondary to systemic disease, which may cause itch by central or peripheral mechanisms. Even when the mechanism is peripheral, there are not always signs of primary skin disease. The nerve endings that signal itch are in the epidermis or near the dermo-epidermal junction. The underlying mechanisms of itch are not fully understood. Transmission is by unmyelinated slow-conducting C fibres through the spinothalamic tract to the thalamus and then the cortex. Aδ fibres also seem to be involved in transmitting signals to the spinal cord, and the heat-sensitive transient receptor potential (TRP) channels 1–4 are important. There is an inhibitory relationship between pain and itch. Scratching may relieve the symptom of itch after the sensation has ceased and this is either by stimulation of ascending sensory pathways that inhibit itch-transmitting neurons at the spinal cord (Wall’s ‘gate’ mechanism), or by direct damage to cutaneous sensory nerves. The mechanisms of itch in most systemic diseases remain unclear. The itch of kidney disease, for example, may be mediated by circulating endogenous opioids. The clinical observation that peritoneal dialysis helps reduce itch more frequently than haemodialysis is consistent with this, with smaller molecules generally being dialysed more readily if the peritoneal membrane is used rather than a dialysis machine membrane.

ks

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eb o

m

m

eb

oo

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Detailed history-taking and examination are critical. A history of onset, progression, mucosal involvement, drugs and systemic symptoms should be sought. Clinical assessment of the distribution, extent and morphology of the rash should be made. The Nikolsky sign is useful: sliding lateral pressure from a finger on normal-looking epidermis can dislodge and detach the epidermis in conditions with intra-epidermal defects, such as pemphigus and toxic epidermal necrolysis. A systematic approach to diagnosis is required (Fig. 29.3).

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Clinical assessment

Presenting problems in skin disease • 1219

Emollients Topical glucocorticoids Chlorphenamine UVB

ks oo m

m

m

Investigate for underlying causes of itch (Box 29.7)

co

co

Fig. 29.4  An overall approach to the investigation and management of itch (pruritus).

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oo

m

m

m

m

eb

eb o

Cutaneous photosensitivity is an abnormal response of the skin to UVR or visible radiation. The sun is the natural source but patients may also be exposed to artificial sources of UVR through the use of sunbeds and/or phototherapy (p. 1227). Chronic UVR exposure increases skin cancer risk and photo-ageing (p. 1215). Acute exposure can induce erythema (redness) as a normal response (Fig. 29.5). However, abnormal photosensitivity occurs when a patient reacts to lower doses than would normally cause a response, either with a heightened erythemal reaction or the development of a rash. Photo-aggravated skin diseases are exacerbated by sunlight but not caused by it. The main photosensitive and photo-aggravated diseases are listed in Box 29.9.

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fre ok s

Photosensitivity

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ok

sf

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co

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sf re

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ks oo eb

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eb m

Diagnose and manage underlying skin disease (Box 29.6)

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ks fre

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eb

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co

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Only secondary changes of excoriation due to itch

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co m

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Itch, no rash

sf

fre

Itch plus rash

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Investigations should be directed towards finding an underlying cause and there will be a different approach for itch with rash, as opposed to itch with no signs of primary skin disease (Fig. 29.4). If there are no signs of primary skin disease, investigations should be undertaken to exclude systemic disease or iatrogenic causes. Psychogenic itch should be considered only if organic disease has been ruled out. There are no consistently effective therapies to suppress itch, and so establishing the underlying cause is critical. If a clear-cut diagnosis cannot be made, non-specific approaches can be used for symptom relief. These include sedation, often with H1 receptor antihistamines, along with emollients and counter-irritants (such as topical menthol-containing preparations). UVB phototherapy is useful for generalised itch due to a variety of causes but the only randomised controlled study of efficacy is in chronic kidney disease. Other treatments include low-dose tricyclic antidepressants (probably through similar mechanisms to those involved when these drugs are used for chronic pain) and opiate antagonists. If a psychogenic itch is considered likely, antidepressants and/or cognitive behavioural therapy may be effective. Itch of any cause can be severe and its potentially major adverse effects on quality of life are not always fully appreciated. Assessments of impact on quality of life, such as Dermatology Life Quality Index (DLQI) scores, are essential.

re

Itch (pruritus)

Primary skin disease

Investigations and management

sf

fre e. ks oo m

m

eb

eb

eb

of lymphoma), haematological conditions (generalised itch in chronic iron deficiency or water contact-provoked (aquagenic) intense itch in polycythaemia), endocrine diseases (including hypo- and hyperthyroidism), chronic kidney disease (in which severity of itch is not always clearly associated with plasma creatinine concentration) and psychogenic causes (such as in ‘delusions of infestation’). Itch is common in pregnancy and may be due to one of the pregnancy-specific dermatoses. Making a correct diagnosis is particularly important in pregnancy, as some disorders can be associated with increased fetal risk (Box 29.8).

eb oo ks

Topical glucocorticoids UVB

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oo

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3rd trimester Sterile pustules on trunk

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co m

2nd trimester Excoriated papules

(UVB = ultraviolet B)

ok

ks

Topical or oral glucocorticoids

fre

Pruritic folliculitis

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oo

Any stage, often 2nd trimester and commonly recurs in subsequent pregnancies Urticated erythema, blistering initially periumbilical Characteristic histology and immunofluorescence

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m

eb

eb o

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Prurigo gestationis

Emollients Chlorphenamine Colestyramine UVB Early delivery

ks

3rd trimester and commonly recurs in subsequent pregnancies Abnormal liver function tests Increased fetal and maternal risk

oo

Acute cholestasis of pregnancy (p. 1284)

Chlorphenamine, emollients Topical glucocorticoids

eb

Typically first pregnancy and uncommonly recurs 3rd trimester, after delivery Polymorphic urticated papules and plaques, start in striae

m

Polymorphic eruption of pregnancy (pruritic urticarial papules and plaques, PUPP)

m

Treatment

ok s

Pregnancy, gestation and features

ks f

Diagnosis

Pemphigoid gestationis

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29.8  Causes of pruritus in pregnancy

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1220 • Dermatology

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Seasonal, itchy, papulovesicular rash on photo-exposed sites; face and back of hands often spared. Often hours of UVR exposure needed to provoke; lasts a few days; affects about 20% in Northern Europe, more common in young women Chronic dermatitis on sun-exposed sites. Most common in elderly males. Predominantly UVB, but also often UVA and visible light photosensitivity. Most also have contact allergies Immediate-onset urticaria on photo-exposed sites. Usually UVA and visible light photosensitivity. Can occur at any age Uncommon, presents in childhood. Often familial, with strong HLA association. Some similarities to PLE, although scarring occurs Rare childhood photodermatosis. Varioliform scarring

fre

Porphyrias Pellagra

Photogenodermatoses

Xeroderma pigmentosum

Photo-aggravation of pre-existing conditions

Lupus erythematosus Erythema multiforme Rosacea

m

Mainly porphyria cutanea tarda and erythropoietic protoporphyria (p. 378). Photo-exposed site dermatitis due to tryptophan deficiency (see Fig. 14.15, p. 378)

oo

ks

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Metabolic

eb

eb

eb

Rare. Defect in DNA excision repair, abnormal photosensitivity, photo-ageing and skin cancer. There may be neurological features

ks

Pseudoporphyria Photoallergy

Usually UVA (and visible light) photosensitivity Most common. Exaggerated sunburn and exfoliation. Many drugs such as thiazides, tetracyclines, fluoroquinolones, quinine, NSAIDs NSAIDs, retinoids, tetracyclines, furosemide are examples Usually to topical agents, particularly sunscreens and NSAIDs

fre e.

Phototoxicity

co m

e. co m

Hydroa vacciniforme

Can also be drug-induced (see Box 29.35, p. 1266) p. 1264 p. 1243

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m

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eb

oo

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Drugs (variety of mechanisms)

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Actinic prurigo

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eb

m

m

m

Solar urticaria

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ks

eb o

Chronic actinic dermatitis (CAD)

eb

Polymorphic light eruption (PLE)

fre

Immunological (previously known as idiopathic)

eb

oo

Clinical features

ok s

Condition

ks f

Cause

oo

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29.9  The photosensitivity and photo-aggravated diseases

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Presenting problems in skin disease • 1221

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29

m

m co

Investigations and management

e. co

ok s

sf

re

e.

If photosensitivity is suspected, the patient should be referred to a specialist centre for monochromator phototesting (p. 1215), if feasible. Other investigations will often include provocation,

ok

sf re

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fre

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m

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e.

The arbitrary division between UVB and UVA regions is more often considered to be at 320 nm by photobiologists, and the UVA region can be further subdivided into UVA2 (320–340 nm)

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m

co

e.

ks fre

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Sunlight consists mainly of visible light, and the UVR component is divided into three wavebands (Fig. 29.6), according to the Commission Internationale de l’Eclairage (CIE): • UVC (200–280 nm), which is absorbed by ozone and does not reach the Earth’s surface. • UVB (280–315 nm), which constitutes less than 10% of UVR exposure but is around 1000-fold more potent than UVA and so accounts for the erythemal ‘sunburning’ effects of sunlight. • UVA (315–400 nm), which is the most abundant UVR component reaching the Earth’s surface.

ok

Taking a careful history is essential, as the patient may not have the rash when assessed. Seasonal pattern and distribution of rash are important. Key sites are the face (particularly nose, cheeks and forehead), top of ears, neck (Fig. 29.7), bald scalp, back of hands and forearms. Sparing is often seen under the chin and nose, behind the ears, on the upper eyelids and the distal digits – as we normally walk about with our eyes open and fingers flexed! It can be misleading if there is covered site involvement. Patients who are sensitive to UVA and visible light may be affected through clothing. These patients commonly experience perennial symptoms and may not be aware of the association with daylight exposure. Other photosensitive conditions, such as actinic prurigo or chronic actinic dermatitis, may also involve covered sites. Sparing of habitually exposed sites, such as the face and back of hands, occurs most commonly in polymorphic light eruption (PLE) and is called the ‘hardening phenomenon’. Importantly, some conditions, such as solar urticaria, develop rapidly after sunlight exposure, whereas others, such as cutaneous lupus, can take several days to evolve.

m

m co m

e.

erythemal response that peaks 12–24 hours later. Sensitivity depends on the individual’s constitutive skin phototype.

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.c

sf

eb

eb

oo

oo k

ks

eb oo ks

m

Clinical assessment

Fig. 29.5  Sunburn. Acute exposure to ultraviolet radiation results in an

m

re e

and UVA1 (340–400 nm). UVA2 behaves biologically more like UVB, and UVA1 can be used therapeutically for several skin conditions, such as morphoea and eczema. Patients with photosensitivity diseases can be abnormally sensitive to UVB, UVA, visible light (over 400 nm) or, commonly, a combination of wavebands. UVB is absorbed by window glass, whereas UVA and visible light are transmitted through glass.

fre

fre

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m

m

(HLA = human leucocyte antigen; NSAID = non-steroidal anti-inflammatory drug; UVA/UVB = ultraviolet A/B; UVR = ultraviolet radiation)

fre e. c

Sunscreens

320 nm

760 nm

400 nm

eb

oo

oo Infrared

m

290 nm

Visible

UVA1

m

Wavelength 200 nm

UVA2

eb

UVA

UVB

m

UVC

ks

ks

ok s

Grenz rays X-rays

eb o

oo

ks f

Window glass Atmospheric ozone

m

eb

fre

re

Behavioural avoidance, shelter, clothing

UVR absorbers or reflectors

γ-rays

e. co m

om

m

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1222 • Dermatology

Skin cancer

ks

ks

Most photodermatoses

oo

eb

eb

oo

Most drug photosensitivity

Fig. 29.6  The electromagnetic spectrum. The action spectrum is not well defined for many conditions and, for some, is approximate and may vary between patients. The action spectrum for non-melanoma skin cancer mirrors that for erythema. The action spectrum for melanoma is not known but includes ultraviolet (UV) B. Photoprotection measures vary, depending on condition, although the mainstay always includes behavioural modification, clothing cover and appropriate sunscreen choices. (UVR = ultraviolet radiation)

om

re e

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eb

oo

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fre

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eb o

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m

m

m

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ok

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co

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sf re

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sf

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co e.

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eb

m

m

co

e.

re

Sunscreens can be divided into two categories: chemical sunscreens, which absorb specific wavelengths of UVR, and physical sunscreens, which reflect UVR and the shorter visible wavelengths (see Fig. 29.6). Sunscreens are now highly sophisticated and most offer protection against UVB and most UVA wavelengths. If a patient is abnormally photosensitive to the longer wavelengths of UVA and the visible part of the spectrum (for example, in cutaneous porphyrias and solar urticaria), then conventional sunscreens are not beneficial and specific reflectant sunscreens are required. Historically, these agents were less cosmetically acceptable due to visible light reflection, but current formulations, some of which are tinted, have reduced this problem. Sunscreen protection levels are described by sun protection factor (SPF). This is the ratio of the dose of UVR required to produce skin erythema in the presence and absence of the sunscreen. A sunscreen of SPF20 means that it would take 20 times as long for a person to develop sunburn in the presence of the sunscreen, as compared to not using it. Therefore, SPF is really a sunburn protection factor and is not a good guide to how well a sunscreen will perform in protecting against other reactions (such as skin pain in erythropoietic protoporphyria or UVR-induced immunosuppression). SPF values are determined under experimental conditions whereas, in practice, people tend to use 25–33% of the amount of sunscreen required to achieve

m

co m e.

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oo

patch or photopatch testing and screening for lupus and the porphyrias (p. 1263). Rarely, investigations such as human leucocyte antigen (HLA) typing in suspected actinic prurigo, or DNA excision repair functional activity or genotyping in suspected xeroderma pigmentosum, may be required. Management depends on the cause. If there is a phototoxic drug or chemical cause, this must be addressed: for instance, by stopping the drug or treating the porphyria. Counselling in regard to sun avoidance is essential: keeping out of direct sun in the middle of the day, covering up with clothing, wearing hats with a wide brim and careful use of high-factor sunscreens. Paradoxically, in some conditions, particularly PLE and solar urticaria, phototherapy can be used to induce ‘hardening’; the

sf

eb

oo k

ks oo eb m

Sunscreens

behind the ear in the shadow cast by the earlobe (Wilkinson’s triangle).

ok

.c

e. co fre

fre eb oo ks

m

m

m

m

m e. co

mechanism of desensitisation is uncertain. Other approaches may be necessary, depending on disease and severity, and may include antihistamines (useful in two-thirds of patients with solar urticaria) and systemic immunosuppression (sometimes required in the immunological photodermatoses). Patients with photosensitivity are at risk of vitamin D deficiency because of reduced synthesis in the skin and should be advised to optimise dietary vitamin D intake or take supplements (p. 1052).

Fig. 29.7  Chronic actinic dermatitis. Note the sharp cut-off and sparing

eb

fre e.

Porphyria

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m

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fre

ks fre

Skin ageing

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e. co

Pigmentation

Skin disorders and the main wavelengths involved

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co m

e. co m

m

Sunburn (erythema)

fre

oo eb m om .c re e

Posterior

Arterial

Neuropathic

eb

eb

eb

oo

Vasculitis

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ks

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Venous

tend to affect particular sites.

m

m

m

Venous hypertension

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ks oo eb m m

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fre

Anterior

Fig. 29.8  Causes of lower limb ulceration. The main types of leg ulcer

29.10  Causes of leg ulceration

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fre

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m

fre e.

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ks fre

Leg ulceration due to venous disease

Varicose veins, a history of deep venous thrombosis and obesity are predisposing factors. Incompetent valves in the deep and perforating veins of the lower leg result in retrograde flow of blood to the superficial system, and a rise in capillary pressure (‘venous hypertension’). Pericapillary fibrin cuffing occurs, leading to impairment of local tissue oxygenation and homeostasis. The first symptom in venous ulceration is often heaviness of the legs, followed by oedema. Haemosiderin pigmentation, pallor and firmness of surrounding skin, and sometimes venous/gravitational eczema (p. 1247) subsequently develop. This progresses to lipodermatosclerosis – firm induration due to fibrosis of the dermis

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m

Deep, painful, punched-out ulcers on the lower leg, especially the shin and foot and in the context of intermittent claudication, are

A detailed history of the onset and course of leg ulceration and predisposing conditions should be elicited. The site and surrounding skin should be assessed. Varicose veins are often present, although not inevitably. Assessment of the venous and arterial vasculature and neurological examination are critical. The site of ulceration may also help to indicate the underlying primary cause (Fig. 29.8). Full clinical examination is essential as the ulcer may be arising in the context of systemic disease, such as vasculitis.

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m

Leg ulceration due to arterial disease

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Clinical assessment

and subcutis, which may produce the well-known ‘inverted champagne bottle’ appearance. Ulceration, often precipitated by trauma or infection, follows. Venous ulcers typically occur on the medial lower leg (Fig. 29.9). Complications of venous leg ulceration include bacterial colonisation and infection, and contact allergic dermatitis to topical medicaments, dressings and bandages. Lipodermatosclerosis may cause lymphoedema and hyperkeratosis; rarely, a squamous cell carcinoma (SCC) may develop in a long-standing venous ulcer (Marjolin’s ulcer).

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eb o

Leg ulcer is not a diagnosis, but a symptom of an underlying disease in which there is complete loss of the epidermis, leaving dermal layers exposed. Ulcers on the lower leg are frequently caused by vascular disease but there are other causes, as summarised in Box 29.10.

m

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eb

oo

Leg ulcers

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om

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the stated SPF. Patient counselling is therefore important with regard to adequate application of sunscreen. All sunscreens offer, at best, partial protection only and are no substitute for modifying behaviour and covering up.

Presenting problems in skin disease • 1223

• Sometimes following deep vein thrombosis

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29

• Syphilis

m

m

• Diabetes mellitus • Leprosy (Hansen’s disease)

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Neuropathy

e.

• Myeloma • Waldenström’s macroglobulinaemia • Immune complex disease

ks fre

Sickle-cell disease Cryoglobulinaemia Spherocytosis Polycythaemia

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m co

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• Malignant melanoma • Kaposi’s sarcoma

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sf re

surrounding lipodermatosclerosis.

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Fig. 29.9  A chronic venous ulcer on the medial lower leg, with

• Factitious

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• Injury

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Trauma

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m

• Squamous cell carcinoma • Basal cell carcinoma

m

Tumour

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• • • •

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re

• Vasculitis

Haematological disorders

m

• Buerger’s disease

Small-vessel disease • Diabetes mellitus

m

• Atherosclerosis • Vasculitis

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co m

Arterial disease

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ks

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m

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Clinical assessment

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Detailed history-taking and full examination are required. Particular attention should be paid to drug history, chronology and history of any preceding skin disease. Eczema, psoriasis, drug eruptions and cutaneous T-cell lymphoma (Sézary’s syndrome, p. 1232) are among the diseases that can either present with, or progress to, erythroderma. Other causes include the psoriasis-like condition, pityriasis rubra pilaris, and rare types of ichthyosis. Erythroderma may occur at any age and is associated with severe morbidity and significant mortality (see Fig. 29.35D, p. 1249). Older people are at greatest risk, especially if they have comorbidities. Erythroderma may appear suddenly or evolve slowly. In dark skin, the presence of pigmentation may mask erythema, giving a purplish hue. Erythrodermic patients are usually systemically unwell with shivering and hypothermia, secondary to excess heat loss. They may also be pyrexial, however, and unable to lose heat due to damage to sweat gland function and sweat duct occlusion.

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ok s

ok

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co

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sf re

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ks

oo

oo

Acute skin failure is a medical emergency. Several conditions can cause widespread and acute failure of many skin functions (see Box 29.1, p. 1214), including thermoregulation, fluid balance control and barrier to infection. Many of these conditions involve widespread dilatation of the dermal vasculature and can provoke high-output cardiac failure; they are also associated with increased protein loss from the skin and often from the gut. Many lead to acute skin failure by causing erythroderma (erythema affecting at least 90% of the body surface area), although severe autoimmune blistering diseases and the spectrum of Stevens–Johnson syndrome/toxic epidermal necrolysis (TEN) disease can produce acute skin failure without erythroderma (p. 1254).

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Acute skin failure

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ks f

sf ok

Many conditions affect the skin appendages, particularly hair and nails. Conditions causing hair loss (alopecia) are listed in Box 29.30 (p. 1259). Nail changes may be a marker for systemic disease (e.g. iron deficiency) or be a feature of certain skin conditions (e.g. psoriasis).

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General advice on exercise, weight loss and smoking cessation is important in all cases. Specific management depends on making the correct diagnosis to identify the cause(s) of ulceration. Underlying factors, such as diabetes or anaemia, must be treated. Oedema must be reduced by leg elevation and, if there is no arterial compromise, graduated compression bandaging from toes to knees to enhance venous return and improve healing. Compression bandaging is effective for individuals with an ABPI of more than 0.8 but should be avoided if the ABPI is less than 0.8. If the ulcer is purulent, weak potassium permanganate soaks may help, and exudate and slough can be removed with normal saline or clean water. Dressings do not themselves heal leg ulcers, but can reduce discomfort and odour and, by reducing colonisation by potential pathogens, may reduce the frequency of secondary infection. A variety of dressings may be used, including non-adherent and absorbent (alginates, hydrogels, hydrocolloids) types. The frequency of dressing changes varies; heavily exudative ulcers may need daily dressings, whereas changes once weekly may suffice for drier ulcers. Occasionally, leeches may be used topically for ulcers with heavy adherent exudate. Surrounding eczema should be suppressed with a topical glucocorticoid. Commonly, this is venous eczema, but there should be a low threshold for referral for patch testing, as contact allergy to topical applications is common (p. 1215). Systemic antibiotics are indicated only if there is evidence of infection, as opposed to colonisation. Various techniques of split-thickness

oo eb

Hair and nail abnormalities

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fre

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Management

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Appropriate investigations include: • Full blood count to detect anaemia and blood dyscrasias. • Urea and electrolytes to assess renal function. • Urinalysis for glycosuria. • Bacterial swab if there is a purulent discharge, rapid extension, cellulitis, lymphangitis or sepsis. This can guide antibiotic therapy for secondary infection but pathogenic bacteria are not always the same as those identified from the ulcer surface. • Doppler ultrasound to assess arterial circulation. An ankle systolic pressure to brachial systolic pressure index (ABPI) of below 0.8 suggests significant arterial disease and a vascular surgery opinion should be sought. However, arterial calcification, such as in diabetes, can produce a spuriously high ABPI. Pulse oximetry may also be useful, although ABPI is the preferred investigation if feasible.

m

Investigations

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fre

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m

The most common causes of neuropathic ulcers are diabetes and leprosy. Microangiopathy also contributes to ulceration in diabetes (p. 758). The ulcers occur over weight-bearing areas, such as the heel. In the presence of neuropathy, protection of skin from trauma is essential to prevent ulceration.

Loss of skin pigmentation (depigmentation), reduction in pigmentation (hypopigmentation) and increased pigment (hyperpigmentation) are features of a variety of disorders. A detailed history and examination, including use of a Wood’s light, are required to establish the diagnosis. Investigations will depend on the presentation. For example, microscopy of skin scrapings should be undertaken if hypopigmentation is associated with inflammation and scaling; screening for autoimmune disease may be required if vitiligo is suspected; and investigation for endocrine disease or the porphyrias may be appropriate in hyperpigmentation. Further details of the specific conditions are included on page 1257.

eb

Leg ulceration due to neuropathy

Abnormal pigmentation

eb

eb o

Vasculitis can cause leg ulceration either directly through epidermal necrosis due to damage to the underlying vasculature, or indirectly due to neuropathy.

m

m

eb

Leg ulceration due to vasculitis

grafting (such as pinch and mince grafts) may hasten healing of clean ulcers but do not reduce recurrence risk. Leg ulcers can be very persistent. Symptomatic relief, including oral analgesics and sometimes chronic pain management, is important. Once the ulcer has healed, ongoing use of compression hosiery may limit the risk of recurrence.

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oo

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re

likely to be due to arterial disease. Risk factors include smoking, hypertension, diabetes and hyperlipidaemia. The foot is cold and dusky, and the skin atrophic and hairless. Peripheral pulses are absent or reduced. A vascular surgical assessment should be sought urgently (p. 502).

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1224 • Dermatology

impact of the disease on quality of life and the person’s support network. The psychological impact of chronic skin diseases should not be under-estimated and it is important to remember that psychiatric illness can also manifest as a skin disease, such as in delusions of infestation or trichotillomania. Careful clinical assessment, taking psychological factors into account, is essential and any management strategy must include approaches to address the psychological well-being of the patient.

Avoid hair-bearing areas and flexures

Moderate

Cooling effect Cleans the skin and removes exudates

Large areas of the skin and the scalp

Low

Pastes

Semi-solid preparations consisting of finely powdered solids suspended in an ointment

Occlusive, protective Hydrating Circumscribed skin lesions, (psoriasis, lichen simplex chronicus)

Any area of skin Often used in medicated bandages

Moderate

Moderate

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ok s

re sf ok

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sf re ok

co e.

m

Good

m

Hair-bearing areas and the face

m

For specific sites

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eb

29

Thickened lotions Hydrophilic and hydrophobic bases

sf

ks

Rare

oo

Good, but can sting if in an alcoholic base

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eb o

m

Low

Gels

ok

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co

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fre

e.

ks fre

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m

ok s

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co

co m

Acute presentations Cooling, soothing Well absorbed Mild emollients

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eb

Chronic dry skin conditions Occlusive and emollient Hydrating Mildly anti-inflammatory

Emulsions of oil and water (aqueous cream)

Water-based Liquid formulations Often antiseptic and astringent (potassium permanganate)

m Significant, due to preservatives, antimicrobials and often lanolin

Creams

m

Very good Helps adherence

Site

re

m

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re e

sf

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eb m All sites, including mucous membranes and flexures, but not hair-bearing areas

Use

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fre

ks

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Risk of contact sensitisation

Definition

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Cosmetic acceptability

Vehicle

Greasy preparations Insoluble in water (white soft paraffin) Soluble (emulsifying ointment)

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fre e.

fre

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eb

eb

29.11  Characteristics of vehicles used in topical treatments

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General measures that apply in all skin diseases include establishment of the correct diagnosis, removal of precipitating or aggravating factors, use of safe, effective treatments and consideration of the patient holistically, taking into account the

Lotions

m

m

Topical treatments are first-line therapy for most skin diseases and many can be treated effectively by topical therapies alone. Selection of the appropriate active drug/ingredient and vehicle is essential. Ointments are preferred to creams for dry skin conditions, such as chronic eczemas, as they are more hydrating and contain fewer preservatives than creams, and so allergy risk is reduced. However, patients find creams easier to apply and so adherence may be better. Gels and lotions can be easier to use on hair-bearing sites. The molecular weight and lipid–water coefficient of a drug determine its skin penetration, with larger, water-soluble, polar molecules penetrating poorly. In skin disease, if the stratum corneum is impaired – as in eczema – increased drug absorption occurs. Occlusion under dressings also increases absorption. Drugs can be used in different potencies or concentrations, or in combination with other active ingredients, and many are available in more than one formulation. The properties of different vehicles are listed in Box 29.11. Overall, adherence to topical treatments can be problematic, so it is essential for patients to know exactly what is required of them and for regimens to be kept as simple as possible. Emollients, topical glucocorticoids and other selected key topical therapies that are widely used in a diverse range of skin conditions are detailed below. For the more diseasespecific therapies, detailed descriptions are included in the disease sections.

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General measures

Ointments

eb

eb

Topical treatments

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m

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ks fre oo eb

m

Principles of management of skin disease

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Investigations are required to establish the underlying cause and to identify any systemic impact, such as hypoalbuminaemia and electrolyte disturbances. Skin biopsy may be necessary if the cause is unclear. Regardless of the cause, important aspects of the management of erythroderma include supportive measures to ensure adequate hydration, maintenance of core temperature and adequate nutrition. Insensible fluid loss can be many litres above normal losses. Protein may be lost directly from the skin and through the gut because of the protein-losing enteropathy that often accompanies conditions such as erythrodermic psoriasis. To reduce the risks of infection, any intravenous cannulae should be sited in peripheral veins, if possible. In the initial management of acute erythroderma, urinary catheterisation is often required (for patient comfort and accurate fluid balance monitoring) but catheters should be removed as soon as possible. Frequent application of a simple ointment emollient (such as white soft paraffin/liquid paraffin mix) is usually appropriate.

m

m

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Investigations and management

• 1225

fre

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Tachycardia and hypotension may be present because of volume depletion. Peripheral oedema is common in erythroderma, owing to low albumin and high-output cardiac failure. Lymph nodes may be enlarged, either as a reaction to skin inflammation or, rarely, due to lymphomatous infiltration.

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m e. co

Principles of management of skin disease

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fre

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ok s

Topical imiquimod was introduced for the treatment of anogenital warts but can be used for a diverse range of other skin diseases, including actinic keratosis, Bowen’s disease, basal cell carcinoma, lentigo maligna, cutaneous lupus and common and planar warts. Its mechanism of action is via stimulation of endogenous Th2 immune responses and release of cytokines, including interferon-gamma (IFN-γ). It can cause significant inflammation, requiring dose adjustments, but subclinical disease may respond to treatment.

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fre

Immune response modifiers

m co

e. co

ok s

sf

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e.

A ‘wound’ covering is called a dressing. Box 29.13 shows the indications for their use. The active agent, vehicle and ‘wound’ type should be considered. Wet lesions should be treated with

ok

sf re ok

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ks

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eb

m

eb

m

m co

The topical calcineurin inhibitors, tacrolimus and pimecrolimus, can be used to treat eczema and a variety of other conditions, through local cutaneous immunosuppression (p. 1244).

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co

e.

*UK trade names are given in brackets.

re

Calcineurin inhibitors

Dressings

• Clobetasol propionate 0.05% (Dermovate)

sf

Antiseptics should be considered before antibiotics, as they cover a wide range of organisms and help to reduce the risk of antibiotic resistance. Antibiotics can be used either for their anti-infective properties (p. 1236) or for their anti-inflammatory properties (pp. 1242 and 1244). Topical antiviral and antifungal agents are also widely used for a range of mild skin infections (p. 1239).

eb o

eb

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Betamethasone valerate 0.1% (Betnovate) Betamethasone valerate 0.1% and clioquinol 3% (Betnovate-C) Fluocinolone acetonide 0.025% (Synalar) Hydrocortisone butyrate 0.1% (Locoid) Mometasone furoate 0.1% (Elocon)

Very potent

Anti-infective agents

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oo

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• Clobetasone butyrate 0.05% (Eumovate) • Betamethasone valerate 0.025% (Betnovate-RD) • Fluocinolone acetonide 0.00625% (Synalar 1 : 4)

ok

cessation of use. Nevertheless, glucocorticoids are invaluable for many sites, particularly the flexures. Topical glucocorticoids are often formulated in combination with antiseptics, antibiotics or antifungals, and their controlled use may be appropriate in infected eczema or flexural psoriasis. Intralesional injections of glucocorticoids can be used in a variety of indications, including nodular prurigo, keloid scar (definition of ‘scar’: replacement of normal structures by fibrous tissue at the site of an injury, although keloid scar describes a pathological process extending beyond the site of injury), acne cysts and alopecia areata.

e. co

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oo

eb

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co m

e.

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ks f

Moderate

eb

topical glucocorticoid use.

fre

fre

eb oo ks

m

• Hydrocortisone 0.5%, 1%, 2.5% • Hydrocortisone 1% and fusidic acid 2% (Fucidin H)

• • • • •

Fig. 29.10  Striae and atrophy induced by excess prolonged potent

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m

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fre

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m

Glucocorticoids are available in a variety of formulations, potencies and strengths, most commonly as creams and ointments (Box 29.12). Selection of the correct product depends on the condition being treated, body site and duration of expected use. Mild topical glucocorticoids are used in delicate areas, such as the face or genitals, and close supervision of glucocorticoid use at these sites is required. In contrast, very potent glucocorticoids may be required under occlusion for chronic resistant disease such as nodular prurigo. Adverse cutaneous effects of chronic glucocorticoid use include atrophy (definition: an area of thin, translucent skin caused by loss of epidermis, dermis or subcutaneous fat – Fig. 29.10), striae (definition: linear, atrophic, pink, purple or white bands caused by connective tissue changes – Fig. 29.10), petechiae and purpura (definition: haemorrhagic macules or papules caused by extravasated blood – see p. 1211) and telangiectasiae (definition: visible dilatations of small cutaneous blood vessels – see Fig. 29.11A), increased risk of infection and systemic absorption, causing Cushingoid features and suppression of the hypothalamic–pituitary–adrenal axis. However, under-treatment with glucocorticoids is more common than over-treatment in routine clinical practice. In general, the lowest potency of glucocorticoid should be used for the shortest period to gain control of the disease; this can be achieved by initial use of a more potent glucocorticoid, with reduction in potency or frequency of application as control is gained. Tolerance or tachyphylaxis can develop with chronic use, so intermittent courses of treatment are advised. Caution is required with glucocorticoids in psoriasis, as rebound, unstable or pustular psoriasis can occur with sudden

Potent

ks

ks oo m

Topical glucocorticoids

29.12  Potencies and strengths of commonly used topical glucocorticoid preparations*

m

eb

eb o

m

m

eb

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These are mainstays in the treatment of eczema, psoriasis and many other conditions, and are used to moisturise, lubricate, protect and ‘soften’ skin. They are essentially vehicles without active drug and are available in many formulations: creams, ointments, gels and bath, shower and soap substitutes. White soft paraffin is the most effective and is widely used.

eb

Emollients

Mild

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1226 • Dermatology

fre

ks

eb

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co m

fre e.

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ks

ks

oo

eb

m

om

.c

re e

eb

oo

ks

sf

oo k

m

m

co

e.

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ks

fre

ok s

29

eb

eb o

m

m

m

m

ok s

ok

sf

re

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co

e. co

sf re

ok

oo

oo

eb

m

eb

m

eb

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Systemic glucocorticoids, particularly prednisolone, are widely used in inflammatory skin diseases, such as eczema, immunobullous disease and connective tissue disorders. Methotrexate, azathioprine and mycophenolate mofetil are effective in eczema and psoriasis either alone or as glucocorticoid-sparing agents. Further details on the mechanism of action, adverse effects and monitoring requirements for these agents are provided on page 1004, although it is important to be aware that there may be different approaches to treatment regimens and doses between specialties for some drugs. For example, in dermatology, methotrexate is used in a once-weekly regimen, with doses of up to 25 mg per week, depending on the response (p. 1004). Hydroxycarbamide is an alternative immunosuppressant to methotrexate in psoriasis, but appears to be less effective and the risk of myelosuppression is greater. Ciclosporin (p. 1005) has a rapid onset of action and is effective in inducing clearance of psoriasis and eczema. Monitoring of blood pressure and renal function is required. Ciclosporin should be used only with caution after phototherapy, particularly PUVA, because of the

co

e.

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oo

eb m

m

co

e.

re

sf

Immunosuppressants

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ks f oo

Antibiotics are generally used for their anti-infective properties, particularly for staphylococcal and streptococcal skin infections. In these indications, the correct antibiotic should be selected, based on bacterial sensitivity and patient factors. As examples, oral flucloxacillin may be indicated for clinically infected eczema, intravenous flucloxacillin for cellulitis, and clarithromycin for a patient with a staphylococcal carbuncle who is penicillin-allergic. Optimal therapeutic doses and courses must be chosen, based

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Oral retinoids are used in a range of conditions, including acne, psoriasis and other keratinisation disorders. They promote differentiation of skin cells and have anti-inflammatory effects. Isotretinoin (13-cis-retinoic acid) is widely used for moderate to severe acne (p. 1243). Acitretin can be effective in psoriasis and other keratinisation disorders, such as ichthyosis, as can alitretinoin (9-cis-retinoic acid) in hand and foot eczema and bexarotene in cutaneous T-cell lymphoma. Adverse effects of retinoids include dryness of the skin and mucous membranes, abnormalities in liver function or hepatitis, increase in serum triglycerides (levels should be checked before and during therapy) and mood disturbances. Alitretinoin and bexarotene can cause hypothyroidism. Systemic retinoids are teratogenic and must be prescribed along with a robust form of contraception. Females must have a negative pregnancy test before, during and after therapy, and pregnancy must be avoided for 2 months after stopping isotretinoin and 2 years after stopping acitretin.

e. co

fre

fre

eb oo ks

General information is provided here for drugs used in a range of skin diseases; details of other drugs are provided in diseasespecific sections.

eb

Retinoids

m

oo ks

e. co

m

m

eb

oo eb

m

m

Systemic therapies

m

A range of H1 and H2 receptor antagonists are used in dermatology. For diseases in which histamine in the skin is relevant (such as urticaria), non-sedating antihistamines should be given: for example, fexofenadine or cetirizine. For pruritic conditions such as eczema, the sedating effect of antihistamines like hydroxyzine or chlorphenamine is important. However, antihistamines are widely used in older patients for the symptom of pruritus due to a variety of causes such as xeroderma, metabolic impairment, malignancy or concomitant drugs. Sedating antihistamines should be used with caution in older patients, as they may increase the risk of falls and accidents in the home, with disastrous consequences. Careful choice of drug and dose is therefore essential. Leukotriene receptor antagonists, such as montelukast, may be added to antihistamine regimes.

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Ultraviolet radiation (UVR) treatments (most commonly, narrowband ultraviolet B and psoralen–ultraviolet A (PUVA)) are used in the management of many different diseases. The best evidence for their efficacy is in psoriasis, atopic eczema, vitiligo and chronic urticaria, although there is also evidence that UVB is helpful in treating generalised itch associated with chronic kidney disease and a range of other diverse skin conditions. Psoralens are natural photosensitisers found in a number of plants. They intercalate between the strands of DNA and, on excitation with UVA, cross-link the DNA strands. Psoralens are therefore prodrugs that are activated only in skin that is exposed to UVA. Psoralens can also be applied topically in a bath before irradiation with UVA (bath PUVA) or can be applied in creams or gels for localised topical PUVA. PUVA is a more complex treatment than UVB and has more adverse effects; in particular, cumulative exposure to PUVA increases the risk of skin cancer, particularly squamous cell carcinoma. Therefore, PUVA is generally used for poor responders to UVB, or in diseases such as plaque-stage cutaneous T-cell lymphoma or pityriasis rubra pilaris, where it is the phototherapy of first choice. Phototherapy or PUVA may be offered as a whole-body or localised treatment. Longer-wavelength UVA1 (340–400 nm) is also used for several conditions, particularly the fibrosing skin diseases such as morphoea, where efficacy has been shown and there is a lack of other well-proven therapies. The evidence base for its place in the management of several diseases, such as eczema, is not fully proven and availability of UVA1 is mainly through centres of specialist expertise.

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wet dressings. Paste bandages can be used in conjunction with topical emollients and glucocorticoids to soothe and cool, ease pruritus and scratching, and reduce inflammation. Dressings for venous leg ulcers are described on page 1224.

Phototherapy and photochemotherapy

• 1227

on local antimicrobial prescribing guidelines. Several antibiotics, such as tetracyclines, erythromycin and co-trimoxazole are used predominantly for their anti-inflammatory effects in indications such as acne vulgaris, bullous pemphigoid and pyoderma gangrenosum.

Antihistamines

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Protection Symptomatic relief from pain or itch Maintenance of direct application of topical treatment Possible improvement in healing time Reduction of exudate Reduction of odour

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29.13  Indications for dressings

• • • • • •

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Principles of management of skin disease

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Photodynamic therapy (PDT) is widely used in dermatology, predominantly for actinic keratoses, Bowen’s disease and superficial basal cell carcinoma (p. 1229).

Radiotherapy and grenz (Bucky) ray therapy

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Radiotherapy can be employed for several skin conditions, including non-melanoma skin cancer or lentigo maligna that is not suitable for surgical treatment, but its use in dermatology has declined. Scarring and poikiloderma can occur at treated

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Shave excision using local anaesthetic may be used for simple and effective treatment of raised superficial benign skin lesions

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Photodynamic therapy

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Shave excision

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Laser therapy involves treatment with monochromatic light. Skin components (chromophores), such as haemoglobin and melanin, absorb specific wavelengths of electromagnetic radiation, and these wavelengths can therefore be used to destroy these targets selectively and to treat certain skin disorders. Lasers targeting haemoglobin are employed for vascular abnormalities, such as spider naevi, telangiectasiae and port-wine stains, and lasers targeting melanin can treat benign pigmentary disorders or pigment in tattoos or drug-induced hyperpigmentation (for example, secondary to minocycline). Melanin lasers can also be used for hair removal if the hair is pigmented. Light delivery in short pulses restricts damage to the treated site. The carbon dioxide laser emits infrared light that is absorbed by water in tissues and can therefore be used for destructive purposes. The depth of effect can be controlled, such that the carbon dioxide laser is widely employed for resurfacing in photorejuvenation or acne scarring. Significant morbidity is associated with this destructive laser, although this may be minimised with fractionated regimens, and general anaesthesia is usually required.

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Curettage involves using a small, spoon-shaped implement (curette), not only as a definitive treatment but also to obtain histology. Curettage does not preserve tissue architecture very well, however, and it may be difficult to distinguish between dysplasia and invasive malignancy. It can be an effective treatment for basal cell papillomas, actinic keratoses, intra-epidermal carcinoma and superficial basal cell carcinoma.

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Laser therapy

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Curettage

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Cryotherapy is a destructive treatment using liquid nitrogen to cause cell-wall and membrane destruction and cell death. Liquid nitrogen can be applied either with a cotton bud or, more effectively, with a spray gun. A wide variety of conditions can be treated but it is essential for the correct diagnosis to be made first, if necessary by diagnostic biopsy. Cryotherapy should not be used to treat melanocytic naevi. Benign lesions, such as viral warts and basal cell papillomas, respond well, and cryotherapy can also be effective for actinic keratoses, Bowen’s disease or superficial non-melanoma skin cancer. Malignant indications require more vigorous treatment, usually with two cycles, and this is normally carried out in secondary care. Considerable inflammation, blistering and pigmentary change, particularly hypopigmentation, can occur. Caution is required to avoid damage to tendons and nerves, especially when using cryotherapy on digits.

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This involves surgical removal of the lesion followed by histological examination. The most common indication is suspicion of malignancy. The lesion and line of excision should be marked out and the margin of excision decided before the procedure. It is important to excise down to the appropriate anatomical plane. Depending on body site, a range of procedures can minimise the resulting defect. Healing by secondary intention may also achieve good cosmetic results.

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Cryotherapy

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Most dermatological surgical procedures are performed under local anaesthetic. Knowledge of local anatomy is essential, particularly the locations of vessels and nerves. In certain sites, such as the fingers, soles of the feet and nose, local cutaneous nerve blocks are useful. Some sites are associated with particular risks, such as keloidal scarring on the upper trunk of young patients, unsightly scars over the scapulae, and poor healing and risk of ulceration following procedures on the lower legs.

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Mohs’ micrographic surgery is employed to ensure adequate tumour excision margins, while conserving unaffected tissue. It is most commonly used for basal cell carcinoma (p. 1229).

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Dermatological surgery

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Mohs’ micrographic surgery

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Biological inhibitors of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNF-α) inhibitors, ustekinumab (an antibody to the p40 component of interleukin (IL)-12 and IL-23), guselkumab (an antibody to IL-23), secukinumab and ixekizumab (antibodies to IL-17A) and brodalumab (an antibody to the IL-17 receptor) are effective treatments for psoriasis. Rituximab, which causes depletion of B cells, may be used in pemphigus vulgaris. More details on the dosages, mechanism of action and adverse effects of these agents are provided on page 1006. Omalizumab, a monoclonal antibody directed against immunoglobulin E (IgE), was introduced for allergic asthma but may also have a role in non-allergic diseases, such as treatment-resistant urticaria (pp. 86 and 572). Intravenous immunoglobulin, pooled from donor plasma, may be used in the treatment of dermatomyositis (p. 1039) and occasionally may be indicated in other dermatological diseases.

Excision biopsy

affecting epidermis and upper dermis, such as benign naevi and skin tags.

Non-surgical treatments

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Biological therapies

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increased risk of skin cancer. Long-term use of ciclosporin is not advised. Dapsone is an immunomodulator and may be used in diseases in which neutrophils are implicated, such as dermatitis herpetiformis (p. 1256). Haemolysis, methaemoglobinaemia and hypersensitivity can occur, and monitoring is required (pp. 123 and 269). Hydroxychloroquine is of particular value in cutaneous lupus. More details on the mechanism of action, adverse effects and monitoring requirements are provided on page 1005.

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1228 • Dermatology

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Early BCCs usually present as pale, translucent papules or nodules, with overlying superficial telangiectatic vessels (nodular BCC). If untreated, they increase in size and ulcerate, to form a crater with a rolled, pearled edge and ectatic vessels (Fig. 29.11). There may be some pigmentation or a cystic component. A superficial multifocal type can occur, frequently on the trunk, and may be large (up to 10 cm in diameter); often there are multiple lesions. Superficial BCC usually presents as a red/ brown plaque or patch with a raised, thread-like edge, which is

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Fig. 29.11  Basal cell carcinoma. A A nodular BCC showing the

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translucent nature of the tumour and the abnormal arborising vessels. B An ulcerated BCC showing the raised, rolled edge.

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Clinical features

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The incidence of NMSC has increased dramatically in recent decades and basal cell carcinoma (BCC) accounts for more than 70% of cases. In Europe, the ratio of BCC to SCC is 4–5 : 1 in immunocompetent patients. It is a malignant tumour that rarely metastasises; it is thought to derive from immature pluripotent epidermal cells and is composed of cells with similarities to basal layer epidermis and appendages. Lesions typically occur at sites of moderate sun exposure, particularly the face, and are slow-growing. The incidence increases with age and males are more commonly affected. Lesions may ulcerate and invade locally; hence the term ‘rodent ulcer’.

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Basal cell carcinoma

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Malignant tumours

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Skin cancer is the most common malignancy in fair-skinned populations. It is subdivided into non-melanoma skin cancer (NMSC) and melanoma. NMSC is further subdivided into the most common skin cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). The latter has precursor noninvasive states of intra-epithelial carcinoma (Bowen’s disease, BD) and dysplasia (actinic keratosis, AK). Melanoma is much less common than NMSC, but because of its metastatic risk it is the cause of most skin cancer deaths. UVR is a complete carcinogen and is the main environmental risk factor for skin cancer, which is much more common in countries with high ambient sun exposure, such as Australia. Skin cancer risk also increases if an individual migrates to such a country when young, particularly if less than 10 years of age. Epidemiological evidence supports a close link between chronic UVR exposure and risk of SCC and AK, and a modest link between sun exposure and BCC risk. Melanoma usually arises on sites that are intermittently exposed to UVR, and episodes of sunburn have been implicated as a risk factor for melanoma. There is good evidence to show that sunbed exposure is also a risk for both melanoma and NMSC, particularly when exposure starts in adolescence and early adult life. Strategies to reduce sun exposure are therefore important for skin cancer prevention, with reliance mainly on behavioural modification, covering up and judicious sunscreen use. Indeed, there is evidence to show that sunscreen use reduces naevi development in children, and in adults regular sunscreen use reduces the risk of AK and SCC and is likely also to have preventative roles in melanoma and BCC development. There are identifiable genetic predispositions for some skin cancers, such as in xeroderma pigmentosum, an autosomal recessive condition caused by an inherited defect in DNA excision repair (pp. 1221 and 1321), or basal cell naevus (Gorlin’s) syndrome, an autosomal dominant disorder caused by lossof-function mutations affecting the PTCH1 tumour suppressor genes, with consequent activation of the Hedgehog pathway (p. 1321). Interestingly, the Hedgehog pathway is also almost invariably activated in sporadic BCC, which usually contain somatic mutations in PTCH1 and less commonly in the SMO gene, which lies in the same signalling pathway. The genetics of SCC are heterogeneous and less clearly defined, with several mutations and pathways implicated, including TP53, CDKN2A/p16, NOTCH, EGFR and the MAPK signalling pathways. Interestingly, many of the mutations seen in SCC also occur in the pre-cancers AK and BD. The genetics of melanoma are discussed on page 1232. Cutaneous immune surveillance is also critical and immunosuppressed organ transplant recipients have a greatly increased risk of skin cancer, particularly SCC. Interestingly, patients who have received high treatment numbers of PUVA

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(more than 150), which is immunosuppressive, are also at increased risk of skin cancer, particularly SCC. Despite UVB being a complete carcinogen, there is no evidence at present that UVB phototherapy significantly increases skin cancer risk, although ongoing vigilance is required. Ionising radiation, notably radiotherapy, thermal radiation and chemical carcinogens, such as arsenic or coal tar, can increase NMSC risk, particularly SCC. A role for oncogenic human papillomaviruses in SCC development is also implicated, particularly in immunosuppressed patients, where viral DNA is detected in more than 80% of tumours. Chronic inflammation is a risk factor for SCC, which may arise in chronic skin ulcers (p. 1223), discoid lupus erythematosus or vulgaris, and the scarring genetic skin disease dystrophic epidermolysis bullosa (see Box 29.25, p. 1254), in which up to 50% of patients develop SCC.

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Pathogenesis

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Skin tumours

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sites, although these are minimised if fractionated regimens are chosen. Superficial radiotherapy is now rarely employed to treat benign dermatoses. Even more superficial ionising radiation (grenz, or Bucky, rays) can be useful for localised dermatoses that are having severe effects on quality of life, if conventional treatments have been inadequate; for example, it may avoid the need for systemic immunosuppression in a patient with severe recalcitrant localised scalp psoriasis.

Skin tumours • 1229

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Squamous cell carcinoma (SCC) is a malignancy that arises from epidermal keratinocytes and is the second most common skin cancer, occurring most frequently in elderly males and smokers. There is a close association between cumulative UVR exposure and SCC risk, with most SCC lesions occurring on chronically sun-exposed sites in white populations and often arising at sites of field-change carcinogenesis, with coexistent precursors of AK and BD commonly evident. In the immunosuppressed patient population, such as organ transplant recipients, SCC is the most common skin cancer and its incidence is dramatically increased, particularly in association with the duration of immunosuppression

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• For single/few lesions on good healing sites, cryotherapy, curettage, 5-fluorouracil/salicylic acid and ingenol mebutate are options. especially if hyperkeratotic • For multiple lesions/field change, conventional or daylight photodynamic therapy, topical 5-fluorouracil, imiquimod or diclofenac in hyaluronic acid gel may be effective

Squamous cell carcinoma

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• For single/few lesions on good healing sites, cryotherapy, curettage, photodynamic therapy, topical imiquimod and 5-fluorouracil are options • For multiple lesions and/or poor healing sites such as the lower leg, photodynamic therapy, where feasible, is the treatment of choice, although topical 5-fluorouracil or imiquimod is an alternative

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Carcinoma in situ (Bowen’s disease)

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• Excision is the treatment of choice for invasive SCC • Most recurrences or metastases occur within 5 years • Medical management is not usually considered for invasive SCC

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Squamous cell carcinoma

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• Excision results in the lowest recurrence rates • Mohs’ micrographic surgery is effective for high-risk BCC • Medical treatments are often appropriate for low-risk superficial tumours in patients with comorbidities • Cryotherapy and topical 5-fluorouracil can be used for superficial BCC • Topical photodynamic therapy and topical imiquimod are both effective in superficial BCC • BCC in patients with Gorlin’s syndrome should not be treated with radiotherapy • Hedgehog pathway inhibitors can induce clinical response in patients with advanced inoperable BCC

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Basal cell carcinoma

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29.14  Management of non-melanoma skin cancer and pre-cancer

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The diagnosis is often obvious clinically, based on the features mentioned above, although a diagnostic confirmatory biopsy may be required prior to definitive treatment. Management depends on the characteristics of the tumour and on patient factors, including comorbidities and patient wishes. Essentially, treatment will be either surgical or, in some cases, medical (Box 29.14). Surgical excision, ideally with a 4–5 mm margin, is the treatment of choice, with a cure rate of approximately 95%. Curettage and cautery may also be effective for selected lesions. Management of infiltrative morphoeic BCC and/or lesions at difficult sites, such as around the eye, may require more complex techniques such as Mohs’ micrographic surgery to ensure adequate tumour excision margins, while conserving unaffected tissue. This involves processing of frozen sections of all margins in stages (usually on the same day) until all the tumour is removed. The procedure is time-consuming (so can be difficult for elderly, frail patients) and requires particular surgical and pathology skills, but is associated with the highest long-term cure rates, with 98–99% clear at 5-year follow-up. If a surgical approach is used for management of BCC and the primary tumour is not completely excised, re-excision may

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Diagnosis and management

be required, although follow-up may be appropriate as not all tumours that are incompletely excised recur. However, this is not recommended for tumours at high-risk sites or for infiltrative morphoeic BCC, where complete excision is advisable. Cryotherapy may be effective for BCC but can cause blistering and scarring, so is best suited to small, superficial lesions at low-risk sites. Radiotherapy can be invaluable for large BCC lesions in frail patients but is less commonly used because of the risk of scarring. Medical therapies can be used to treat low-risk BCC, particularly when surgery is not appropriate for a patient. Topical immunomodulators, such as imiquimod, are effective for low-risk BCC and may be particularly useful for patients who are not able to attend a hospital clinic setting but are able to apply a topical preparation at home over a 6-week period. Imiquimod usually induces a prominent inflammatory reaction and patients should be advised that dose adjustments may be required. Topical 5-fluorouracil can also be effective for low-risk small lesions of superficial BCC, but is rarely used since it usually provokes an intense inflammatory reaction. Intralesional interferon-alpha2b has been used for BCC but multiple treatments and high cost preclude its regular use. PDT is an effective treatment for low-risk, predominantly superficial BCC, as well as AK and BD. Usually, topical porphyrin PDT is employed, which involves application of a porphyrin prodrug to the lesion to be treated. The prodrug is taken up and converted by the cell’s haem cycle to protoporphyrin IX, a photosensitiser. This is photochemically activated by visible (normally red) light, usually delivered by a light-emitting diode (LED), in the presence of oxygen, causing the production of reactive oxygen species, which cause destruction of treated tissue. The photosensitiser is taken up preferentially by diseased skin, and adverse effects in normal skin are minimised. PDT is at least as effective as cryotherapy and surgery for superficial BCC and may be preferred at sites of poor healing, such as the lower leg, or where cosmetic outcome is important. PDT is not as effective as surgery for long-term clearance of nodular BCC but can be considered if surgery is not appropriate. Pain during irradiation may occur during PDT, although adjustments to the irradiation regime can reduce discomfort. PDT is usually undertaken in the outpatient clinic setting and is well suited to frail elderly patients who are not able to undertake treatment with topical agents at home. Rarely, advanced BCC may be locally invasive or even metastasise. Major advances have been made in targeted drug development, and Hedgehog pathway inhibitors, such as vismodegib and sonidegib, can be used effectively for disease control and palliation in this setting, although there may be significant associated drug-induced toxicity.

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often best seen by stretching the skin; this helps to distinguish it from Bowen’s disease. Less commonly, a morphoeic, infiltrative BCC presents as a poorly defined, slowly enlarging, sclerotic yellow/grey plaque.

Actinic keratosis

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1230 • Dermatology

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Fig. 29.13  Actinic keratosis. Close-up of a hyperkeratotic AK on the ear.

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symmetrical, well-differentiated SCC. Clinically, this could be confused with keratoacanthoma. B An SCC arising from an area of epidermal dysplasia.

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29

Fig. 29.12  Squamous cell carcinoma. A A centrally keratinous,

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Several treatments are available for AK (see Box 29.14). Emollients and photoprotection, including high-factor sunscreens, may suffice for mild disease. Single or low numbers of lesions of AK can be effectively treated with cryotherapy. Hyperkeratotic lesions may be treated with the antimetabolite 5-fluorouracil, combined with salicylic acid, or may require curettage and cautery. Multiple lesions require field-directed therapy; 5-fluorouracil is widely used in this setting and is effective but topical imiquimod is an alternative. Diclofenac in a hyaluronic acid gel base can also be used topically for low-grade maintenance control of AK, the rationale for its use being the over-expression of cyclooxygenase (COX)-2 in AK lesions. Topical ingenol mebutate can also be used and has the advantage of a short treatment regime, although severe inflammation may be induced. PDT is widely used for field-change multiple AK, with high efficacy rates; it is at least as effective as cryotherapy or 5-fluorouracil. The relative selectivity of treatment allows subclinical disease to be treated, while sparing normal skin. A regimen using daylight to activate the photosensitiser is increasingly used worldwide for extensive mild AK, with high efficacy rates, comparable to hospital-based PDT but without the need for specialised equipment and allowing patients to be treated at home.

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Management

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Early diagnosis is important and complete surgical excision is the usual treatment of choice (see Box 29.14). Standard excision with a 4–6 mm margin is advised and the cure rate is approximately 90–95%. Mohs’ surgery is an option but is used less frequently for SCC than for BCC. High-risk SCC should be treated aggressively, with a wider margin of excision of at least 6 mm where feasible. This may include larger, thicker lesions, tumours at sites where metastases are more likely, such as the ear, lip or non-sun-exposed sites, and those occurring in the immunosuppressed and/or with histology showing the tumour to be poorly differentiated, with evidence of lymphatic, vascular or perineural involvement or a high mitotic index. Such patients and those with metastatic disease require management via a multidisciplinary team. In patients who are at high risk for further SCC, systemic retinoids may have a role in reducing the rate of SCC development, but rapid appearance of tumours occurs on drug cessation. Occasionally, curettage and cautery may be appropriate if the tumour is small and low-risk and either surgical excision is contraindicated or the patient is unwilling to proceed. Radiotherapy may be indicated if surgical excision is not feasible. Cryotherapy and topical non-surgical therapies are not usually used in invasive SCC because of risk of recurrence and metastasis.

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Actinic keratoses (AK) are scaly, erythematous lesions arising on chronically sun-exposed sites. Histology shows dysplasia, although the diagnosis of typical AK is usually made on clinical grounds (Fig. 29.13). They are common in fair-skinned people who have had significant sun exposure, are often multiple and increase with age. The prevalence is much higher in Australia than in the UK and some surveys have shown a prevalence of more than 50% in those over 40 years old. The rate of progression to SCC is less than 0.1% and spontaneous resolution is possible. However, SCC can also arise de novo and without progression from AK. Increase in size, ulceration, bleeding, pain or tenderness can be indicative of transformation into SCC.

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Management

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The tumours usually occur on chronically sun-exposed sites, such as bald scalp, tops of ears, face and back of hands. The clinical presentation may be diverse, ranging from rapid development of a painful keratotic nodule in a pre-existing area of dysplasia (Fig. 29.12) to the de novo presentation of an erythematous, infiltrated, often-warty nodule or plaque that may ulcerate. The clinical appearance depends on histological grading; well-differentiated tumours more often present as defined keratotic nodules (Fig. 29.12), whereas poorly differentiated tumours tend to be ill defined and infiltrative, and may ulcerate. SCC has metastatic potential; some tumours, such as those on lips and ears and in immunosuppressed patients, behave more aggressively and are more likely to metastasise to draining lymph nodes.

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Clinical features

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and the degree of sun exposure and damage accrued pretransplant. The risk of SCC is also increased in HIV infection. Furthermore, SCC arising in the immunosuppressed is more likely to behave aggressively or to metastasise.

Skin tumours • 1231

• Melanoma in situ

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Clinical features

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Melanoma can occur at any age and site and in either sex, but typically affects the leg in females and back in males. It is rare before puberty. The classification of invasive malignant melanoma is shown in Box 29.15. Early lesions may be in situ and pre-invasive before becoming invasive melanoma with metastatic potential. Any change in naevi or development of new lesions should be assessed to exclude malignancy and, for this, the dermatoscope is invaluable (see Fig. 29.2, p. 1217). Real-time non-invasive imaging techniques are being investigated as tools to assist in diagnosis but are largely experimental. If there is any doubt, excision is advised.

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Superficial spreading melanoma

Superficial spreading melanoma (SSM) is the most common type in Caucasians. It usually presents as a slowly enlarging, macular, pigmented lesion, with increasing irregularity in shape and pigment; this superficial, radial growth phase can last for

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Risk factors for melanoma include fair skin, freckles, red hair, number of naevi and sunlight exposure. The type of sunlight exposure is under debate but intermittent exposure, such as recreational time in the sun, sunburn and sunbed use, is implicated. Patients with multiple atypical naevi (dysplastic naevus syndrome) and fair-skinned people, often with variant alleles in the melanocortin-1 gene, are at increased risk of melanoma. A family history of melanoma increases the risk but a strong family history is unusual. Rarely, autosomal dominant inheritance of melanoma with incomplete penetrance can occur due to mutations in CDKN2A, which encodes the p16 tumour suppressor protein. In these patients, the lifetime risk of melanoma is more than 50%. Several other susceptibility genes and potential genetic targets for therapeutic intervention in advanced disease have also been identified.

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The most common form of cutaneous T-cell lymphoma is mycosis fungoides (MF). This can persist for years in patch and plaque stages, often resembling eczema or psoriasis. Only sometimes does it progress through to nodules and finally a systemic stage, Sézary’s syndrome. B-cell lymphomas, on the other hand, usually present as nodules or plaque-like tumours. The diagnosis of cutaneous T-cell lymphoma requires a high index of suspicion, particularly in patients thought to have unusual recalcitrant forms of eczema or psoriasis. Treatment is symptomatic and there is no evidence that it alters prognosis. In the early stages of cutaneous T-cell lymphoma, systemic or local glucocorticoids may be indicated; alternatively, narrowband UVB phototherapy (for patch-stage MF) or PUVA (for plaque-stage MF) may be used. Once lesions have moved beyond plaque stage, localised radiotherapy, electron beam

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Melanoma is a malignant tumour of epidermal melanocytes. While only 4% of skin cancers are melanomas, they account for 80% of skin cancer deaths. There has been a steady rise in the incidence of melanoma in fair-skinned populations over recent decades, with the highest figures in Australasia. Primary prevention and early detection are essential, as therapy for advanced and metastatic disease remains unsatisfactory.

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Cutaneous lymphomas

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While curettage or excision may be appropriate in some settings, non-surgical therapies are generally preferred (see Box 29.14), especially on the lower legs. PDT, in particular, may be advantageous for BD on the lower leg because of relative selectivity of treatment and sparing of normal tissue, thus reducing the risk of poor healing and ulceration at this vulnerable site. Given the low risk of malignant transformation, the option of no active treatment may also be appropriate for some elderly frail patients.

eb

Melanoma

Pathophysiology

Management

eb

oo

eb

eb o

Bowen’s disease (BD) is the name given to an intra-epidermal carcinoma that usually presents as a slowly enlarging, erythematous, scaly plaque on the lower legs of fair-skinned elderly women (Fig. 29.14) but other sites can also be involved. It can be confused with eczema or psoriasis, but is usually asymptomatic and does not respond to topical glucocorticoids. It may also be hard to distinguish from superficial BCC. Transformation into SCC occurs in 3% or less.

oo eb

m

• Acral lentiginous melanoma • Subungual melanoma • Lentigo maligna melanoma

radiation, the synthetic retinoid bexarotene, interferon-alpha, extracorporeal photopheresis and systemic anti-lymphoma chemotherapy regimens may be needed. Management of advanced disease invariably requires a multidisciplinary team approach, with collaboration between dermatologists, pathologists and haematological oncologists.

Incisional biopsy is usually undertaken to confirm the diagnosis. This shows an intra-epidermal carcinoma with no invasion through the basement membrane. Histology may also be obtained by curettage but this does not allow distinction from invasive SCC to be made, due to loss of tissue orientation and architecture.

m

• Lentigo maligna

• Superficial spreading melanoma • Nodular melanoma

m m

e. co

ks fre

Bowen’s disease

Diagnosis

fre

ok s

Melanoma without metastatic potential

ks

fre e. c

re ks f oo eb

m

leg is a common site and lesions are often treated non-surgically.

m

29.15  Classification of cutaneous malignant melanoma

Melanoma with metastatic potential

Fig. 29.14  Intra-epidermal carcinoma (Bowen’s disease). The lower

Clinical features

e. co m

om

m

e. co

1232 • Dermatology

e. co m

ks oo

eb

m

fre e.

eb

oo

ks

ks

oo

eb

m

om

.c

re e

eb

oo

ks

sf

oo k

m

m

co

e.

oo

ks

fre

ok s

eb

m

co

Prognosis

ok s

sf

re

e.

Patients with a primary tumour of less than 1 mm Breslow thickness have more than a 95% chance of disease-free survival

ok

sf re

ok

ok

sf

re

e.

e. co

co

m

The diagnosis is made by excision biopsy of a suspicious lesion. The initial biopsy should include a 2 mm margin, followed up where possible by wider excision if the diagnosis is confirmed. Occasionally, radiotherapy or imiquimod may be used for lentigo maligna, if surgery is not feasible. The Breslow thickness of the

29

m

eb

m

Diagnosis and management

eb o

oo

oo eb

m

This form of melanoma is rare. It may present as a painless, proximally expanding streak of pigmentation arising from the nail matrix, and progresses to nail dystrophy and involvement of the adjacent nail fold (Hutchinson’s sign).

m

ks f

ks fre

re

This accounts for only approximately 10% of melanomas in fair-skinned races and is more common in dark-skinned people, in whom it is responsible for 50% of cases. This indicates that UVR exposure may not be implicated in acral melanoma risk.

m

e.

e.

Acral lentiginous or palmoplantar melanoma

Subungual melanoma

eb

co

co m

m

m

This arises from a prolonged pre-invasive phase termed lentigo maligna. It occurs as a very slowly expanding, pigmented, macular lesion, usually on photo-exposed head and neck sites of elderly patients; histology shows in situ changes only. This phase may last for several years before a nodule of invasive melanoma develops in a proportion of cases (lentigo maligna melanoma).

m

eb

Lentigo maligna melanoma

m

oo

ks

eb oo ks

fre

fre

e. co

e. co

m

Nodular melanoma is most common in the fifth and sixth decades, particularly in men and on the trunk (Fig. 29.15B). This may account in part for the increased mortality rates from melanoma in men, as these are tumours with greater metastatic risk. They often present as a rapidly growing nodule that may bleed and ulcerate. Nodular melanomas may be heavily pigmented, or relatively amelanotic and erythematous, and be confused with benign vascular lesions. A rim of pigmentation may, however, be seen under the dermatoscope. Lesions may develop de novo or from a pre-existing naevus or SSM.

m

eb

m

m

eb

oo

oo ks

approximately 2 years. Subsequently, the lesion may become palpable and this is indicative of a vertical growth phase, with dermal invasion; when this occurs, the tumour has the potential to invade lymphatics and vessels and to become metastatic (Fig. 29.15A). Approximately 50% of melanomas arise from a pre-existing naevus.

m

fre

ks fre

e. co

spreading malignant melanoma with a palpable area indicative of vertical growth phase (Breslow thickness 1.3 mm). B A nodular malignant melanoma arising de novo and with Breslow thickness of 3.5 mm.

co m

e. co m

m

m

m

eb

eb o

oo

ks

ok s

ks f oo eb

m

Fig. 29.15  Superficial spreading melanoma. A A superficial

Nodular melanoma

tumour (the maximal depth from epidermal granular cell layer to deepest tumour cells) is critical for management and prognosis. The presence of ulceration may lead to under-estimation of the Breslow thickness. The mitotic rate and the presence or absence of any evidence of lymphovascular or perineural involvement should also be ascertained. The clinical staging of melanoma extent is essential, in order to establish whether disease is primary and localised, or if there is nodal or metastatic spread. Wide excision of melanoma with a low risk of metastasis (stage 1 disease, Breslow thickness  10 mmol/L (28 mg/dL) Serum bicarbonate  150 µmol/L (> 1.7 mg/dL)) Coagulopathy (prothrombin time > 14 secs or activated partial thromboplastin time > 34 secs) Microvascular steatosis on liver biopsy

oo k

m fre

fre

40

e. co

50

e. co

60

m

70

• • • • • • • • • •

m

eb

80

20

m

30.16  Criteria for diagnosis of acute fatty liver of pregnancy

eb

90 Percentage affected

Creatinine >180 Dialysis

m

100

m

oo ks

Creatinine  90

2

60–89

3a

45–59

3b

30–44

4

15–29

Severely decreased

5

 10 mmHg diastolic pressure on standing from supine), reducing or stopping hypotensive drugs may be helpful. Evidence supporting the efficacy of other interventions for postural hypotension is lacking but drugs, including fludrocortisone and midodrine, are sometimes used to try to improve dizziness on standing. Other interventions, such as cataract extraction and podiatry, can also have a significant impact on function in those who fall. If osteoporosis is diagnosed, specific drug therapy should be considered (p. 1046). In the frailest patients, such as those in institutional care, calcium and vitamin D3 administration has been shown to reduce both falls and fracture rates, probably by exerting positive effects on bone mineral density and on neuromuscular function. Supplementation does not reduce falls risk beyond this very frail group, however, and very high doses of vitamin D may paradoxically increase the risk of falls and fractures. In the UK, government policy and National Institute for Health and Clinical Excellence guidelines (www.nice.org.uk) for falls prevention have led to the development of specific Falls and Fracture Prevention Services in many parts of the country.

Delirium

eb

fre

fre

eb oo ks

In lightheaded patients, structural cardiac disease (such as aortic stenosis) and arrhythmia must be considered, but disorders of autonomic cardiovascular control, such as vasovagal syndrome and postural hypotension, are the most common causes in old age. Antihypertensive medications may exacerbate these conditions. Further investigation and treatment are described on page 181. Vertigo in older patients is most commonly due to benign positional vertigo (p. 1086), but if other brainstem symptoms or signs are present, MRI of the brain is required to exclude a cerebello-pontine angle lesion.

e. co

e. co

m

m

m

m

Although older people more commonly present with recurrent dizzy spells and often find it difficult to describe the sensation they experience, the most effective way of establishing the cause(s) of the problem is nevertheless to determine which of the following is predominant (even if more than one is present): • lightheadedness, suggestive of reduced cerebral perfusion • vertigo, suggestive of labyrinthine or brainstem disease (p. 1086) • unsteadiness/poor balance, suggestive of joint or neurological disease.

m

fre

oo ks

• Exercise (should include components of lower limb strength and balance training): Multimodal group exercise and tai chi both effective • Calcium and vitamin D supplementation: Evidence of effectiveness only in patients in institutional care Large doses of vitamin D may increase risk of falls and fractures • Home environment assessment and modification • Medication review: Particularly medications with central actions such as hypnotics but also those with anticholinergic and hypotensive actions • Cataract surgery: Effective if for first cataract Other vision interventions ineffective and may increase falls risk • Anti-slip shoes: Effective only in icy conditions • Cardiac pacemaker for carotid sinus hypersensitivity

eb

eb

oo

32.6  Interventions to reduce the risk of falls and fractures

m

Dizziness is very common, affecting at least 30% of those aged over 65 years in community surveys. It can be disabling in its own right and is also a risk factor for falls. Acute dizziness is relatively straightforward and common causes include: • hypotension due to arrhythmia, myocardial infarction, gastrointestinal bleed or pulmonary embolism • posterior fossa stroke onset • vestibular neuronitis.

e. co m

m

eb o

m

e. co

oo eb

m

ks fre

Bilateral hemisphere lesions

• 1309

fre

Antalgic

ok s

Probable cause

ks f

Gait abnormality

m

re

32.5  Abnormal gaits and probable causes

Apraxic

e. co m

om

m e. co

Presenting problems in geriatric medicine

fre

Renal impairment, electrolyte disturbance Gout Hypotension, postural hypotension

Warfarin

Bleeding

m

Constipation, vomiting Delirium Urinary retention

Antidepressants

Delirium Hyponatraemia (SSRIs) Hypotension, postural hypotension Falls

Benzodiazepines

Delirium Falls

Anticholinergics

Delirium Urinary retention Constipation

oo eb

m

.c

re e

ks oo eb

eb

m

m

m

m

co

e.

eb

oo

ks

fre

ok s

eb o

m

m

m

m

ok s

ok

sf

re

e.

co

e. co

ok

sf re

e.

re

sf

diseases (Box 32.7). However, the more drugs that are taken, the greater the risk of an adverse drug reaction (ADR). ADRs and the effects of drug interactions are discussed on page 21. They may result in symptoms, abnormal physical signs and altered laboratory test results (Box 32.8). ADRs are the cause of around 5% of all hospital admissions but account for up to 20% of admissions in those aged over 65. The risk of polypharmacy is compounded by age-related changes in pharmacodynamic and pharmacokinetic factors (p. 14), and by impaired homeostatic mechanisms, such as baroreceptor responses, plasma volume and electrolyte control. Older people are thus especially sensitive to drugs that can cause postural hypotension or volume depletion (Box 32.8). Non-adherence to drug therapy also rises with the number of drugs prescribed. The clinical presentations of ADRs are diverse, so for any presenting problem in old age the possibility that the patient’s medication is a contributory factor should always be considered. Failure to recognise this may lead to the use of a further drug to treat the problem, making matters worse, when the better

co

e.

ks fre

oo

co

m

m

eb

The large number of comorbidities that accompany ageing often leads to polypharmacy. This has been defined as the use of four or more drugs, and is associated with several adverse outcomes including falls, hospitalisation and increased risk of death. While some of these outcomes are caused by drug–drug interactions and adverse effects, others are as much due to the underlying multimorbidities for which the drugs were prescribed in the first place In view of this, it is essential for prescribing for older people to be appropriate. For many older people, taking multiple drugs is appropriate, as such therapy is required to treat multiple

ok

om

Opiates

Bradycardia, heart block Hypotension, postural hypotension

sf

ks

oo

eb

m

co m

e.

re

ks f oo eb

m

ks

ks

oo

m

β-blockers

Renal impairment, electrolyte disturbance Hypotension, postural hypotension

(ACE = angiotensin-converting enzyme; NSAIDs = non-steroidal anti-inflammatory drugs; SSRIs = selective serotonin re-uptake inhibitors)

In patients with severe stroke disease or dementia, treatment may be ineffective, as frontal cortical inhibitory signals to bladder emptying are lost. A timed/prompted toileting programme may help. Other than in overflow incontinence, urinary catheterisation should never be viewed as first-line management, but may be required as a final resort if the perineal skin is at risk of breakdown or quality of life is affected.

Prescribing and deprescribing

eb

Diuretics

e. co

fre

fre

eb oo ks

m

vaginitis, associated with oestrogen deficiency in old age, which can be treated with oestrogen pessaries. • Overflow incontinence is most commonly seen in elderly men with prostatic enlargement, which obstructs bladder outflow.

m Gastrointestinal bleeding and peptic ulceration Renal impairment

Fig. 32.4  Assessment and management of urinary incontinence in old age. See also page 436 and NICE guideline on the Management of Incontinence in Women: nice.org.uk. (UTI = urinary tract infection)

co m

Adverse reaction

NSAIDs

fre e.

Drug class

oo k

fre

oo ks

m

m

Overflow (residual volume > 100 mL) Surgical relief of obstruction (prostatectomy) Intermittent catheterisation if no obstruction

e. co

32.8  Common adverse drug reactions in old age

ACE inhibitors

eb

oo eb

m

Stress Pelvic floor muscle training Surgical intervention if unsuccessful

oo

oo

m e. co m

m

ks fre

e. co

If still incontinent: • Establish the pattern of urinary loss (diary is helpful) • Measure residual urine volume (by ultrasound) • Assess for vaginal prolapse and atrophic vaginitis (women) • Assess prostate by rectal examination (men)

Urge Bladder retraining Antimuscarinic drugs (solifenacin, tolterodine)

ks

ks

Multiple pathology Poor patient education (see Box 2.20, p. 31) Lack of routine review of all medications Patient expectations of prescribing Over-use of drug interventions by doctors Attendance at multiple specialist clinics Poor communication between specialists

m

• • • • • • •

eb

eb

m

32.7  Factors leading to polypharmacy in old age

eb

fre e. c

ok s

Address contributory factors: • UTI • Severe constipation • Diuretics • Hyperglycaemia • Hypercalcaemia • Restricted mobility • Acute delirium

eb o

oo

ks f

re

Urinary incontinence

e. co m

om

m

e. co

1310 • Ageing and disease

fre e. c

ok

fre

eb

oo

ks

ks

m

co m

fre e.

eb

oo

ks

ks

oo

m

om

.c

re e

eb

oo

ks

sf

oo k

m

m

co

e.

ks

m

m

co

e.

sf re

p. 1191

32

re

p. 1147

sf

• Stroke

e.

eb o

m

pp. 994 and 1049

co

• Bone disease and fracture

e. co

p. 992

m

p. 954

The core rehabilitation team includes all members of the multidisciplinary team (p. 1303). Others may also be involved, such as audiometrists to correct hearing impairment, podiatrists for foot problems, and orthoticists where a prosthesis or splinting is required. Good communication and mutual respect are essential. Regular team meetings allow sharing of assessments, agreement on rehabilitation goals and interventions, evaluation of progress and planning for the patient’s discharge home. Rehabilitation is not when the doctor orders ‘physiotherapy’ or ‘a home visit’ and takes no further role.

m

p. 801

• Painful joints

oo

eb m

p. 732

• Anaemia

re

Multidisciplinary team working

p. 710

ok s

p. 512

• Under-nutrition

eb

p. 472

• Hypertension

fre

• Atrial fibrillation

ok s

p. 466

oo

• Heart failure

sf

eb

m

p. 360

ks fre

pp. 218 and 228

• Fluid balance problems

re

• Infection

ok

e.

m

p. 183

co

• Delirium

e.

p. 181

ok

eb

m

m p. 166

co m

• Hypothermia

• Dizziness and blackouts

ks f oo eb

m

Rehabilitation is a problem-solving process focused on improving the patient’s physical, psychological and social function. It entails: • Assessment. The nature and extent of the patient’s problems can be identified using the International Classification of Functioning, Disability and Health framework, which focuses on health conditions (such as stroke), the associated physical impairments (such as arm weakness caused by the stroke), the effect on activity (such as the inability to dress oneself due to arm weakness) and restriction of participation in activities (such as inability to go out of the house due to the inability to dress oneself). Such an approach helps to ensure a whole-person approach to participation in society, rather than a focus merely on disease. Specific assessment scales, such as the Elderly Mobility Scale or Barthel Index of Activities of Daily Living (Box 32.10), are useful to quantify components of disability but additional assessment is needed to determine the underlying causes or the interventions required in individual patients. • Goal-setting. Goals should be specific to the patient’s problems, realistic, and agreed between the patient and the rehabilitation team. • Intervention. This includes the active treatments needed to achieve the established goals and to maintain the patient’s health and quality of life. Interventions include hands-on treatment by therapists using a functional, task-orientated approach to improve day-to-day activities, and also psychological support and education. The emphasis on the type of intervention will be individualised, according to the patient’s disabilities, psychological status and progress. The patient and carer(s) must be active participants. • Re-assessment. There is ongoing re-evaluation of the patient’s function and progress towards the goals by the rehabilitation team, the patient and the carer. Interventions may be modified as a result.

e. co

fre

eb

oo

ks

eb oo ks

m

32.9  Other presenting problems in old age

• Dementia

The rehabilitation process

m

fre

oo ks

eb

m

m

e. co

fre

A vast range of other presenting problems in older people present to many medical specialties. End-of-life care is an important facet of clinical practice in old age and is discussed on page 1354. Relevant sections in other chapters are referenced in Box 32.9. Within each chapter, ‘In Old Age’ boxes highlight the areas in which presentation or management differs from that in younger individuals.

• Peptic ulceration

oo

e. co m

e. co

ks fre oo eb

m

Other problems in old age

• Diabetes mellitus

Rehabilitation aims to improve the ability of people of all ages to perform day-to-day activities and to optimise their physical, mental and social capabilities. Acute illness in older people is often associated with loss of their usual ability to walk or care for themselves, and common disabling conditions such as stroke, fractured neck of femur, arthritis and cardiorespiratory disease become increasingly prevalent with advancing age. Doctors tend to focus on health conditions and impairments but patients are more concerned with the effect on their activities and ability to participate in everyday life.

eb

eb o

m

m

m

eb

oo

The key to appropriate prescribing is first to ensure that medications are started only for reasons that accord with the patient’s goals and wishes. Thoughtless adherence to guidelines quickly leads to polypharmacy that may be inappropriate. Some medications (such as chronic use of non-steroidal anti-inflammatory medications) are much less suitable for older people because of the much higher risk of side-effects. Other medications, such as statins and bisphosphonates, lack evidence of efficacy in very old people, who may not live for long enough to derive benefit. Deprescribing is as important as prescribing in older people. Regular review of medications should be undertaken to ensure that medications are still required, to establish that they are still working, to check that they are not causing side-effects, and to ascertain whether the patient is actually taking them. If any of the above issues is problematic, the medication should be deprescribed. This may need to be done in a controlled manner, with dose reduction to ensure that rebound symptoms or withdrawal effects do not occur. The patient or carer should therefore be asked to bring all medication for review rather than the doctor relying on previous records; such reviews should take place regularly, not just at a point of crisis such as after a fall or on hospital admission.

Rehabilitation

m

ok s

ks f

Appropriate prescribing and deprescribing

e. co m

om

m e. co

re

course would be to stop or reduce the dose of the offending drug or to find an alternative.

Rehabilitation • 1311

fre e. c

Rehabilitation outcomes

There is evidence that rehabilitation improves functional outcomes in older people following acute illness, stroke and hip fracture. It also reduces mortality after stroke and hip fracture. These benefits accrue from complex multicomponent interventions, but occupational therapy to improve personal ADLs and individualised exercise interventions have now been shown to be effective in improving functional outcome in their own right.

Independent = 2  Needs some help = 1  Completely dependent = 0

ks oo

ks oo

ks oo eb

eb o

m

m

m

m ok

sf

re

e.

co

e. co sf re ok

oo

eb

eb

eb m m e.

ok s

fre

ks fre oo eb m m co

e. re sf

co

co e.

e. re ks f oo eb

m ok

re e

sf

eb m

co m

m

m

m

eb

oo

oo k

ks

eb oo ks

fre

fre

*The 20-point version is illustrated. The total score reflects the degree of dependency; scores of 14 and above are usually consistent with living in the community; scores below 10 suggest the patient is heavily dependent on carers.

.c

e. co

e. co

Independent = 1  Needs help = 0

om

m

m

Bathing

m

m

Dressing

m

ks

eb

eb

Independent = 2  Needs help = 1  Unable = 0

m

m

eb

oo

Independent = 2  Needs help = 1  Unable = 0

oo

Toilet use

oo ks

Independent = 1  Needs help = 0

Feeding

americangeriatrics.org American Geriatrics Society: education, careers vignettes from geriatricians, advocacy and clinical guidelines. bgs.org.uk British Geriatrics Society: useful publications on management of common problems in older people and links to other relevant websites. cochrane.org Cochrane review CD006211 Comprehensive geriatric assessment for older adults admitted to hospital; CD007146 Interventions for preventing falls in older people living in the community. eugms.org European Union Geriatric Medicine Society: research, position papers and educational resources. iagg.info International Association of Gerontology and Geriatrics: promoting care of older people and the science of gerontology globally; research, policy and educational resources. knowledge.scot.nhs.uk/effectiveolderpeoplecare.aspx Collates and summarises the Cochrane evidence for best practice in the healthcare and rehabilitation of frail older people. profane.co Prevention of Falls Network Earth: focuses on the prevention of falls and improvement of postural stability in older people. qfracture.org Fracture risk calculator validated in the UK population. Includes a wider range of risk factors than FRAX. shef.ac.uk/FRAX/tool.jsp Fracture risk calculator: can be used to calculate risk in several populations. Includes option to calculate with or without measurement of hip bone mineral density.

fre

ks fre

Grooming

Websites

ok s

Continent = 2  Occasional incontinence = 1  Incontinent = 0

Further information

e. co m

m

e. co

Continent = 2  Occasional incontinence = 1  Incontinent = 0 Bowels

ks

ks

oo

m

Independent = 3  Needs minor help = 2  Needs major help = 1  Unable = 0

co m

Transfers (e.g. from bed to chair)

eb

Independent = 2  Needs help = 1  Unable = 0

m

m

eb

Stairs

eb o

oo

ok s

Independent = 3  Needs help = 2  Wheelchair independent = 1  Immobile = 0

fre e.

ks f

Mobility

fre

re

32.10  How to assess dependency using the Modified Barthel Index*

Bladder

e. co m

om

m

e. co

1312 • Ageing and disease

oo eb m

co m

ks oo eb m om .c

re e

ks

sf

oo k

ks

ks oo e.

ok s

re sf ok

sf re ok

co

e. co

m

m

m

m

eb

eb

eb o

oo

ok s

fre

ks fre

e.

e.

co

co

m

m

m

m

eb

eb

oo

oo

eb

m

m m co e. re sf

fre e.

m

m e. co fre

Specific cancers 1333 Breast cancer 1333 Ovarian cancer 1334 Endometrial cancer 1334 Cervical cancer 1335 Head and neck tumours 1335 Carcinoma of unknown origin 1336 Multidisciplinary teams 1336

co m e. re ks f oo eb

m ok

ks

eb

eb

oo

Therapeutics in oncology 1329 Surgical treatment 1330 Systemic chemotherapy 1330 Radiation therapy 1331 Hormone therapy 1332 Immunotherapy 1332 Biological therapies 1332 Evaluation of treatment 1332 Late toxicity of therapy 1332

m

fre

Investigations 1321 Histology 1322 Imaging 1323 Biochemical markers 1323 Presenting problems in oncology 1323 Palpable mass 1323 Weight loss and fever 1323 Thromboembolism 1324 Ectopic hormone production 1325 Neurological paraneoplastic syndromes 1325 Cutaneous manifestations of cancer 1326

ks

ks

oo

eb

m

e. co m fre

Metastatic disease 1328

m

e. co

Environmental and genetic determinants of cancer 1320

eb oo ks

Oncology

Emergency complications of cancer 1326

oo ks

The 10 hallmarks of cancer 1316 1. Genome instability and mutation 1316 2. Resisting cell death 1316 3. Sustaining proliferative signalling 1317 4. Evading growth suppressors 1318 5. Enabling replicative immortality 1318 6. Inducing angiogenesis 1318 7. Activating invasion and metastasis 1319 8. Reprogramming energy metabolism 1319 9. Tumour-promoting inflammation 1319 10. Evading immune destruction 1320

oo eb

m

33  fre

fre e. c ok s eb o m

m e. co ks fre

Clinical examination of the cancer patient 1314

m

e. co m

om

m e. co re ks f oo eb

m

GG Dark

fre e. c

e. co m

om

m

4

ks oo eb

m

m

co

e.

ks

m

m

co e.

ok s

re sf ok

sf re ok

oo

eb

10 Periphery Calf tenderness, venous thrombosis Clubbing (if present in hands)

m

m

eb o

10

ok s

fre

9 Skeletal survey Focal bone tenderness (pelvis, spine, long bones) Wrist tenderness (hypertrophic pulmonary osteoarthropathy)

e. co

co

oo

om

re e

sf oo k

eb m co e. ks fre

oo

eb

m

m

Observation • Skin changes • Ascites • Cushingoid appearance • Cachexia • Dehydration

e. re sf ok

Ascites (ovarian carcinoma)

8 Neurological Focal neurological signs Sensory deficit Spinal cord compression Memory deficit Personality change

m

co m

e. re ks f oo eb

.c

e. co fre ks

oo eb m

m

m

8

9

Finger clubbing in lung cancer

Cushing’s syndrome in a patient with ectopic adrenocorticotrophic hormone (ACTH) production

7 Abdomen Surgical scars Umbilical nodule Mass in epigastrium Visible peristalsis Abdominal distension Ascites Hepatomegaly Splenomegaly Renal mass Pelvic or adnexal mass

eb

m m

m

e. co

eb oo ks

fre

1

ks

ks oo

eb

eb m

m

6 Respiratory Stridor Consolidation Pleural effusion

7

1 Hands Clubbing Signs of smoking Pallor Tylosis of palms

oo

SVC obstruction in a patient with a mediastinal mass

fre oo ks

oo eb

6

2

Skin tethering above the nipple

eb

m co m

5

fre e.

2 Breast

ks

ks oo m e. co m

3

ks fre

5 Cardiovascular Superior vena cava (SVC) obstruction Atrial fibrillation Pericardial effusion Hypo-/hypertension

eb

eb o m

e. co

3 Lymph nodes Neck Supraclavicular Axillary Antecubital Inguinal Para-aortic

m

m

eb

oo

ok s

4 Face Conjunctival pallor Icterus, jaundice Horner’s syndrome Cushingoid features

fre

ks f

re

Clinical examination of the cancer patient

m

e. co

1314 • Oncology

fre e. c

fre

ks

ks

oo

oo

Epitrochlear

Pre-auricular

om

.c

re e sf

fre

Anterior cervical

ks

oo k

eb

eb

m

m

Malignant pleural effusions

Large right pleural effusion

e.

e.

oo

m co e.

33

ok s

re sf ok

sf re ok

eb

m

eb o m m e. co

co e.

ks

ok s

fre

ks fre oo

eb

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Inspection Tachypnoea Palpation ↓Expansion on R Trachea and apex may be moved to L Percussion Stony dull R mid- and lower zones Auscultation Absent breath sounds and diminished or absent vocal resonance R base Crackles above effusion

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Supraclavicular

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5  Pericardial effusion • Tachycardia • Falling blood pressure • Rising jugular venous pressure • Muffled heart sounds • Kussmaul’s sign (p. 544)

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Posterior cervical

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Superior vena cava obstruction

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Submandibular

Popliteal fossa

• Venous distension of neck • Elevated but non-pulsatile jugular venous pulse • Venous distension of chest wall • Facial oedema • Cyanosis • Plethora of face • Oedema of arms

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Parotid

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Inguinal

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Axillary

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Examination of the lymph nodes

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Important features of skin lesions that should alert suspicion include: • Asymmetry: irregular shape • Bleeding • Border: not a smooth edge • Colour: uneven, variegated or changing colour • Diameter: > 6 mm in diameter or growing • Itching or pain in a pre-existing mole

7  Abdominal examination • Are there scars from previous surgery? • Is the umbilicus everted, suggesting ascites? • Is there a firm nodule at the umbilicus due to ovarian or gastric cancer metastasis, causing a Sister Mary Joseph nodule (p. 1334)? • Is there smooth hepatomegaly – possibly primary liver cancer or heart failure? • Is the liver firm or knobbly, suggesting metastasis? • Is the ascites too tense to demonstrate hepatomegaly? • Are other masses palpable in the abdomen? • Are there signs of obstruction or paralytic ileus with absence of bowel sounds? • Palpate for inguinal nodes (occasionally involved in ovarian cancer) • Percuss for flank dullness and shifting dullness • Perform vaginal and rectal examinations to detect adnexal or rectal masses

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Examination of the skin

3 

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Clinical examination of the cancer patient • 1315

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non-Hodgkin lymphoma) Statistics from Cancer Research UK website (http://info.cancerresearchuk.org).

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This is the premature death of cells and is characterised by the release of cellular contents into the local tissue microenvironment, in marked contrast to apoptosis, where cells are disassembled in a step-by-step fashion and the resulting cellular fragments are phagocytosed. Necrotic cell death results in the recruitment of inflammatory immune cells, promotion of angiogenesis, and release of stimulatory factors that increase cellular proliferation

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Fig. 33.1  The most commonly diagnosed cancers in the UK. (NHL =

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Necrosis

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5

This is a catabolic process during which cellular constituents are degraded by lysosomal machinery within the cell. It is an important physiological mechanism; it usually occurs at low levels in cells but can be induced in response to environmental stresses, particularly radiotherapy and cytotoxic chemotherapy, which induce elevated levels of autophagy that are cytoprotective for malignant cells, thus impeding rather than perpetuating the killing actions of these stress situations. Severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy.

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25 20

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Autophagy

30

Breast Lung Large bowel Prostate Bladder NHL Stomach Head and neck Oesophagus Melanoma Pancreas Ovary Leukaemia Kidney Body of uterus Other

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Male Female

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Number of new cases (thousands)

40

This is programmed cell death. It is frequently found at markedly reduced rates in cancers, particularly those of high grade or those resistant to treatment. The cellular apoptotic system has regulatory elements that sense intrinsic and extrinsic pro-apoptotic signals and initiate a cascade of proteolysis and cell disassembly with nuclear fragmentation, chromosomal condensation, and shrinking of the cell with loss of intercellular contact, followed by cellular fragmentation and the formation of apoptotic bodies that are phagocytosed by neighbouring cells. The most important regulator of apoptosis is the TP53 tumour suppressor gene, often described as the ‘guardian of the genome’, as it is able to induce apoptosis in response to sufficient levels of genomic damage. The largest initiator of apoptosis via TP53 is cellular injury, particularly that due to DNA damage from chemotherapy, oxidative damage and ultraviolet (UV) radiation.

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45

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There are three principal mechanisms through which cell death occurs in healthy tissues: apoptosis, autophagy and necrosis.

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2.  Resisting cell death

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The 10 hallmarks of cancer

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Random genetic mutations occur continuously throughout all cells of the body and very rarely confer a selective advantage on single cells, allowing overgrowth and dominance in local tissue environments. Multistep carcinogenesis results from successive clonal expansions of pre-malignant cells, each expansion being triggered by acquisition of a random enabling genetic mutation. Under normal circumstances, cellular DNA repair mechanisms are so effective that almost all spontaneous mutations are corrected without producing phenotypic changes, keeping the overall mutation rates very low. In cancer cells, the accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence or apoptosis. They can therefore become more sensitive to mutagenic actions or develop DNA repair mechanism failure.

Apoptosis

The formation and growth of cancer constitute a multistep process, during which sequentially occurring gene mutations result in the formation of a cancerous cell. For cells to initiate carcinogenesis successfully, they require key characteristics, collectively referred to as the hallmarks of cancer.

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1.  Genome instability and mutation

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Cancer represents a significant economic burden for the global economy and is now the third leading cause of death worldwide. By 2030, it is projected that there will be 26 million new cancer cases and 17 million cancer deaths per year. The developing world is disproportionately affected by cancer and in 2008 developing nations accounted for 56% of new cancer cases and 75% of cancer deaths. These deaths happen in countries with limited or no access to treatment and with low per capita expenditure on health care. The most common solid organ malignancies arise in the lung, breast and gastrointestinal tract (Fig. 33.1), but the most common form worldwide is skin cancer. Cigarette smoking accounts for more than 20% of all global cancer deaths, 80% of lung cancer cases in men and 50% of lung cancer cases in women worldwide, which could be prevented by smoking cessation. Diet and alcohol contribute to a further 30% of cancers, including those of the stomach, colon, oesophagus, breast and liver. Lifestyle modification could reduce these if steps were taken to avoid animal fat and red meat, reduce alcohol, increase fibre, fresh fruit and vegetable intake, and avoid obesity. Infections account for a further 15% of cancers, including those of the cervix, stomach, liver, nasopharynx and bladder, and some of these could be prevented by infection control and vaccination.

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1316 • Oncology

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DNA replication

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Antimetabolites

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G1 checkpoint for Damaged DNA RB blocks TP53 → CDKs blocked

Cyclin A CDK2

Cyclin B Mitosis CDK1 Prophase → telophase Nuclear and cellular division Terminal differentiation G2 Apoptosis G checkpoint for 2 Further growth DNA damage DNA replication or DNA repair incomplete

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Topoisomerase inhibitors

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Cyclin E CDK2

M

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Mitotic spindle poisons

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Cell G1 growth

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G0

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Many cancer cells produce growth factors, which drive their own proliferation by a positive feedback known as autocrine stimulation. Examples include transforming growth factor-alpha (TGF-α) and platelet-derived growth factor (PDGF). Other cancer cells express growth factor receptors at increased levels due to gene amplification or express abnormal receptors that are permanently activated. This results in abnormal cell growth in response to physiological growth factor stimulation or even in the absence of growth factor stimulation (ligand-independent signalling). The epidermal growth factor receptor (EGFR) is often over-expressed in lung and gastrointestinal tumours and the human epidermal growth factor receptor 2 (HER2)/neu receptor is frequently over-expressed in breast cancer. Both receptors activate the Ras–Raf–mitogen activated protein (MAP) kinase pathway, causing cell proliferation.

Cell growth Cyclin D CDK4, 6

Terminal differentiation Apoptosis

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Stimulation of the cell cycle

Quiescent

Antibiotics and alkylating agents (act on entire cycle)

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The cell cycle is orchestrated by a number of molecular mechanisms: most importantly, by cyclins and cyclin-dependent kinases (CDKs). Cyclins bind to CDKs and are regulated by both activating and inactivating phosphorylation, with two main checkpoints at G1/S and G2/M transition. The genes that inhibit progression play an important part in tumour prevention and are referred to as tumour suppressor genes (e.g. TP53, TP21, TP16 genes). The products of these genes deactivate the cyclin–CDK complexes and are thus able to halt the cell cycle. The complexity of cell cycle control is susceptible to dysregulation, which may produce a malignant phenotype.

The cell cycle is composed of four ordered, strictly regulated phases referred to as G1 (gap 1), S (DNA synthesis), G2 (gap 2) and M (mitosis) (Fig. 33.2). Normal cells grown in culture will stop proliferating and enter a quiescent state called G0 once they become confluent or are deprived of serum or growth factors. The first gap phase (G1) prior to the initiation of DNA synthesis represents the period of commitment that separates M and S phases as cells prepare for DNA duplication. Cells in G0 and G1 are receptive to growth signals, but once they have passed a restriction point, they are committed to enter DNA synthesis (S phase). Cells demonstrate arrest at different points in G1 in response to different inhibitory growth signals. Mitogenic signals promote progression through G1 to S phase, utilising phosphorylation of the retinoblastoma gene product (pRB, p. 40). Following DNA synthesis, there is a second gap phase (G2) prior to mitosis (M), allowing cells to repair errors

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The cell cycle

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that have occurred during DNA replication and thus preventing propagation of these errors to daughter cells. Although the duration of individual phases may vary, depending on cell and tissue type, most adult cells are in a G0 state at any one time.

Cell cycle regulation

Cancer cells can sustain proliferation beyond what would be expected for normal cells; this is typically due to growth factors, which are able to bind to cell surface-bound receptors that activate an intracellular tyrosine kinase-mediated signalling cascade, ultimately leading to changes in gene expression and promoting cellular proliferation and growth. Sustained proliferative capacity can result from over-production of growth factor ligands or receptors and production of structurally altered receptors, which can signal in the absence of ligand binding and activation of intracellular signalling pathway components, so that signalling is no longer ligand-dependent.

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3.  Sustaining proliferative signalling

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and tissue invasion, thereby enhancing rather than inhibiting carcinogenesis.

The 10 hallmarks of cancer • 1317

33

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Fig. 33.2  The cell cycle and sites of action of chemotherapeutic agents. (CDK = cyclin-dependent kinase; RB = retinoblastoma gene)

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Local invasion through basal lamina

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↑ Angiogenesis to support tumour growth (see Fig. 33.4)

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Failed apoptosis (e.g. TP53 mutation)

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Carcinoma

Ectopic growth factor production and autostimulation

Breakdown of connective tissue via tumour production of e.g. collagenase tissue metalloproteinases Loss of cell adhesion molecules e.g. E-cadherin

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Further mutation; subset selected for rapid growth

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Further mutation → invasion or metastasis

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Inherited or acquired gain of oncogene Loss of tumour suppressor gene

Blood spread

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Connective tissue Lymphatic

Lymphatic spread

Further mutation

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Small adenoma

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Basal lamina Blood vessel

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Initial proliferation First mutation Normal epithelium

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First mutation

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All cancers require a functional vascular network to ensure continued growth and will be unable to grow beyond 1 mm3 without stimulating the development of a vascular supply. Tumours require sustenance in the form of nutrients and oxygen, as well as an ability to evacuate metabolic waste products and carbon dioxide. This entails the development of new blood vessels, which is termed angiogenesis (Figs 33.3 and 33.4). Angiogenesis is dependent on the production of angiogenic growth factors, of which vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are the best characterised. During tumour progression, an angiogenic switch is activated and remains on, causing normally quiescent vasculature to sprout new vessels continually that help sustain expanding tumour growth. Angiogenesis is governed by a balance of pro-angiogenic stimuli and angiogenesis inhibitors, such as thrombospondin (TSP)-1, which binds to transmembrane receptors on endothelial cells and evokes suppressive signals. A number of cells can contribute to the maintenance of a functional tumour vasculature and therefore sustain angiogenesis. These include pericytes and a variety of bone marrow-derived cells such as macrophages, neutrophils, mast cells and myeloid progenitors.

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For cancer cells to evolve into macroscopic tumours, they need to acquire the ability for unlimited proliferation. Telomeric DNA sequences, which protect and stabilise chromosomal ends, play a central role in conferring this limitless replicative potential. During replication of normal cells, telomeres shorten progressively as small fragments of telomeric DNA are lost with successive cycles of replication. This shortening process is thought to represent a mitotic clock and eventually prevents the cell from dividing further. Telomerase, a specialised polymerase enzyme, adds nucleotides

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5.  Enabling replicative immortality

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6.  Inducing angiogenesis

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In healthy tissues, cell-to-cell contact in dense cell populations acts as an inhibitory factor on proliferation. This contact inhibition is typically absent in many cancer cell populations. Growth-inhibitory factors can modulate the cell cycle regulators and produce activation of the CDK inhibitors, causing inhibition of the CDKs. Mutations within inhibitory proteins are common in cancer. Loss of restriction by disruption of pRB regulation can be found in human tumours, which produces a loss of restraint on transition from G1 to S phase of the cell cycle. Disruption of TP53 function will have downstream effects on p21 that alter the coordination of DNA repair with cycle arrest, and that result in the affected cell accumulating genomic defects. Down-regulation of p21 and p27, which can be found in tumours with normal TP53 function, correlates notably with high tumour grade and poor prognosis.

to telomeres, allowing continued cell division and thus preventing premature arrest of cellular replication. The telomerase enzyme is almost absent in normal cells but is expressed at significant levels in many human cancers.

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4.  Evading growth suppressors

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Fig. 33.3  Oncogenesis. The multistep origin of cancer, showing events implicated in cancer initiation, progression, invasion and metastasis.

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1318 • Oncology

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Cell adhesion

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Urokinase Proteolysis Plasmin

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Fibrin

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αvβ3 integrin Urokinase receptor

A

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Coagulation factor Coagulation Tissue Fibrinogen factor

VEGF receptor VEGF

Inhibition

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Viable tumour cell Apoptoptic tumour cell

The 10 hallmarks of cancer • 1319

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Almost all tumours show infiltration with immune cells on pathological investigation and historically this finding was thought to represent an attempt of the immune system to eradicate the cancer. It is now clear that tumour-associated inflammatory responses promote tumour formation and cancer progression. Cytokines are able to alter blood vessels to permit migration of leucocytes (mainly neutrophils), in order to permeate from the blood vessels into the tissue, a process known as extravasation. Migration across the endothelium occurs via the process of diapedesis, where chemokine gradients stimulate adhered leucocytes to move between endothelial cells and pass through the basement membrane into the surrounding tissues. Once within the tissue interstitium, leucocytes bind to extracellular matrix proteins via integrins and CD44 to prevent their loss from the site. As well as cell-derived mediators, several acellular biochemical cascade systems consisting of pre-formed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria, and the coagulation and fibrinolytic systems activated by necrosis, and also in burns and trauma, as well as cancer. Other bioactive molecules, such as growth factors and pro-angiogenic factors, may be released by inflammatory immune cells into the surrounding tumour microenvironment. In particular, the release of reactive

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9.  Tumour-promoting inflammation

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Under aerobic conditions, oxidative phosphorylation functions as the main metabolic pathway for energy production; cells process glucose, first to pyruvate via glycolysis and thereafter to carbon dioxide in the mitochondria. While under anaerobic conditions, glycolysis is favoured to produce adenosine triphosphate (ATP). Cancer cells can reprogram their glucose metabolism to limit

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8.  Reprogramming energy metabolism

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energy production to glycolysis, even in the presence of oxygen. This has been termed ‘aerobic glycolysis’. Up-regulation of glucose transporters, such as GLUT1, is the main mechanism through which aerobic glycolysis is achieved. This reprogramming of energy metabolism appears paradoxical, as overall energy production from glycolysis is significantly lower (18-fold) than that from oxidative phosphorylation. One explanation may be that the increased production of glycolytic intermediates can be fed into various biosynthetic pathways, including those that generate the nucleosides and amino acids, necessary for the production of new cells.

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Invasion and metastasis are complex processes involving multiple discrete steps; they begin with local tissue invasion, followed by infiltration of nearby blood and lymphatic vessels by cancer cells. Malignant cells are eventually transported through haematogenous and lymphatic spread to distant sites within the body, where they form micrometastases that will eventually grow into macroscopic metastatic lesions (see Fig. 33.3). Cadherin-1 (CDH1) is a calcium-dependent cell–cell adhesion glycoprotein that facilitates assembly of organised cell sheets in tissues, and increased expression is recognised as an antagonist of invasion and metastasis. In situ tumours usually retain CDH1 production, whereas loss of CDH1 production due to downregulation or occasional mutational inactivation of CDH1 has been observed in human cancers, supporting the theory that CDH1 plays a key role in suppression of invasion and metastasis. Cross-talk between cancer cells and cells of the surrounding stromal tissue is involved in the acquired capability for invasive growth and metastasis. Mesenchymal stem cells in tumour stroma have been found to secrete CCL5, a protein chemokine that helps recruit leucocytes into inflammatory sites. With the help of particular T-cell-derived cytokines (interleukin (IL)-2 and interferon-gamma (IFN-γ)), CCL5 induces proliferation and activation of natural killer cells and then acts reciprocally on cancer cells to stimulate invasive behaviour. Macrophages at the tumour periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases and cysteine cathepsin proteases.

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any cancer to grow beyond 1 mm3, it must evoke a blood supply. B New vessel formation results from the release of angiogenic factors by the tumour cells and loss of inhibition of the endothelial cells. C The loss of cellular adhesion and disruption of the extracellular matrix allow cells to extravasate into the blood stream and metastasise to distant sites. (VEGF= vascular endothelial growth factor)

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Fig. 33.4  Angiogenesis, invasion and metastasis. A For

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Angiogenic factors

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Loss of inhibition

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Plasminogen

Viral infection

Epstein–Barr virus Human papillomavirus Hepatitis B and C viruses

Basal cell carcinoma Melanoma Non-melanocytic skin cancer Leukaemia Solid tumours, e.g. thyroid Cholangiocarcinoma following Thorotrast usage Lung cancer Medullary thyroid cancer Sarcoma

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Vaginal cancer Endometrial cancer Breast cancer

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(CT = computed tomography; MALT = mucosa-associated lymphoid tissue; UV = ultraviolet)

Colon cancer

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Use of diethylstilbestrol Oestrogens

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Ulcerative colitis

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Inflammatory diseases

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Diagnostic exposure (e.g. CT) Occupational exposure (e.g. beryllium and strontium mining) Therapeutic radiotherapy

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UV exposure

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Colonic cancer Gastric cancer Hepatocellular cancer

Hormonal

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Low-roughage/high-fat content diet High nitrosamine intake Aflatoxin from contamination of Aspergillus flavus

Nuclear fallout following explosion (e.g. Hiroshima)

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Burkitt’s lymphoma and nasopharyngeal cancer Cervical cancer Hepatocellular carcinoma Cholangiocarcinoma Squamous cell bladder cancer

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Radiation

Lung and bladder cancer

Gastric MALT lymphomas, gastric cancer

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Dietary factors

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Acute myeloid leukaemia

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Helicobacter pylori

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Exposure to carcinogens from inhaled smoke

Bladder cancer Lung cancer and mesothelioma Liver angiosarcoma Acute leukaemia

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Chemotherapy (e.g. melphalan, cyclophosphamide)

Cigarette smoking

Liver fluke (Opisthorchis sinensis ) Schistosoma haematobium

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Chemicals

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Diseases

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Dye and rubber manufacturing (aromatic amines) Asbestos mining, construction work, shipbuilding (asbestos) Vinyl chloride (PVC) manufacturing Petroleum industry (benzene)

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Processes

Occupational exposure (see ‘Radiation’ below)

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Environmental aetiology

Parasitic infection

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33.1  Environmental factors that predispose to cancer

Bacterial infection

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Environmental triggers for cancer have mainly been identified through epidemiological studies that examine patterns of distribution of cancers in patients in whom age, sex, presence of other illnesses, social class, geography and so on differ. Sometimes, these give strong pointers to the molecular or cellular causes of the disease, such as the association between aflatoxin production within contaminated food supplies and hepatocellular carcinomas. For many solid cancers, such as breast and colorectal, however, there is evidence of a multifactorial pathogenesis, even when there is a principal environmental cause (Box 33.1). Smoking is now established beyond all doubt as a major cause of lung cancer, but there are obviously additional predisposing factors since not all smokers develop cancer. Similarly, most carcinomas of the cervix are related to infection with human

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Environmental factors

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The majority of cancers do not have a single cause but rather are the result of a complex interaction between genetic factors and exposure to environmental carcinogens. These are often tumour type-specific but some general principles do apply.

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The immune system operates as a significant barrier to tumour formation and progression, and the ability to escape from immunity is a hallmark of cancer development. Cancer cells continuously shed surface antigens into the circulatory system, prompting an immune response that includes cytotoxic T-cell, natural killer cell and macrophage production. The immune system is thought to provide continuous surveillance, with resultant elimination of cells that undergo malignant transformation. However, deficiencies in the development or function of CD8+ cytotoxic T lymphocytes, CD4+ Th1 helper T cells or natural killer cells can each lead to a demonstrable increase in cancer incidence. Also, highly immunogenic cancer cells may evade immune destruction by disabling components of the immune system. This is done through recruitment of inflammatory cells, including regulatory T cells and myeloid-derived suppressor cells, both actively immunosuppressive against the actions of cytotoxic lymphocytes (see Fig. 4.12, p. 80). Cancers develop and progress when there is loss of recognition by the immune system, lack of susceptibility due to escape from immune cell action and induction of immune dysfunction, often via inflammatory mediators.

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10.  Evading immune destruction

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Environmental and genetic determinants of cancer

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oxygen species, which are actively mutagenic, will accelerate the genetic evolution of surrounding cancer cells, enhancing growth and contributing to cancer progression.

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1320 • Oncology

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AR

AT

Leukaemia, tongue, oesophageal, colonic, Wilms’ tumour

AR

BLM

Breast/ovarian

Breast, ovarian, colonic, prostatic, pancreatic

AD

BRCA1, BRCA2

Cowden’s syndrome

Breast, thyroid, gastrointestinal tract, pancreatic

AD

PTEN

Leukaemia, oesophageal, skin, hepatoma

Gorlin’s syndrome

Basal cell skin, brain

FACA, FACC, FACD

AD

PTCH

AD

E-cadherin

AD

MSH2, MLH1, MSH6, PMS1, PMS2 TP53

Multiple endocrine neoplasia (MEN) 1

Pancreatic islet cell, pituitary adenoma, parathyroid adenoma and hyperplasia

AD

MEN1

MEN 2

Medullary thyroid, phaeochromocytoma, parathyroid hyperplasia

AD

RET

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Neurofibrosarcoma, phaeochromocytoma, optic glioma

AD

Vestibular schwannoma

AD

NF2

Papillary renal cell cancer syndrome

Renal cell cancer

AD

MET

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Nephroblastoma, neuroblastoma, hepatoblastoma, rhabdomyosarcoma

AD

WT1

Skin, leukaemia, melanoma

AR

XPA, XPC, XPD (ERCC2), XPF

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VHL

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RB1

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HPC1

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STK11

AD

Haemangioblastoma of retina and CNS, renal cell, phaeochromocytoma

(AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system)

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Retinoblastoma, osteosarcoma

Xeroderma pigmentosum

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Colonic, ileal, breast, ovarian Prostate

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Wilms’ tumour

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Neurofibromatosis 1

Neurofibromatosis 2

Retinoblastoma

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Sarcoma, breast, osteosarcoma, leukaemia, glioma, adrenocortical

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Li–Fraumeni syndrome

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Colonic, endometrial, ovarian, pancreatic, gastric

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Hereditary non-polyposis colon cancer (HNPCC)

von Hippel–Lindau syndrome

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CDKN2A (TP16)

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APC, MUTYH

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Fanconi anaemia

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Melanoma, pancreas

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Colonic, upper gastrointestinal tract

Familial atypical multiple mole melanoma (FAMMM)

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Familial adenomatous polyposis

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Leukaemia, lymphoma, ovarian, gastric, brain, colon

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Ataxia telangiectasia Bloom’s syndrome

Prostate cancer

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m Gene

Diffuse gastric cancer

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Malignancies

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When a patient is suspected of having cancer, a full history should be taken; specific questions should be included as to potential risk factors such as smoking and occupational exposures or potential complications of the disease. A thorough clinical examination is essential to identify sites of metastases, and to discover any other conditions that may have a bearing on the management plan (pp. 1314–1315). In order to make a diagnosis and to plan the most appropriate management, information is needed on: • the type of tumour • the extent of disease, as assessed by staging investigations • the patient’s general condition and any comorbidity.

33.2  Inherited cancer predisposition syndromes

Peutz–Jeghers syndrome

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m

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ok s

Investigations

A number of inherited cancer syndromes are recognised that account for 5–10% of all cancers (Box 33.2). Their molecular basis is discussed in Chapter 3, but in general they result from inherited mutations in genes that regulate cell growth, cell death and apoptosis. Examples include the BRCA1, BRCA2 and AT (ataxia telangiectasia) genes that cause breast and some other cancers, the FAP gene that causes bowel cancer and the RB gene that causes retinoblastoma. Although carriers of these gene mutations have a greatly elevated risk of cancer, none has

Hereditary diffuse gastric cancer

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100% penetrance and additional modulating factors, both genetic and environmental, are likely to be operative. Exploration of a possible genetic contribution is a key part of cancer management, especially with regard to ascertaining the risk for an affected patient’s offspring.

eb o

oo eb

m

Genetic factors

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ks f

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papillomavirus (HPV subtypes 16 and 18). For carcinomas of the bowel and breast, there is strong evidence of an environmental component. For example, the risk of breast cancer in women of Far Eastern origin remains relatively low when they first migrate to a country with a Western lifestyle, but rises in subsequent generations to approach that of the resident population of the host country. The precise environmental factor that causes this change is unclear but may include diet (higher intake of saturated fat and/or dairy products), reproductive patterns (later onset of first pregnancy) and lifestyle (increased use of artificial light and shift in diurnal rhythm).

Investigations • 1321

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m

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ks

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Cytogenetic analysis

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m

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Some tumours demonstrate typical chromosomal changes that help in diagnosis. The utilisation of fluorescent in situ hybridisation (FISH) techniques can be useful in Ewing’s sarcoma and peripheral neuro-ectodermal tumours where there is a translocation between chromosome 11 and 22–t(11;22)(q24;q12). In some cases, gene amplification can be detected via FISH (e.g. determining over-expression of HER2/neu).

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m

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Electron microscopy (EM) can sometimes be of diagnostic value. Examples include the visualisation of melanosomes in amelanotic melanoma and dense core granules in neuro-endocrine tumours. EM may help to distinguish adenocarcinoma from mesothelioma, as the ultrastructural properties of these two diseases are different (mesothelioma appears to have long, narrow, branching microvilli while adenocarcinomas appear to have short, stubby microvilli). EM is also useful for differentiating spindle-cell tumours (sarcomas, melanomas, squamous cell cancers) from small round-cell tumours, again due to their ultrastructural differences.

m

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sf

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e.

Histological analysis of a biopsy or resected specimen is pivotal in clinching the diagnosis and in deciding on the best form of management. The results of histological analysis are most

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m

Electron microscopy

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The pattern of immunoglobulin, T-cell receptor and cluster designation (CD) antigen expression on the surface is helpful in the diagnosis and classification of lymphomas. This can be achieved by IHC staining of biopsy samples or flow cytometry.

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eb

The overall fitness of a patient is often assessed by the Eastern Cooperative Oncology Group (ECOG) performance status scale (Box 33.3). The outcome for patients with a performance status of 3 or 4 is worse in almost all malignancies than for those with a status of 0–2, and this has a strong influence on the approach to treatment in the individual patient. The process of staging determines the extent of the tumour; it entails clinical examination, imaging and, in some cases, surgery, to establish the extent of disease involvement. The outcome is recorded using a standard staging classification that allows comparisons to be made between different groups of patients. Therapeutic decisions and prognostic predictions can then be made using the evidence base for the disease. One of the most commonly used systems is the T (tumour), N (regional lymph nodes), M (metastatic sites) approach of the International Union against Cancer (UICC, Box 33.4). For some tumours, such as colon cancer, the Dukes system (p. 832) is used rather than the UICC classification.

m

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*Exact criteria for size and region of nodal involvement have been defined for each anatomical site.

Histology

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Not assessed Not present Present

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Increases in involvement

Presence of metastases MX M0 M1

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Not assessed No nodal involvement

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}

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Increases in primary tumour size or depth of invasion

Increased involvement of nodes* NX N0 N1 N2/3

Immunohistochemical (IHC) staining for tumour markers can provide useful diagnostic information and can help with treatment decisions. Commonly used examples of IHC in clinical practice include: • Oestrogen (ER) and progesterone (PR) receptors. Positive results indicate that the tumour may be sensitive to hormonal manipulation. • Alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) with or without placental alkaline phosphatase (PLAP). These favour germ-cell tumours. • Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). These favour prostate cancer. • Carcinoembryonic antigen (CEA), cytokeratin and epithelial membrane antigen (EMA). These favour epithelial carcinomas. • HER2 receptor. Breast cancers that have high levels of expression of HER2 indicate that the tumour may respond to trastuzumab (Herceptin), an antibody directed against the HER2 receptor.

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}

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Not assessed No tumour

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TX T0 T1 T2 T3 T4

Immunohistochemistry

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Extent of primary tumour*

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33.4  TNM classification

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Completely disabled, unable to carry out any self-care and confined totally to bed or chair

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4

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Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

Examination of tumour samples by light microscopy remains the core method of cancer diagnosis and, in cases where the primary site is unclear, may give clues to the origin of the tumour: • Signet-ring cells favour a gastric primary. • Presence of melanin favours melanoma. • Mucin is common in gut/lung/breast/endometrial cancers, but particularly common in ovarian cancer and rare in renal cell or thyroid cancers. • Psammoma bodies are a feature of ovarian cancer (mucin +) and thyroid cancer (mucin −).

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3

ks

Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours

Light microscopy

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2

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Restricted in strenuous activity but ambulatory and able to carry out light work or pursue a sedentary occupation. This group also contains patients who are fully active, as in grade 0, but only with the aid of analgesics

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1

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Fully active, able to carry on all usual activities without restriction and without the aid of analgesics

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informative when combined with knowledge of the clinical picture; biopsy results should therefore be reviewed and discussed within the context of a multidisciplinary team meeting.

33.3  Eastern Cooperative Oncology Group (ECOG) performance status scale

0

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1322 • Oncology

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Palpable mass

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Unintentional weight loss is a characteristic feature of advanced cancer, but can have other causes such as thyrotoxicosis, chronic inflammatory disease and chronic infective disorders. Fever can occur in any cancer secondary to infection, but may be a primary feature in Hodgkin and non-Hodgkin lymphoma, leukaemia, renal cancer and liver cancer. The presence of unexplained weight loss or fever warrants investigation to exclude the presence of occult malignancy.

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33

ok s

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Weight loss and fever

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In the early stages of cancer development, the number of malignant cells is small and the patient is usually asymptomatic. With tumour progression, localised signs or symptoms develop due to mass effects and/or invasion of local tissues. With further progression, symptoms may occur at distant sites as a result of

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ok s

ks fre

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A palpable mass detected by the patient or physician may be the first sign of cancer. Primary tumours of the thyroid, breast, testis and skin are often detected in this way, whereas palpable lymph nodes in the neck, groin or axilla may indicate secondary spread of tumour. Hepatomegaly may be the first sign of primary liver cancer or tumour metastasis, whereas skin cancer may present as an enlarging or changing pigmented lesion.

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Presenting problems in oncology

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metastatic disease or from non-metastatic manifestations due to production of biologically active hormones by the tumour or as the result of an immune response to the tumour. The possible presentations are summarised in Boxes 33.6 and 33.7, and common presenting features discussed below. Although the incidence of cancer increases with patient age, the approach to investigation and management is similar at all ages (Box 33.8).

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Many cancers produce substances called tumour markers, which can assist in diagnosis and surveillance. Some are useful in population screening, diagnosis, determining prognosis, response evaluation, detection of relapse and imaging of metastasis. Unfortunately, most tumour markers are neither sufficiently sensitive nor sufficiently specific to be used in isolation for diagnosis and need to be interpreted in the context of the other clinical features. Some can be used for antibody-directed therapy or imaging, however, where they have a greater role in diagnosis. Tumour markers in routine use are outlined in Box 33.5.

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(PET–CT) images. A There is a neoplastic lesion (arrow) in the left axilla, evidenced by the increased uptake of fluorodeoxyglucose (FDG) tracers. B Imaging after chemotherapy, demonstrating that the abnormal uptake has disappeared and indicating a response to treatment. Courtesy of Dr J. Wilsdon, Freeman Hospital, Newcastle upon Tyne.

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Biochemical markers

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Fig. 33.5  Positron emission tomography–computed tomography

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Positron emission tomography (PET) visualises metabolic activity of tumour cells and is widely used, often in combination with CT (PET–CT), to evaluate the extent of the disease, particularly in the assessment of potential distant metastasis (Fig. 33.5). It can accurately assess the severity and spread of cancer by detecting tumour metabolic activity following injection of small amounts of radioactive tracers such as fluorodeoxyglucose (FDG). In addition to having a role in diagnosis, PET can be used in some patients to assess treatment response.

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Positron emission tomography

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Magnetic resonance imaging

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B

Computed tomography (CT) is a key investigation in cancer patients and is particularly useful in imaging the thorax and abdomen. With modern scanners it is possible to visualise the large bowel if it is prepared (CT colonography), allowing accurate detection of colorectal cancers and adenomas ≥ 10 mm.

Magnetic resonance imaging (MRI) has a high resolution and is the preferred technique for brain and pelvic imaging. It is widely employed for the staging of rectal, cervical and prostate cancers.

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m

Ultrasound

Ultrasound is useful in characterising lesions within the liver, kidney, pancreas and reproductive organs. It can be used for guiding biopsies of tumours in breast and liver. Endoscopic ultrasound is helpful in staging upper gastrointestinal and pancreatic cancers, involving a special endoscope with an ultrasound probe attached.

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m

A

Imaging plays a critical role in oncology, not only in locating the primary tumour but also in staging the disease and determining the response to treatment. The imaging modality employed depends primarily on the site of the disease and likely patterns of spread, and may require more than one modality.

Computed tomography

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Imaging

Presenting problems in oncology • 1323

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om Tumours

Alpha-fetoprotein (AFP)

Glycoprotein found in yolk sac and fetal liver tissue. Transient elevation in liver diseases. Has a role in screening during pregnancy for the detection of neural tube defects and Down’s syndrome

Ovarian non-seminomatous germ cell tumours (80%), testicular teratoma (80%), hepatocellular cancer (50%)

32-amino-acid peptide from C cells of thyroid. Used to screen for MEN 2

Medullary cell carcinoma of thyroid

Differentiation antigen of coelomic epithelium (Müller’s duct). Raised in any cause of ascites, pleural effusion or heart failure. Can be raised in inflammatory conditions

Ovarian epithelial cancer (75%), gastrointestinal cancer (10%), lung cancer (5%) and breast cancer (5%)

A mucin found in epithelium of fetal stomach, intestine and pancreas. It is eliminated exclusively via bile and so any degree of cholestasis can cause levels to rise

Pancreatic cancer (80%), mucinous tumour of the ovary (65%), gastric cancer (30%), colon cancer (30%)

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Colorectal cancer, particularly with liver metastasis, gastric cancer, breast cancer, lung cancer, mucinous cancer of the ovary

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eb

Glycoprotein found in intestinal mucosa during embryonic and fetal life. Elevated in smokers, cirrhosis, chronic hepatitis, ulcerative colitis, pneumonia

Glycoprotein hormone, 14 kD α subunit and 24 kD β subunit from placental syncytiotrophoblasts. Used for disease monitoring in hydatidiform mole and as the basis of a pregnancy test

Choriocarcinoma (100%), hydatidiform moles (97%), ovarian non-seminomatous germ cell tumours (50–80%), seminoma (15%)

Placental alkaline phosphatase (PLAP)

Isoenzyme of alkaline phosphatase

Seminoma (40%), ovarian dysgerminoma (50%)

Prostate-specific antigen (PSA)

Glycoprotein member of human kallikrein gene family. PSA is a serine protease that liquefies semen in excretory ducts of prostate. Can be elevated in benign prostatic hypertrophy and prostatitis

Prostate cancer (95%)

Matrix protein for thyroid hormone synthesis in normal thyroid follicles

Papillary and follicular thyroid cancer

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re e

Typical site or possible tumour

Haemorrhage

Stomach, colon, bronchus, endometrium, bladder, kidney

m

Breast, lymph node (any site), testicle

Bone pain or fracture

Bronchus, thyroid

Odynophagia, early satiety, vomiting

Bronchus, stomach, oesophagus, colon, rectum

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sf ok

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e.

Thrombosis and disseminated intravascular coagulation (DIC) are common complications in patients with cancer. The prothrombotic state is caused by cancer cells activating the coagulation system

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via factors such as tissue factor, cancer procoagulant and inflammatory cytokines. The interaction between tumour cells, monocytes/macrophages, platelets and endothelial cells can promote thrombus formation, as part of a host response to the cancer (i.e. acute phase, inflammation, angiogenesis) or via a reduction in the levels of inhibitors of coagulation or impairment

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Thromboembolism

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Ovary, stomach, pancreas

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Abdominal swelling (ascites)

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Airway obstruction, stridor, cough, recurrent infection

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Colon, rectum, ovary

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Increasing constipation, abdominal discomfort or pain

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Oesophagus, bronchus, gastric

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Oesophagus, stomach, anus, skin

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ks fre

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ks f Dysphagia

Melanoma, basal cell carcinoma (rodent ulcer)

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Bone (primary sarcoma, secondary metastasis from breast, prostate, bronchus, thyroid, kidney)

Skin abnormality Ulcer

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Lump

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Symptom

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33.6  Local features of malignant disease

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Thyroglobulin

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Human chorionic gonadotrophin (hCG)

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Carcinoembryonic antigen (CEA)

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eb

Non-Hodgkin lymphoma, myeloma

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CA-19.9

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A human leucocyte antigen (HLA) common fragment present on surface of lymphocytes, macrophages and some epithelial cells. Can be elevated in autoimmune disease and renal glomerular disease

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Cancer antigen 125 (CA-125)

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Beta-2-microglobulin

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Natural occurrence

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Name

Calcitonin

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33.5  Commonly used serum tumour markers

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1324 • Oncology

ACTH

Cushing’s syndrome

SCLC

Fatigue

Any

Erythropoietin

Polycythaemia

Kidney, hepatoma, cerebellar haemangioblastoma, uterine fibroids

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33

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These form a group of conditions associated with cancer that are thought to be due to an immunological response to the tumour that results in damage to the nervous system or muscle. The cancers most commonly implicated are those of the lung (small cell and non-small cell), pancreas, breast, prostate, ovary and lymphoma. • Peripheral neuropathy results from axonal degeneration or demyelination. • Encephalomyelitis can present with diverse symptoms, depending on which region of the brain is involved. Lumbar puncture shows raised protein in the cerebrospinal fluid and a pleocytosis, predominantly that of lymphocytes. In some centres, flow cytometry of the cerebrospinal fluid can be used to detect carcinomatous cells. MRI shows meningeal enhancement, particularly at the level of the brainstem, and anti-Hu antibodies may be detectable in serum. Encephalomyelitis is due to perivascular inflammation and selective neuronal degeneration. Most cases are caused by small cell lung cancer (75%). • Cerebellar degeneration may be the presenting feature of an underlying malignancy and presents with rapid onset of cerebellar ataxia. Diagnosis is by MRI or CT, which may show cerebellar atrophy. Patients with these neurological paraneoplastic syndromes may be found to have circulating anti-Yo, Tr and Hu antibodies, but these are not completely specific and negative results do not exclude the diagnosis. • Retinopathy is a rare complication of cancer and presents with blurred vision, episodic visual loss and impaired colour vision. If left untreated, it may lead to blindness. The diagnosis should be suspected if the electroretinogram is abnormal and anti-retinal antibodies are detected. • Lambert–Eaton myasthenic syndrome (LEMS) is due to underlying cancer in about 60% of cases. It presents with

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In some cases, the first presentation of cancer is with a metabolic abnormality due to ectopic production of hormones by tumour cells, including insulin, ACTH, vasopressin (antidiuretic hormone, ADH), fibroblast growth factor (FGF)-23, erythropoietin and

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Neurological paraneoplastic syndromes

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m

Ectopic hormone production

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parathyroid hormone-related protein (PTHrP). This can result in a wide variety of presentations, as summarised in Box 33.9. Further details on the presentation and management of ACTH- and vasopressin-producing tumours are given on page 670, and those of FGF23-producing tumours on page 1053. The management of hypercalcaemia associated with malignancy is discussed below.

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of fibrinolysis. Furthermore, the prothrombotic tendency can be enhanced by therapy such as surgery, chemotherapy, hormone therapy and radiotherapy, and by in-dwelling access devices (i.e. central venous catheters). In some patients, the thromboembolism is the first presenting feature of the underlying cancer.

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SCLC

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eb oo ks

Hyponatraemia

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ks fre

(ACTH = adrenocorticotrophic hormone; SIADH = syndrome of inappropriate antidiuretic hormone (vasopressin) secretion)

m

NSCLC (squamous cell), breast, kidney

(ACTH = adrenocorticotrophic hormone; ADH = antidiuretic hormone; FGF = fibroblast growth factor; NSCLC = non-small cell lung cancer; PTHrP = parathyroid hormone-related protein; SCLC = small cell lung cancer)

Stomach, lung

33.8  Cancer in old age

Hypercalcaemia

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Stomach, oesophagus

Vasopressin (ADH)

Mesenchymal tumours

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Acanthosis nigricans

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Small cell lung cancer, ovarian cancer

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Small cell lung cancer

Subacute cerebellar degeneration

PTHrP

Hypophosphataemic osteomalacia

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FGF-23

Small cell lung cancer

Lambert–Eaton myasthenic syndrome

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oo

Ovary, pancreas, gastrointestinal tract

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ok s

eb o

Myeloma, breast, kidney

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Hypercalcaemia

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Lung, gastrointestinal tract

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Weight loss and anorexia

• Incidence: around 50% of cancers occur in the 15% of the population aged over 65 years. • Screening: women aged over 65 in the UK are not invited to breast cancer screening but can request it. Uptake is low despite increasing incidence with age. • Presentation: may be later for some cancers. When symptoms are non-specific, patients (and their doctors) may initially attribute them to age alone. • Life expectancy: an 80-year-old woman can expect to live 8 years, so cancer may still shorten life and an active approach remains appropriate. • Prognosis: histology, stage at presentation and observation for a brief period are better guides to outcome than age. • Rate of progression: malignancy may have a more indolent course. This is poorly understood but may be due to reduced effectiveness of angiogenesis with age, inhibiting the development of metastases. • Response to treatment: equivalent to that in younger people – well documented for a range of cancers and for surgery, radiotherapy, chemotherapy and hormonal therapy. • Treatment selection: chronological age is of minor importance compared to comorbid illness and patient choice. Although older patients can be treated effectively and safely, aggressive intervention is not appropriate for all. Symptom control may be all that is possible or desired by the patient.

eb

e. co m Tumours

Dermatomyositis/polymyositis

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fre

Consequence

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Hormone

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Common cancer site associations

SIADH Ectopic ACTH

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33.9  Ectopic hormone production by tumours

Feature

Prothrombotic tendency

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m e. co re

33.7  Non-metastatic manifestations of malignant disease

Presenting problems in oncology • 1325

fre

• Confirm diagnosis with urgent MRI scan • Administer high-dose glucocorticoids: Dexamethasone 16 mg IV stat Dexamethasone 8 mg twice daily orally • Ensure adequate analgesia • Refer for surgical decompression or urgent radiotherapy

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co m

fre e.

Decreased knee and ankle reflexes with flexor plantar reflex

Symmetrical, sensory level

Symmetrical, saddle distribution

Asymmetrical, radicular pattern

Late loss

Early loss

Often spared

Rapid

Variable

Variable

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sf re ok

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Cauda equina

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Asymmetrical, may be mild

Increased knee reflex, decreased ankle reflex, extensor plantar reflex

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ks oo

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eb o

Symmetrical and variable

Increased (or absent) knee and ankle reflexes with extensor plantar reflex

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Symmetrical and profound

Reflexes

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Conus medullaris

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Weakness

Progression

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fre

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Spinal cord

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Clinical feature

Sphincters

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The typical presentation is with oedema of the arms and face, distended neck and arm veins and dusky skin coloration over the chest, arms and face. Collateral vessels may develop over a period of weeks and the flow of blood in the collaterals helps to confirm the diagnosis. Headache secondary to cerebral oedema arising from the backflow pressure may also occur and tends to be aggravated by bending forwards, stooping or lying down. The severity of symptoms is related to the rate of obstruction and the development of a venous collateral circulation. Accordingly, symptoms may develop rapidly or gradually. Clinical features are summarised in Box 33.12.

33.10  Comparison of features of neurological deficit

Sensory loss

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Clinical features

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Superior vena cava obstruction (SVCO) is a common complication of cancer that can occur through extrinsic compression or intravascular blockage. The most common causes of extrinsic compression are lung cancer, lymphoma and metastatic tumours. Patients with cancer can also develop SVCO due to intravascular blockage in association with a central catheter or thromboembolism secondary to the tumour.

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co m

The earliest sign is back pain, particularly on coughing and lying flat. Subsequently, sensory changes develop in dermatomes below the level of compression and motor weakness distal to the block occurs. Finally, sphincter disturbance, causing urinary retention and bowel incontinence, is observed. Involvement of the lumbar spine may cause conus medullaris or cauda equina compression (Box 33.10). Physical examination reveals findings consistent with an upper motor neuron lesion, but lower motor

Superior vena cava obstruction

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Clinical features

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Spinal cord compression complicates 5% of cancers and is most common in myeloma, prostate, breast and lung cancers that involve bone. Cord compression often results from posterior extension of a vertebral body mass but intrathecal spinal cord metastases can cause similar signs and symptoms. The thoracic region is most commonly affected.

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Spinal cord compression is a medical emergency and should be treated with analgesia and high-dose glucocorticoid therapy (Box 33.11). Neurosurgical intervention produces superior outcome and survival compared to radiotherapy alone, and should be considered first for all patients. Radiotherapy is used for the remaining patients and selected tumour types when the cancer is likely to be radiosensitive. The prognosis varies considerably, depending on tumour type, but the degree of neurological dysfunction at presentation is the strongest predictor of outcome, irrespective of the underlying diagnosis. Mobility can be preserved in more than 80% of patients who are ambulatory at presentation, but neurological function is seldom regained in patients with established deficits such as paraplegia.

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fre

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m

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fre

Emergency complications of cancer

Management

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ks fre

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The clinical features and management of these skin conditions are discussed in Chapter 29.

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m

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neuron findings may predominate early on or in cases of nerve root compression.

Many cancers can present with skin manifestations that are not due to metastases: • Pruritus may be a presenting feature of lymphoma, leukaemia and central nervous system tumours. • Acanthosis nigricans may precede cancers by many years and is particularly associated with gastric cancer. • Vitiligo may be associated with malignant melanoma and is possibly due to an immune response to melanocytes. • Pemphigus may occur in lymphoma, Kaposi’s sarcoma and thymic tumours. • Dermatitis herpetiformis associated with coeliac disease may precede tumour development by many years, and is associated with gastrointestinal lymphoma.

Spinal cord compression

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Cutaneous manifestations of cancer

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33.11  Management of suspected spinal cord compression

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proximal muscle weakness that improves on exercise and is caused by the development of antibodies to presynaptic calcium channels (p. 1143). The diagnosis is made by electromyelogram (EMG), which shows a low-amplitude compound muscle action potential that enhances to near normal following exercise. • Dermatomyositis or polymyositis may be the first presentation of some cancers. Clinical features and management of these conditions are discussed on page 1039.

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1326 • Oncology

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33

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An infection screen should be performed to include blood cultures (both peripheral and from central lines), urine culture, chest X-ray, and swabs for culture (throat, central line, wound). High-dose intravenous antibiotics should then be commenced, pending the results of cultures. The standard approach is to commence empirical antibiotics according to local hospital policies agreed with microbiologists and based on the local antibiotic resistance patterns observed. First-line empirical therapy is either monotherapy with piperacillin–tazobactam or meropenem, or with the addition of gentamicin. Metronidazole may be added if anaerobic infection is suspected, and teicoplanin where Gram-positive infection is suspected (e.g. in patients with central lines). Antibiotics should be adjusted according to culture results, although these are often negative. If there is no response after 36–48 hours, antibiotics should be reviewed with microbiological advice, and antifungal cover should be considered

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The diagnosis is made by measuring serum total calcium and adjusting for albumin. It is especially important to correct for albumin in cancer because hypoalbuminaemia is common and total calcium values under-estimate the level of ionised calcium. The principles of management are outlined in Box 33.13.

Investigations and management

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Investigations and management

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The typical presentation is with high fever, and affected patients are often non-specifically unwell. Examination is usually unhelpful in defining a primary source of the infection. Hypotension is an adverse prognostic feature and may progress to systemic circulatory shutdown and organ failure.

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The symptoms of hypercalcaemia are often non-specific and may mimic those of the underlying malignancy. They include drowsiness, delirium, nausea and vomiting, constipation, polyuria, polydipsia and dehydration.

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Clinical features

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Clinical features

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Hypercalcaemia is the most common metabolic disorder in patients with cancer and has a prevalence of up to 20% in cancer patients. The incidence is highest in myeloma and breast cancer (approximately 40%), intermediate in non-small cell lung cancer, and uncommon in colon, prostate and small cell lung carcinomas. It is most commonly due to over-production of PTHrP (80%), which binds to the PTH receptor and elevates serum calcium by stimulating osteoclastic bone resorption and increasing renal tubular reabsorption of calcium. Direct invasion of bone by metastases accounts for around 20% of cases while other mechanisms, such as ectopic PTH secretion, are rare.

m

Neutropenia is a common complication of malignancy. It is usually secondary to chemotherapy but may occur with radiotherapy if large amounts of bone marrow are irradiated; it may also be a component of pancytopenia due to malignant infiltration of the bone marrow. Neutropenic fever is defined as a pyrexia of 38°C for over 1 hour in a patient with a neutrophil count of  100 × 109/L). • High-dose therapy uses a higher individual drug dose to achieve a higher cell kill but results in more bone marrow toxicity. This can be minimised by using G–CSF. This approach allows more drug to be delivered within the same schedule of administration, but the total received dose can be less than the intended dose due to limitations of non-haematological toxicity. • Dose-dense therapy involves fractionating the intended dose of drug and administering each fraction on a more frequent basis (often weekly). Each individual dose produces less toxicity but the anti-cancer effect is related to the accumulative dose over time. Such an approach can overcome drug resistance, produce a greater cell kill and, in some cases, produce a response with weekly administration when the 3-weekly schedule demonstrates a lack of response or even disease progression. • Alternating therapy involves giving different drugs in an alternating manner. This is most commonly used with haematological malignancies and is designed to treat different subpopulations of cancer cells where individual clones of cells might be resistant to one or more of the agents.

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Surgical treatment

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Combination therapy

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• Neoadjuvant chemotherapy or primary medical therapy is where chemotherapy is administered first before a planned cyto-reductive procedure. This can result in a reduced requirement for surgery, increase the likelihood of successful debulking, reduce the duration of hospitalisation and improve the fitness of the patient prior to interval debulking. This approach has the same goals as adjuvant treatment but creates an opportunity for translational research to measure responses to treatment and correlate with subsequent specimens removed at the time of surgery. • Chemoprevention is the use of pharmacological agents to prevent cancer developing in patients identified as being at particular risk. The agents used therefore aim to modify risk and, as such, should not have significant adverse effects.

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1330 • Oncology

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↑ Risk ischaemic heart disease

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Nausea and vomiting Mucositis, diarrhoea

Nausea, diarrhoea

Premature gonadal failure Amenorrhoea

Premature gonadal failure

Neutropenia, anaemia Thrombocytopenia

Neutropenia ↓ Haemoglobin, platelet count

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Renal impairment

Fertility

Any organs

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Increased risk of malignancy

Children

Reduced growth

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Kidneys

Bone marrow

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Sensory neuropathy Motor neuropathy Nerve deafness

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Neural tissue

Fibrosis and perforation Erythema and desquamation Telangiectasia, thinning of the skin

Erythema

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Small bowel Skin

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↑ Risk breast cancer Arrhythmias Heart failure

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Bowel

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Cough Fibrosis

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Upper GI tract

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Mucositis Strictures

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Fibrosis

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Mucositis

Mucositis Xerostomia

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Oesophagus

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Mucositis

Breast tissue Heart

Alopecia

Alopecia

Oral mucosa

Lung

Radiotherapy

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Chemotherapy (often drug-specific)

Hair follicles

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Therapeutics in oncology • 1331

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33

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The majority of treatments are delivered by linear accelerators, which produce electron or X-ray beams of high energy that are used to target tumour tissue. The biological effect of ionising radiation is to cause lethal and sublethal damage to DNA. Since normal tissues are also radiosensitive, treatment has to be designed to maximise exposure of the tumour and minimise exposure of normal tissues. This is possible with modern imaging techniques such as CT and MRI, which allow better visualisation

ok

of normal and tumour tissue. In addition, techniques such as conformal radiotherapy, in which shaped rather than conventional square or rectangular beams are used, allow much more precise targeting of therapy to the tumour, and reduce the volume of normal tissue irradiated by up to 40% compared to non-conformal techniques. Biological differences between normal and tumour tissues are used to obtain therapeutic gain. Fundamental to this is fractionation, which entails delivering the radiation as a number of small doses on a daily basis. This allows normal cells to recover from radiation damage but recovery occurs to a lesser degree in malignant cells. Fractionation regimens vary, but radical treatments given with curative intent are usually delivered in 20–30 fractions given daily on 5 days a week, over 4–6 weeks. Radiotherapy can be extremely useful for the alleviation of symptoms, and for palliative treatments such as this a smaller number of fractions (1–5) is usually adequate. Both normal and malignant tissues vary widely in their sensitivity to radiotherapy. Germ cell tumours and lymphomas are extremely radiosensitive and relatively low doses are adequate for cure, but most cancers require doses close to or beyond that which can be tolerated by adjacent normal structures. Normal tissue also varies in its radiosensitivity, the central nervous system, small bowel and lung being among the most sensitive. The side-effects of radiotherapy (see Fig. 33.6) depend on the normal tissues treated, their radiosensitivity and the dose delivered.

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co m

Radiation therapy (radiotherapy) involves treating the cancer with ionising radiation; for certain localised cancers it may be curative. Ionising radiation can be delivered by radiation emitted from the decay of radioactive isotopes or by high-energy radiation beams, usually X-rays. Three methods are usually employed: • Teletherapy: application from a distance by a linear accelerator. • Brachytherapy: direct application of a radioactive source on to or into a tumour. This allows the delivery of a very high, localised dose of radiation and is integral to the management of localised cancers of the head and neck, and cancer of the cervix and endometrium. • Intravenous injection of a radioisotope: such as 131iodine for cancer of the thyroid and 89strontium for the treatment of bone metastases from prostate cancer.

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Radiation therapy

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Fig. 33.6  Adverse effects of chemotherapy and radiotherapy. Acute effects are shown in pink and late effects in blue.

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Trastuzumab

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Trastuzumab (Herceptin) targets the HER2 receptor, an oncogene that is over-expressed in around one-third of breast cancers and in a number of other solid tumours (e.g. gastric cancer). It is effective as a single-agent therapy, but also improves survival in patients with advanced breast cancer when used in conjunction with chemotherapy. Unfortunately, trastuzumab can induce cardiac failure by an unknown biological mechanism, especially in combination with doxorubicin.

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The evaluation of treatment includes an assessment of overall survival duration, response to treatment, remission rate, diseasefree survival and response duration, quality of life and treatment toxicity. Uniform criteria have been established to measure these, including the response evaluation criteria in solid tumours (RECIST, Box 33.16) and common toxicity criteria. This allows clinicians to inform patients accurately about the prognosis, effectiveness and toxicity of chemotherapy and empowers patients to take an active role in treatment decisions.

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Evaluation of treatment

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Late toxicity of therapy

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The late toxicities of treatment for cancer are particularly important for patients where the multimodality therapy is given with curative

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This is a humanised monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A), a key stimulant of angiogenesis in tumours. Bevacizumab has activity in colorectal, lung, breast, renal and ovarian cancers, although the licence was subsequently revoked for breast cancer; while bevacizumab slows the rate of progression of metastatic breast cancer, it had little impact on survival or improved quality of life.

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Bevacizumab

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Imatinib was developed to inhibit the BCR-ABL gene product, tyrosine kinase, that is responsible for chronic myeloid leukaemia (p. 958), and it does this extremely effectively. It is also active in malignant gastrointestinal stromal tumour (GIST), a type of sarcoma that has over-expression of another cell surface tyrosine kinase, c-kit. This agent has good tolerability and is particularly useful in GIST, where conventional chemotherapy is less effective.

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A profound stimulus to the patient’s immune system can sometimes alter the natural history of a malignancy, and the discovery of interferons was the impetus for much research. Although solid tumours show little benefit, interferons are active in melanoma and lymphoma, and there is evidence that they are beneficial as adjuvants (after surgery and chemotherapy, respectively) to delay recurrence. Whether interferon-induced stimulation of the immune system is capable of eradicating microscopic disease remains unproven. More powerful immune responses can be achieved with potent agents like IL-2 but the accompanying systemic toxicity is a problem still to be overcome. The most striking example of successful immunotherapy is that with rituximab, an antibody against the common B-cell antigen CD20. It increases complete response rates and improves survival in diffuse large cell non-Hodgkin lymphoma when combined with chemotherapy, and is effective in palliating advanced follicular non-Hodgkin lymphoma (p. 965).

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Immunotherapy

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These agents inhibit the activity of the EGFR, which is overexpressed in many solid tumours. However, the drugs’ activity does not depend on the amount of receptor over-expression but rather on factors such as gene copy number and mutation status.

Imatinib

Hormone therapy is most commonly used in the treatment of breast cancer and prostate cancer. Breast tumours that are positive for expression of the oestrogen receptor (ER) respond well to anti-oestrogen therapy, and assessment of ER status is now standard in the diagnosis of breast cancer. Several drugs are now available that reduce oestrogen levels or block the effects of oestrogen on the receptor. When targeted appropriately, adjuvant hormone therapy reduces the risk of relapse and death at least as much as chemotherapy, and in advanced cases can induce stable disease and remissions that may last months to years, with acceptable toxicity. Hormonal manipulation may be effective in other cancers. In prostate cancer, hormonal therapy (e.g. luteinising hormone releasing hormone (LHRH) analogues such as goserelin and/or anti-androgens such as bicalutamide) aimed at reducing androgen levels can provide good long-term control of advanced disease, but there is no convincing evidence that it is an effective therapy following potentially curative surgery. Progestogens are active in the treatment of endometrial and breast cancer. In the metastatic setting, progestogen use (e.g. megestrol acetate) is associated with response rates of 20–40% in endometrial cancer. In breast cancer, progestogens are used in patients whose disease has progressed with conventional anti-oestrogen therapy. Their exact mechanism in this setting is not fully understood.

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Gefitinib/erlotinib

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Hormone therapy

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Advances in knowledge about the molecular basis of cancer have resulted in the development of a new generation of treatments to block the signalling pathways responsible for the growth of specific tumours. This has created the potential to target cancer cells more selectively, with reduced toxicity to normal tissues. Some examples are discussed below, but in the years to come many more such agents will come into clinical use, with the potential to revolutionise our approach to some cancers.

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An acute inflammatory reaction commonly occurs towards the end of most radical treatments and is localised to the area treated. For example, skin reactions are common with breast or chest wall radiotherapy, and proctitis and cystitis with treatment to the bladder or prostate. These acute reactions settle over a period of a few weeks after treatment, assuming normal tissue tolerance has not been exceeded. Late effects of radiotherapy develop 6 weeks or more after treatment and occur in 5–10% of patients. Examples include brachial nerve damage and subcutaneous fibrosis after breast cancer treatment, and shrinkage and fibrosis of the bladder after treatment for bladder cancer. There is a risk of inducing cancer after radiotherapy, which varies depending on the site treated and on whether the patient has had other treatment such as chemotherapy.

Biological therapies

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Adverse effects

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1332 • Oncology

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Colorectal cancer

At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD

Familial cancer syndromes

p. 56

Gastric cancer

p. 803

Hepatocellular carcinoma

p. 890

At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started and at least 5 mm increase or the appearance of one or more new lesions

Leukaemia

p. 954

Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

p. 618

Myeloma

p. 966

Oesophageal cancer

p. 796

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p. 649

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33.18  Five-year survival rates for breast cancer by stage Stage definition

I

Tumour  1 cm, a tumour that is ER-negative or the presence of involved axillary lymph nodes. Such patients should be offered adjuvant chemotherapy, which improves disease-free and overall survival. The role of adjuvant treatment has been studied by meta-analyses and data support the use of adjuvant trastuzumab, a humanised monoclonal antibody to HER2, in addition to standard chemotherapy for women with early HER2-positive breast cancer. Metastatic disease management includes radiotherapy to palliate painful bone metastases and second-line endocrine therapy with aromatase inhibitors, which inhibit peripheral oestrogen production in adrenal and adipose tissues. Advanced ER-negative disease may be treated with combination chemotherapy.

eb oo ks

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m

Genetic and environmental factors play a role. The risk of ovarian cancer is increased in patients with BRCA1 or BRCA2 mutations, and Lynch type II families (a subtype of hereditary non-polyposis colon cancer, HNPCC) have ovarian, endometrial, colorectal and gastric tumours due to mutations of mismatch repair enzymes. Advanced age, nulliparity, ovarian stimulation and Caucasian descent all increase the risk of ovarian cancer, while suppressed ovulation appears to protect, so pregnancy, prolonged breastfeeding and the contraceptive pill have all been shown to reduce the risk of ovarian cancer.

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Management

Ovarian cancer

Pathogenesis

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Following clinical examination, patients should have imaging with mammography or ultrasound evaluation, and a biopsy using fine needle aspiration for cytology or core biopsy for histology. Histological assessment should be carried out to assess tumour type and to determine oestrogen and progesterone receptor (ER/PR) status and HER2 status. If distant spread is suspected, CT of the thorax and abdomen and an isotope bone scan are required. Molecular subtyping is being used to classify tumours into four major subtypes: luminal A, luminal B, HER2 type and basal-like (often called ‘triple negative’, as these tumours are ER-, PR- and HER2-negative). This may allow more targeted selection of therapies in future.

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breast, and this confers an adverse prognosis. Around 40% of patients will have axillary nodal disease, with likelihood correlating with increasing size of the primary tumour. Distant metastases are infrequently present at diagnosis and the most common sites of spread are bone (70%), lung (60%), liver (55%), pleura (40%), adrenals (35%), skin (30%) and brain (10–20%).

Investigations

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1334 • Oncology

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• Diplopia • Hoarse voice • Horner’s syndrome

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• Painless swelling

• Facial nerve palsy

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where oropharyngeal cancers are concerned. The rising incidence of oropharyngeal cancers, especially in the developed world, is thought to be secondary to HPV infection. Presentation depends on the location of the primary tumour and the extent of disease. For example, early laryngeal cancers may present with hoarseness, while more extensive local disease may present with pain due to invasion of local structures or with a lump in the neck. Patients who present late often have pulmonary symptoms, as this is the most common site of distant metastases (Box 33.19).

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Investigations

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Generally speaking, the majority of patients with early or locally advanced disease are treated with curative intent. In localised disease where there is no involvement of the lymph nodes, long-term remission can be achieved in up to 90% of patients with surgery or radiotherapy. The choice of surgery versus radiotherapy often depends on patient preference, as surgical treatment can be mutilating with an adverse cosmetic outcome. Patients with lymph node involvement or metastasis are treated with a combination of surgery and radiotherapy (often with chemotherapy as a radiosensitising agent – proven agents include cisplatin or cetuximab), and this produces long-term remission in approximately 60–70% of patients. Recurrent or metastatic tumour may be palliated with further surgery or radiotherapy to aid local control, and systemic chemotherapy has a response rate of around 20–30%. Second malignancies are common (3%

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Management

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Careful inspection of the primary site is required as part of the staging process, and most patients will require endoscopic evaluation and examination under anaesthesia. Tissue biopsies should be taken from the most accessible site. CT of the primary site and the thorax is the investigation of choice for visualising the tumour, while MRI may be useful in certain cases.

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Head and neck cancers are typically squamous tumours that arise in the nasopharynx, hypopharynx and larynx. They are most common in elderly males but now occur with increasing frequency in a younger cohort, as well as in women, especially

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The tumours are strongly associated with a history of smoking and excess alcohol intake, but other recognised risk factors include Epstein–Barr virus for nasopharyngeal cancer and HPV infection for oropharyngeal tumours.

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Head and neck tumours

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Salivary gland

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• Otalgia

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This depends on the stage of disease. Pre-malignant disease can be treated with laser ablation or diathermy, whereas in microinvasive disease a large loop excision of the transformation zone (LLETZ) or a simple hysterectomy is employed. Invasive but localised disease requires radical surgery, while chemotherapy and radiotherapy, including brachytherapy, may be given as primary treatment, especially in patients with adverse prognostic features such as bulky or locally advanced disease, or lymph node or parametrium invasion. In metastatic disease, cisplatin-based chemotherapy may be beneficial in improving symptoms but does not increase survival significantly.

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• Dysphagia • Pain

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Management

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Oropharynx

Pathogenesis

Diagnosis is made by smear or cone biopsy. Further examination may require cystoscopy and flexible sigmoidoscopy if there are symptoms referable to the bladder, colon or rectum. In contrast to other gynaecological malignancies, cervical cancer is a clinically staged disease, although MRI is often used to characterise the primary tumour. A routine chest X-ray should be obtained to help rule out pulmonary metastasis. CT of the abdomen and pelvis is performed to look for metastasis in the liver and lymph nodes, and to exclude hydronephrosis and hydroureter.

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• Nasal discharge or obstruction • Conduction deafness • Atypical facial pain

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Investigations

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• Discharge (bloody) or obstruction

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• Ipsilateral otalgia

Nasal cavity and sinuses

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This is the second most common gynaecological tumour worldwide and the leading cause of death from gynaecological cancer. The incidence is decreasing in developed countries but continues to rise in developing nations. The most common presentation is with an abnormal smear test, but with locally advanced disease the presentation is with vaginal bleeding, discomfort, discharge or symptoms attributable to involvement of adjacent structures, such as bladder, or rectal or pelvic wall. Occasionally, patients present with distant metastases to bone and lung.

There is a strong association between cervical cancer and sexual activity that includes sex at a young age and multiple sexual partners. Infection with HPV has an important causal role, and this has underpinned the introduction of programmes to immunise teenagers against HPV in an effort to prevent the later development of cervical cancer (p. 342).

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• Non-healing ulcers

• Referred otalgia • Enlarged lymph nodes

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Mouth

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• Dysphagia • Odynophagia

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Hypopharynx

Nasopharynx

Cervical cancer

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33.19  Common presenting features by location in head and neck cancer

Surgery is the treatment of choice and is used for staging. A hysterectomy and bilateral salpingo-oophorectomy are performed with peritoneal cytology and, in some cases, lymph node dissection. Where the tumour extends beyond the inner 50% of the myometrium or involves the cervix and local lymph nodes, or there is lymphovascular space invasion, adjuvant pelvic radiotherapy is recommended. Chemotherapy is used as adjuvant therapy and hormonal therapy and chemotherapy are used to palliate symptoms in recurrent disease.

Pathogenesis

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Management

Specific cancers • 1335

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Websites

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Cassidy J, Bissett D, Spence RAJ, et al. Oxford handbook of oncology, 4th edn. Oxford: Oxford University Press; 2015. Dark GG. Oncology at a glance. Chichester: Wiley–Blackwell; 2013. Hanahan D, Weinberg RA. The hallmarks of cancer: the next generation. Cell 2011; 144:646–674. Tobias J, Hochhauser D. Cancer and its management, 7th edn. Chichester: Wiley–Blackwell; 2014.

cancer.org American Cancer Society: clinical practice guidelines. ctep.cancer.gov/reporting/ctc.html Common toxicity criteria. info.cancerresearchuk.org/cancerstats/ A wide range of cancer statistics that can be sorted by type or geographical location.

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Books and journal articles

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*Offer when clinically appropriate.

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Further information

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• Detailed history and examination, including breast, nodal areas, skin, genital, rectal and pelvic regions • Full blood count, urea and electrolytes, renal function, liver function tests, calcium, urinalysis, lactate dehydrogenase • Chest X-ray • Myeloma screen (if lytic bone lesions) • CT scan of chest, abdomen and pelvis • Symptom-directed upper and lower gastrointestinal endoscopy • Tumour markers: prostate-specific antigen (PSA) in men, cancer antigen 125 (CA-125) in women with peritoneal malignancy or ascites, α-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) • Testicular ultrasound (if clinical features suggest germ cell tumour) • Histological examination of biopsy, with immunohistochemistry if required

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33.20  Initial diagnostic tests in patients presenting with carcinoma of unknown primary*

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Management of the patient will depend on that person’s circumstances, as well as on the site(s) involved and the likely primary sites. The overriding principle is to ensure that a curable diagnosis has been excluded. For example, lung metastases from a testicular teratoma do not preclude cure; nor do one or two liver metastases from a colorectal cancer. Early discussion with an oncologist within a multidisciplinary team is essential and avoids unnecessary investigation; for example, a single hCG-based pregnancy test in a young man with lung metastases might confirm the presence of a teratoma and allow rapid administration of potentially curative chemotherapy. Treatment should not necessarily wait for a definitive diagnosis; appropriate analgesia,

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Management

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The multidisciplinary team (MDT) is well established in oncology and meets on a regular basis to discuss patient progress and provide a forum for patient-centred, interdisciplinary communication to coordinate care and decision-making. It is a platform on which individual clinicians can discuss complex cases or situations and draw on the collective experience of the team membership to decide on the best approach for an individual patient. This can be particularly important when discussing patients with a rare condition or in a rare situation. Specific roles of the MDT include: • planning the diagnostic and staging procedures • deciding on the appropriate primary treatment modality (most commonly surgery but the use of neoadjuvant chemotherapy before interval surgery is increasing) • arranging review by the oncology team to plan assessment of the patient prior to systemic therapy or radiotherapy • discussing additional support requirements for the individual patient, such as physiotherapy; psychological support; symptom control; nutritional care or rehabilitation in the post-operative period • ensuring access to accurate information on treatment, prognosis, side-effects and other related matters, such as stoma care • planning surveillance strategies • ensuring the appropriate transition from treatment with curative intent to that of palliation of symptoms • promoting recruitment into clinical trials • agreeing on operational policies to deliver high-quality care to patients • planning and reviewing audit data to ensure the delivery of quality care to patients by the team.

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Multidisciplinary teams

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In this situation, there is a temptation to investigate the patient endlessly in order to determine the original primary site. There is a compromise, however, between exhaustive investigation and obtaining sufficient information to plan appropriate management. For all patients, histological examination of an accessible site of metastasis is required. The architecture of the tissue can assist the pathologist in determining the likely primary site, and therefore it is better to perform a biopsy rather than fine needle aspiration. The greater volume of tissue permits the use of immunohistochemistry. Extensive imaging to search for the primary is rarely indicated; a careful history to identify symptoms and risk factors (including familial) will often permit a judicious choice of imaging and other diagnostic tests, reserving additional tests for specific patients (Box 33.20).

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Investigations

m

radiotherapy and surgical palliation can all be helpful. Some patients remain free of cancer for some years after resection of a single metastasis of an adenocarcinoma of unknown primary, justifying this approach in selected patients. In those with no obvious primary, systemic chemotherapy may achieve some reduction in tumour burden and alleviation of symptoms, but long-term survival is rare.

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Some patients are found to have evidence of metastatic disease at their initial presentation, prior to diagnosis of a primary site. In many cases, a subsequent biopsy reveals adenocarcinoma but the primary site is not always clear.

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Carcinoma of unknown origin

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per year) following successful treatment for primary disease, and all patients should be encouraged to give up smoking and drinking alcohol to lower their risk.

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1336 • Oncology

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Death and dying 1354

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Palliative care 1349 Presenting problems in palliative care 1350 Pain 1350 Breathlessness 1353 Cough 1353 Nausea and vomiting 1353 Gastrointestinal obstruction 1354 Weight loss 1354 Anxiety and depression 1354 Delirium and agitation 1354 Dehydration 1354

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Pain 1338 Functional anatomy and physiology 1338 Investigations 1342 Principles of management 1343 Interventions 1344 Chronic pain syndromes 1348

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Pain and palliative care

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34  ks

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LA Colvin M Fallon

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Well-localised pain Thermal sensation Pre-ganglionic autonomic

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3–15 0.5–3

Diffuse pain Poorly localised thermal sensation Post-ganglionic autonomic

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Unmyelinated C 0.4–1.3

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12–30

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Spinal cord

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re

e.

Sensory neurons, through their central termination, synapse with second-order neurons in the dorsal horn of the spinal cord. There is considerable modulation of pain messages at

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m

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When a noxious stimulus is encountered, activation of nociceptors leads to generation of an action potential, which travels upwards to the dorsal root ganglion and also stimulates the release of neurotransmitters that have secondary effects on surrounding neurons.

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velocity and are responsible for transmitting diffuse and poorly localised pain, as well as other sensations (Box 34.1). Sensory neurons (also known as primary afferent neurons) connect the spinal cord to the periphery and supply a defined territory or a dermatome, which can be used to identify the position of a nerve lesion (see Fig. 25.10, p. 1071). In healthy individuals dermatomes have distinct borders, but in pathological pain syndromes these may become blurred as the result of neuronal plasticity, which means that pain may be felt in an area adjacent to that supplied by a specific nerve root. Autonomic neurons also contain pain fibres and are responsible for transmitting visceral sensations, such as colic. In general, visceral pain is diffuse and less well localised than pain transmitted by sensory neurons. Anatomical features of the afferent pain pathway are illustrated in Figure 34.2. Pain signals are transmitted from the periphery to the spinal cord by sensory neurons. These have the following components: • A cell body, containing the nucleus, which is situated in the dorsal root ganglion close to the spinal cord. The cell body is essential for survival of the neuron, production of neurotransmitters and neuronal function. • The nerve fibre (axon) and peripheral nerve endings, which are located in the periphery and contain a range of receptors in the neuronal membrane. • Specialised receptors in the periphery, consisting of bare nerve endings known as nociceptors or pain receptors, which are activated by various mediators. They are situated mainly in the epidermis. • The central termination, which travels to the dorsal horn of the spinal cord to form the first central synapse with neurons that transmit pain sensation to the brain.

Sensory (genetic, anatomical, biomedical)

as a symptom is dependent not only on sensory inputs but also on the individual’s cognitive reaction to the pain, their emotional state, their underlying disease and their social and cultural background.

re

 42°C) amplifies action potentials, which increase pain signals and cause peripheral sensitisation. Adapted from Bennett DL, Woods CG. Painful and painless channelopathies. Reprinted with permission from Elsevier (The Lancet Neurol 2014; 13:587–599). NMDA receptor

m

ks

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m

m

eb

eb o

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A

fre

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Pain • 1341

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fre

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ks oo eb

eb

m

m Increased or decreased thermal sensation

e.

e.

Erythromelalgia, paroxysmal pain, burning pain, autonomic dysfunction

Ion channel

Burning pain, autonomic dysfunction Absent pain Absent pain

LoF (AR)

Tyrosine kinase; promotes neuron development

Absent pain; anhydrosis, mental retardation, increased cancer risk

co

e.

e. co

co

e.

m

Ion channel Transcription factor; neuron development

m

GoF (AD) LoF (AR)

m

TRPA1 (TRPA1)

re sf ok

sf re ok

sf

re

(AD = autosomal dominant; AR = autosomal recessive; GoF = gain of function; LoF = loss of function; NGF = nerve growth factor)

ok

ks

Absent pain, hyperhydrosis, muscular weakness, gut dysmotility

PDRM12 (PDRM12) NTRK1 (high-affinity NGF receptor)

oo

eb o m

eb

m

Ion channel

ok s

GoF (AD)

Ion channel

eb

SCN10A (Na,1.8)

Phenotypes

Absent pain, hypohydrosis, anosmia

m

GoF (AD)

fre

SCN11A (Na,1.9)

Protein function

Ion channel

ok s

GoF (AD)

ks fre

SCN9A (Na,1.7)

co

co

m

m

Fig. 34.5  Equipment for bedside sensory testing.

oo

Mutation (inheritance) LoF (AR)

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Gene (protein)

SCN9A (Na,1.7)

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co m e.

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34.3  Genetic regulators of pain perception

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co m

fre e. ks

m m

Warm and cool thermal rollers

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eb oo ks eb

Hyperalgesia

fre

fre

Quantitative sensory testing can be helpful in the detailed assessment of patients with chronic pain. A simple set of tools can be used in the clinical setting (Fig. 34.5). Lightly touching the skin with a brush, swab or cotton-wool ball can be used to test for abnormalities of fine touch (allodynia). Assessing the patient’s response to a pin-prick can be used to test for abnormalities in mechanical hyperalgesia. Finally, touching the patient’s skin with warm and cool thermal rollers can be used to test for abnormalities of thermal sensation. An unaffected area of skin should be tested first, to establish normal sensation, before testing the affected area.

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Allodynia

e. co

Quantitative sensory testing

 

Neurology pin

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eb

e. co

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m

Blood tests are not generally helpful in the diagnosis of chronic pain, except in patients with peripheral neuropathy; in this case, a number of blood tests may be required to investigate the underlying causes of the neuropathy. Full details are provided in Box 25.86 (p. 1139). Genetic testing may be of value in patients with clinical features that point to an inherited disorder of pain processing (Box 34.3).

ks

ks

oo

Cotton wool

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oo

Blood tests

eb

Performing a nerve block with infiltration of a local anaesthetic such as 1% lidocaine can be used diagnostically, in assessing whether a pain syndrome is due to involvement of a specific nerve or nerve root. Where inflammation and or swelling may be contributing to the underlying pain – for example, if there is compression of a nerve root – then a mixture of local anaesthetic

oo ks

fre

ks fre

Magnetic resonance imaging (MRI) can be helpful in the assessment of an underlying cause in patients with focal pain that follows a nerve root or peripheral nerve distribution. Imaging is seldom helpful in individuals with CWP.

m

Nerve blocks

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Magnetic resonance imaging

m

Nerve conduction studies can be helpful in demonstrating and quantifying a definitive nerve lesion, either peripherally or centrally. They can be used to help differentiate between central and peripheral neuropathic pain. They do not, however, effectively examine small nerve fibre function.

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Pain can be a presenting feature of a wide range of disorders and the first step in evaluation of a patient with pain should be to perform whatever investigations are required to define the underlying cause of the pain, unless this is already known. However, with most chronic pain syndromes, such as fibromyalgia, complex regional pain syndrome and CWP, investigations are negative and the diagnosis is made on the basis of clinical history and exclusion of other causes. Specific investigations that are useful in the assessment of selected patients with chronic pain are discussed below.

Nerve conduction studies

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Investigations

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1342 • Pain and palliative care

fre

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eb

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.c

re e

Tampa Scale of Kinesiophobia

Measures how much an individual is fearful of movement

Pain Self-efficacy Questionnaire

Assesses individual beliefs about self-efficacy in the context of chronic pain, and how this impacts on function

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Patient marks pain intensity on a horizontal line Body chart, allowing the patient to indicate where pain is situated

Beck Depression Inventory

Assesses emotional function

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m

Localisation of pain

Assesses health-related quality of life

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sf

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(DN-4 = Douleur Neuropathique questionnaire; EQ-5D = EuroQol 5-Domain questionnaire; SF-36 = Short Form 36; s-LANSS = self-completed Leeds Assessment of Neuropathic Signs and Symptoms)

34

ok s

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eb

Developed to assess individual levels of catastrophising, encompassing three different domains: helplessness, rumination and magnification

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Pain Catastrophising Scale

SF-36/EQ-5D

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sf

eb m

A number of screening questionnaires to aid diagnosis of neuropathic pain

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e. co

sf re

Pain Detect, s-LANSS, DN-4

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co

e.

ks fre

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eb

ok

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eb

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co m

fre e.

oo

Developed for use in cancer pain, validated and widely employed for chronic pain; based on 0–10 ratings of pain intensity and the impact of pain on a range of domains, including sleep, work and enjoyment of life

oo k

ks

Comments

Brief Pain Inventory

Visual analogue scale (VAS)

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sf ok

Instrument

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34.4  Instruments used in the assessment of pain and its impact

 

oo

A full biopsychosocial assessment should be performed in all patients with chronic pain. Although this is time-consuming, the time invested is likely to pay dividends in improving the long-term outcome for patients. A biopsychosocial assessment takes account of the underlying neurobiology of the condition in the context of wider influences, including cognition and beliefs, emotions, and social and cultural factors. For example, an individual with abdominal pain might respond differently if a close relative had recently died of gastric cancer than if a colleague had been off work with gastric upset. An accurate clinical history is important, taking note of the duration of pain, any precipitating and relieving factors, its location and, if the pain is located at more than one site, which site is the one that impacts most on the patient’s quality of life. The characteristics of the pain should be documented, by assessing whether it is described as dull, sharp, aching or burning. Associated features, such as hypersensitivity to fine touch or temperature, numbness, paraesthesia, tingling and formication (the feeling of insects crawling over the skin), should be noted. It is important to determine to what extent the pain is interfering with normal daily activities, such as work, leisure pursuits and sleep. The patient’s social circumstances and cultural background should be documented, including any caring responsibilities, employment status and social and family support. The intensity of pain should also be recorded, preferably using a validated questionnaire (Box 34.4). The patient’s mood should be assessed and, if evidence of low mood is detected, a suicide risk assessment should be considered (see Box 28.12, p. 1187).

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oo

eb

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eb

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fre

Biopsychosocial assessment

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m

m

Effective management of chronic pain depends in part on the underlying cause but some general principles can be applied. In general terms, the treatment goals are to: • educate the patient • promote self-management • optimise function • enhance quality of life • control pain.

Clinical history

m

The patient’s general appearance should be noted, including ability to walk and use of a walking aid. In those with focal pain, neurological examination should be performed, focusing particularly on any areas of abnormal sensation, reflexes and evidence of muscle wasting. A general examination should be carried out to determine whether there is any evidence of an underlying physical disorder that can account for the pain. In addition to the use of investigations to find the underlying cause of pain, patients with persistent or chronic pain may benefit from sensory testing or diagnostic nerve blocks to explore the underlying mechanisms and direct treatment. For example, a combined femoral and sciatic nerve block may be used in a patient with lower limb amputation to assess whether the pain is predominantly peripherally or centrally generated. If the pain is not improved by an effective nerve block, then peripherally directed therapies are unlikely to be effective.

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Principles of management

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Examination

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m

Various questionnaires and other instruments have been devised to localise pain, rate its severity and assess its impact on quality of life. Some of the most widely used are listed in Box 34.4. The distribution of pain can be documented on a diagram of the body, on which the patient can mark the sites that are painful. Similarly, other methods have been developed with which to assess the severity of pain using verbal, numerical and behavioural rating scales. Visual scoring systems employing different facial expressions may be of value in paediatric patients and those with cognitive impairment. Documenting changes in pain scores using questionnaires can be helpful in indicating to what extent drug treatments have been successful and can reduce the time taken to achieve pain control.

The past medical and medication history should be recorded and specific enquiry made about substance misuse and any previous history of physical or mental abuse. It is also useful to enquire specifically about the patient’s beliefs as to what is causing their pain, as well as what their expectation of treatment is; unless these are addressed, management may be less effective. There are some patient populations in whom particular challenges arise, often related to differences in communication ability. Strategies that can be used to overcome these difficulties are summarised in Box 34.5.

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Pain scoring systems

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and depot glucocorticoid may be helpful in alleviating pain. Nerve blockade can also be used to determine whether more radical therapies, such as nerve ablation, might be helpful in controlling pain, particularly that related to cancer.

Pain • 1343

Assessment needs to be appropriate to developmental stage

Consider visual tools to aid pain assessment

Elderly

May have impaired cognitive function Cultural factors may reduce self-reporting of pain Risk of adverse effects of medication increased

Consider formal assessment of cognitive function Consider non-verbal assessment Consider visual tools to assess pain Employ a number of tools assessing pain behaviours

Cognitive impairment

Reporting and expression of pain may change Increased sensitivity to central nervous system effects of analgesics

Perform formal assessment of cognitive function Use non-verbal assessment: facial expressions, vocalisations, body movements, changes in social interactions

Substance misuse

Response to analgesics altered Increased tolerance Increased risk of addiction Substance misuse may affect reporting of pain

Seek specialist support early Ensure prescribing is safe

• Hydrotherapy • Swimming

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om

m

• Exercise classes

.c

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to the individual patient. A successful exercise programme can help overcome ‘fear avoidance’, a well-recognised problem in chronic pain, where patients associate activity with an increase in pain and therefore do progressively less activity, with resultant deconditioning. Because of this it is important to pace physical activity to ensure that patients do not cycle from over-activity, with a flare in pain, to fatigue and deconditioning. This can be done by working with patients to establish their baseline level of activity and using an individually tailored, graded exercise programme (Box 34.6). This may include normal household activities, as well as targeted exercises and stretches. Manual therapy covers a variety of hands-on treatments, including manipulation, mobilisation and massage. Manual therapy can be provided by a range of therapists, including physiotherapists, osteopaths and chiropractors. There is some evidence of shortterm benefit for manual therapy but limited evidence of long-term efficacy.

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eb

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A range of analgesics can be used in the management of chronic pain but, for most of these, the evidence of long-term benefit is limited. In general, it is advisable to use a multimodal approach in the treatment of chronic pain, choosing different drugs to target pain processing at multiple points (Box 34.7). By employing different classes of analgesic, it is possible to use lower doses of each, thereby improving the side-effect profile. There is considerable inter-individual variability in response to analgesics, even within the same class. There are many reasons for this, including genetic variations in the enzymes that metabolise drugs. For example, the CYP2D6 gene encodes for a liver enzyme, cytochrome P450 2D6, which metabolises a number of commonly used analgesics. Genetic variation in CYP2D6 can influence circulating levels of many drugs, depending on whether

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Pharmacological therapies

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sf ok

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Water-based

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co

There is strong evidence that exercise can help in the management of chronic pain. Several types of exercise have been successfully used delivered in various ways, through physiotherapists, exercise classes or individual tuition. In choosing a form of exercise therapy, it is important to tailor the approach most likely to be acceptable

e.

oo

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eb

• Yoga • Pilates • Tai-chi

eb

• Walking • Gym work • Exercise classes

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Physical therapies

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Land-based

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There are a number of useful online self-help resources (see ‘Further reading’).

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34.6  Physical therapies for chronic pain

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eb

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Self-management strategies are useful in the treatment of chronic pain. Self-management works best if the patient has some understanding of their chronic pain, and acceptance that it is unlikely to resolve completely. The aim is for patients to maximise their quality of life and function despite ongoing pain. Support for self-management can be delivered by health-care professionals, patients who suffer from the same condition or lay people, either on an individual basis, in a group setting or, increasingly, through web-based resources. There is a strong educational component to supported self-management, which seeks to generate an interaction between patient and tutor. The key aspects include: • increasing activity levels, while understanding and practising pacing techniques (not overdoing things and cycling between over- and under-activity) • using relaxation and mindfulness techniques as part of daily management • using medication when appropriate • having a plan to manage pain flares.

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Solutions

 

Probably the most effective mode of treatment for pain is to identify the underlying cause. Examples include the use of immunosuppressive medication in inflammatory disease, chemotherapy, radiotherapy or hormone therapy in cancer, and antimicrobial therapy in patients with infection. There are many circumstances, however, in which the underlying cause of pain cannot be treated or the treatments available are incompletely effective. Under these circumstances, several management options are available. In all cases, a multidisciplinary approach is necessary that combines pharmacological management with supported self-management, and other specific interventions when appropriate.

Supported self-management

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fre

Paediatric

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Challenges

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Patient population

Interventions

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34.5  Challenges in pain assessment in particular patient populations

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1344 • Pain and palliative care

fre e. c

ks

Antagonist of NMDA receptors Reduction of central sensitisation

eb

co m

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m

Inhibition of glutamate release by primary afferent neurons at first central synapse Decrease of excitatory neuronal activity

Serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) re-uptake inhibitors

Inhibition of serotonin and noradrenaline re-uptake at synapses in the spinal cord, and also potential effects in the limbic system

ks eb

m

m

m

eb

Temporary denervation due to blockade of Na+ channels in sensory neurons Local anti-inflammatory effect

Nerve blocks with lidocaine and glucocorticoids

oo

oo

Activation of TRPV1 channels on subset of C fibres, causing selective pharmacological denervation, with a decrease in intra-epidermal nerve fibre density

eb

Capsaicin patch

ks

fre

oo ks

Inhibition of Na+ in sensory neurons

Lidocaine patches

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fre e.

Inhibition of serotonin and noradrenaline (norepinephrine) re-uptake at synapses in the spinal cord, and also potential effects in the limbic system Inhibition of Na+ channels in neurons

e. co

Tricyclic antidepressants

ks fre oo eb

m

m

Ketamine

oo

Agonists at OP3 receptors at multiple levels in the central nervous system Blockade of ascending pain pathways

eb

Opioids

oo

Inhibition of prostaglandin production

eb o

Non-steroidal anti-inflammatory drugs

ks

ok s

Central inhibition of COX-1 and COX-2 enzymes Mechanisms of action incompletely understood

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eb

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Paracetamol

Gabapentin Pregabalin

fre

Mechanism of action

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Drug or class of drug

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34.7  Pharmacological management of chronic pain

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Pain • 1345

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Topical capsaicin cream (0.025 or 0.075%) has some efficacy for osteoarthritis and may be used for neuropathic pain, although evidence of benefit is limited. A single application (done by a trained health-care professional) of a high-dose 8% capsaicin patch can give around 12 weeks of pain relief for neuropathic pain and can be repeated thereafter. Capsaicin is an agonist at the transient receptor potential vanilloid 1 (TRPV1) ion channel, found on some C fibres. Capsaicin activates the channel, causing an initial sensation of heat, but an analgesic effect subsequently results due to desensitisation of the channel. Lidocaine 5% patches can also be helpful in focal neuropathic pain and should be applied for 12 hours out of 24 hours, with up to 4–6 weeks before maximum benefit is seen. The mode of action is blockade of sodium channels in primary afferent neurons and nociceptors, which reduces peripheral input to the spinal cord.

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co

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co

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e.

Adjuvant analgesics is the term used to cover a range of agents that are used in the treatment of neuropathic pain, usually in combination with classical analgesics. Typically, these agents

34

ok s

Adjuvant analgesics

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sf

Topical analgesics

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eb

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Paracetamol is widely used in the treatment of mild to moderate pain. Its mechanism of action is incompletely understood but it is known to be a weak inhibitor of the cyclo-oxygenase type 1 (COX-1) and cyclo-oxygenase type 2 (COX-2) enzymes, providing weak anti-inflammatory properties. There is also some of evidence that it activates inhibitory descending spinal pathways, via a serotonergic mechanism. Other postulated mechanisms include endocannabinoid re-uptake inhibition, and inhibition of nitric oxide and tumour necrosis factor alpha. For migraine and tension-type headache it has moderate efficacy at a dose of 1000 mg. It is used widely for musculoskeletal disorders and osteoarthritis, with very little high-quality evidence that it is much better than placebo, even at doses of up to 4000 mg per day. Acute liver failure is a well-recognised complication of paracetamol overdose but this risk may also be increased with long-term use, even within the recommended dose range. In view of this, it should

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Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory pain and osteoarthritis. These drugs can be given systemically or locally and are discussed in more detail on page 1002. They are also useful in the management of pain in cancer patients, as discussed later in this chapter (p. 1350). Although widely prescribed, there is limited high-quality evidence of long-term efficacy in chronic pain, with a need for further studies in this area.

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ks

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eb

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co m

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Paracetamol

eb

Non-steroidal anti-inflammatory drugs

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fre

fre

eb oo ks

m

Non-opioid analgesics

m

be employed with caution in elderly patients and those weighing less than 50 kg.

e. co

e. co

someone is a rapid or poor metaboliser. This is particularly important if metabolites are active, as is the case with codeine and tramadol, which are metabolised to morphine. Genetic variations have also been described in the opioid receptors and downstream pathways that they affect, with good pre-clinical evidence that variations in mu opioid receptors alter analgesic response to different opioids. Because of this there is a good rationale to try different drugs, even ones from the same class, if there is an inadequate response or there are unacceptable side-effects with one agent. Whatever drug or combination of drugs is chosen, the key to successful pharmacological management is careful assessment and review, aiming for an acceptable balance between the benefits of treatment in providing pain relief, maximising function, and improving quality of life and adverse effects. Specific drug treatments are described below.

m

m

(COX = cyclo-oxygenase; NMDA = N-methyl-D-aspartate; OP = opioid; TRPV1 = transient receptor potential vanilloid 1)

fre e. c

fre

Kappa; OP2

Orphanin FQ (nociceptin)

NOP

Orphan; ORL-1; OP4

oo

eb

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sf

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m

m Oral

Buprenorphine

5 µg/hr

Fentanyl

e. ks fre

30 mg/day

Use with care in opioid-naïve patients; patch change usually every 72 hrs

20 mg

Use with care in opioid-naïve patients

10 mg

Semi-synthetic; hepatic metabolism

10 mg

Mainly used for acute pain or palliative care

eb

m

m

e. co

sf re ok

co

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re

co

Subcutaneous, intramuscular, intravenous

e.

3 mg

re

Diamorphine

sf

Oral

m

Oral

2 mg

ok

m

m 50 mg

m

Tapentadol

Patch change usually every 7 days (frequency of change dependent on manufacturer and dose); advantages in impaired renal function

oo

Transdermal

eb o

12 µg/hr

eb

30 mg/day

m

Transdermal

Hydromorphone

sf

More predictable bioavailability than morphine

oo

e.

re

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Synthetic

10 mg

ks

6.6 mg

Semi-synthetic

10 mg

ok s

Oxycodone

m

Oral

Metabolised to morphine

10 mg

co

100 mg

10 mg

e.

Tramadol

Comments

Most widely used

fre

Oral

Oral morphine equivalent

10 mg

ok s

Oral

100 mg

Route

m

100 mg

Dihydrocodeine

Codeine

Typical starting dose

10 mg

co

co m

Oral

Morphine

ok

Opioid tolerance, anxiety, depression, increased appetite

34.9  Commonly used opioids

Opioid

eb

Analgesia, neuroendocrine (e.g. on hypothalamic–pituitary axis), diuresis, dysphoria

oo k

(IUPHAR = International Union of Basic and Clinical Pharmacology; OP = opioid; ORL = opioid-like receptor)

m

om

m e. co fre

ks

Nucleus raphe magnus, spinal cord, afferent neurons

eb

oo

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fre

eb oo ks

Brain (nucleus accumbens, neocortex, brainstem, cerebellum)

Analgesia, cardioprotection, thermoregulation

ks

KOP

Analgesia, reduced gastrointestinal motility, respiratory depression, pruritus

oo

Dynorphin A Dynorphin B β-endorphin

Brain, spinal cord, peripheral nerves

m

Delta; OP1

 

m

co m

ks oo eb

DOP

Leu-enkephalin Met-enkephalin β-endorphin

Pharmacological effects

Brain, spinal cord, peripheral nerves, immune cells

m

Mu; OP3

m

Potential sites

MOP

eb

Endomorphin 1 and 2 Met-enkephalin Dynorphin A Dynorphin B

Alternative classification

ks

ks

fre e.

fre

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Receptor (IUPHAR)

Endogenous ligand

eb

34.8  Opioids and opioid receptors

m

eb

oo

ks fre

e. co

e. co m

m

Opioids are a class of drugs that target opioid receptors. The original receptor classification was based on pharmacological activity (mu, delta, kappa), with the more recent International Union of Basic and Clinical Pharmacology (IUPHAR) classification being generally accepted in current use (Box 34.8). Opioid receptors are G-protein-coupled receptors. Ligand binding activates several intracellular signalling pathways, increasing cyclic adenosine monophosphate (cAMP) levels, as well as altering calcium and

m

oo

m

Opioid analgesics

potassium permeability of neurons. Opioids are traditionally divided into subclasses of weak opioids, such as codeine and dihydrocodeine, and strong opioids, such as morphine and oxycodone. While tramadol is a weak agonist at the mu opioid receptor, it is classified as a strong opioid in some countries. The dosages and characteristics of commonly prescribed opioids are shown in Box 34.9. There has been a large increase in the use of strong opioids for chronic pain over the last 10–20 years. A number of factors contribute to this, including a rising incidence of chronic pain with an ageing population, reluctance to use NSAIDs because of cardiovascular and gastrointestinal adverse effects, changes in patient expectation, societal attitudes and availability of new formulations of opioids. There is evidence of short- to medium-term benefit for strong opioids in low back pain and osteoarthritis but there have been very few good-quality studies of long-term use. Additionally, there is increasing concern about potential harm from long-term use. This includes addiction, dependence, opioid-induced hyperalgesia, endocrine dysfunction, fracture risk (especially in the elderly), overdose and cardiovascular

eb

eb o

m

m

eb

oo

ok s

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do not produce an immediate reduction in pain, but rather exert an analgesic effect over a longer timeframe through their effects on central processing of pain. They are of particular value when used in combination in the management of pain with a neuropathic component but require careful dose titration over a number of weeks, to reach a dose that balances efficacy with side-effects. While the response to individual agents is variable, it is often possible to find an agent or combination of agents that works for most patients.

 

e. co m

om

m

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1346 • Pain and palliative care

1. Assess suitability for opioids

Type of pain Likelihood of dependence Co-morbidity

Neuropathic pain less likely to respond History of substance or alcohol misuse, including stimulant misuse Avoid use in conditions where adverse effects more likely: Chronic obstructive pulmonary disease Chronic liver disease Chronic kidney disease

Discuss potential benefits

Improvement in pain Improvement in function Nausea Constipation Drowsiness Improvement in function

fre

ks

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re e

ks

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oo eb m

m

m

m

co e. eb

oo

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fre

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eb o

m

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co

34

ok s

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re

sf ok

ok

sf re

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co

m

These range from minimally invasive procedures like acupuncture and transcutaneous electrical nerve stimulation (TENS) to more invasive techniques such as spinal cord stimulation. Acupuncture (Fig. 34.6) has been used successfully in Eastern medicine for centuries. The mechanisms are incompletely understood, although endorphin release may explain, in part,

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the analgesic effect. Acupuncture is particularly effective in pain related to muscle spasm, with some evidence of short-term benefit for patients with low back pain. Similar mechanisms probably apply to TENS, which is worth considering in many types of chronic pain. Neuromodulation, using implanted electrodes in the epidural space (or, more recently, adjacent to peripheral nerves), has been shown to be an effective option for neuropathic pain, including failed back surgery syndrome and chronic regional pain syndrome (see below). Specialist assessment and ongoing support is necessary, as there are many potential complications, including infection, malfunction and battery failure. The likelihood of success is increased when this technique is used within the context of multidisciplinary assessment and management.

m

Stimulation therapies

sf

Fig. 34.6  Acupuncture.

m

m

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oo

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m

eb

eb

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The aims of psychological therapy are to increase coping skills and improve quality of life when facing the challenges of living with chronic pain. There are a range of ways in which psychological therapies can be delivered, including individual one-to-one sessions, group sessions, multidisciplinary pain management programmes, or web-based or telephone-based programmes. There is a good evidence for the use of a cognitive behavioural therapy (CBT)-based approach for chronic pain, delivered either individually or in a group. The overall aim is to reduce negative thoughts and beliefs, and develop positive coping strategies. The interaction between thoughts, behaviours and emotions is explored, and a problem-focused approach is used in therapy delivery. Relaxation techniques, such as biofeedback and mindfulness meditation, require a degree of stillness and withdrawal, with regular practice required for sustained benefit (see ‘Further information’). Acceptance and commitment therapy (ACT) is based on CBT principles but also uses components of mindfulness to improve psychological flexibility in the context of living with chronic pain.

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ks

eb oo ks

Psychological therapies

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m

m

fre

fre

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m

events, with many of these adverse effects being dose-related. There is evidence that doses of more than 120 mg morphine equivalents per day are associated with increased harm, and regular review to assess ongoing benefit is needed in this patient group. A suggested strategy for using strong opioids in chronic pain is shown in Box 34.10.

eb

m

ks

oo

eb

m

m

m

eb

eb

oo

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Agree on stopping rules

Define duration of treatment Agree frequency of review Aim for lowest effective dose Set upper dose limit Consider stopping if: Treatment goal is not met There is no dose response Tolerance develops rapidly

om

ks fre

Agree on dose

co m

Set timescale

fre e.

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3. Plan treatment trial

eb

eb

m

m

m e. co

Establish treatment goal

oo

oo

ks

ok s

eb o

oo 2. Discuss with patient

m

fre

Comment

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Factors to take into account

ks f

Step

Discuss adverse effects

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m e. co

34.10  Use of opioids in chronic pain

re

 

Pain • 1347

fre

Negative sensory disturbance

Numbness Tingling Loss of temperature sensitivity

Loss of sensation Paraesthesia

Other features

Feeling of insects crawling over skin Affected area feels abnormal

eb

m

fre e.

ks

ks

oo

eb

m om

.c re e No

co

oo eb m

Continue

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m

Yes

fre

Capsaicin patch Lidocaine patch Tramadol

Yes

Continue

No Botulinum toxin Strong opioids

m

eb

Response?

oo

ks

ok s eb o m

Third line (moderate evidence; weak recommendation)

ks

sf eb

m

m

Response?

m

m

Fig. 34.7  Algorithm for pharmacological management of neuropathic pain. (SNRI = serotonin noradrenaline (norepinephrine) re-uptake inhibitor) Adapted from SIGN 136 and NeuPSIG recommendations (Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Reprinted with permission from Elsevier (The Lancet Neurol 2015; 14:162–173)).

ok s

ok

sf

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co

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sf re

ok

Definite

Tricyclic antidepressant Gabapentin or pregabalin SNRI

co

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eb

m

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co

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co m

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ks oo

eb

Second line (moderate evidence; weak recommendation)

Complex regional pain syndrome

ok

Probable

First line (moderate to high evidence; strong recommendation)

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co m

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oo eb

Dysaesthesia

Assess likelihood of neuropathic pain

fre

fre

eb oo ks

m

m

Formication

m m

Yes

oo k

fre

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eb

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Are there clinical features of neuropathic pain? (Box 34.11)

Possible

Complex regional pain syndrome (CRPS) is a type of neuropathic pain that affects one or more limbs. It was previously termed reflex sympathetic dystrophy (RSD), reflecting the fact the disease is thought to be caused in part by an abnormality in the autonomic nervous system. It is a rare syndrome, occurring in about 20 per 100 000 individuals, and is more common in females, typically presenting between the ages of 35 and 50. It is classified into type I CRPS, which may be precipitated by a traumatic event

Thermal allodynia

*Symptoms may cluster, with a predominance of either positive or negative symptoms, or a mixture of both, reflecting differences in underlying mechanisms.

Chronic pain is a feature of several recognised syndromes, which are discussed in more detail below.

Neuropathic pain is defined as ‘pain associated with a lesion or disease of the somatosensory nervous system’. Neuropathic pain may be acute, such as in sciatica, which occurs as the result of a prolapsed disc, but is most problematic when it becomes chronic. Neuropathic pain causes major morbidity; in a recent study, 17% of those affected rated their quality of life as ‘worse than death’. The clinical features of neuropathic pain are summarised in Box 34.11. The diagnosis is easily missed and so careful assessment is vital, in order to make the diagnosis in the first place and then to direct management appropriately. An algorithm for the management of neuropathic pain is provided in Figure 34.7. It is important to recognise the negative impact of neuropathic pain on quality of life, which has been shown to be greater than with other types of chronic pain. As a result, appropriate support and multidisciplinary management should always be considered in addition to pharmacological therapies.

ks

Dynamic allodynia Punctate allodynia Hyperalgesia

oo

Light touch painful Pressure painful Increased pain on pin-prick Cool and warm temperatures painful

m

m

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Chronic pain syndromes

Neuropathic pain

No stimulus required to evoke pain

oo

Positive sensory disturbance

Descriptive term

ks

Spontaneous pain

eb

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ks fre

The use of specialist nerve blocks and nerve ablation therapy can be considered for pain that is unresponsive to less invasive approaches. If these are being considered, they should form part of a multidisciplinary management plan, with the aim of restoring function and reducing pain. Local anaesthetic with or without depot glucocorticoid (non-particulate for neuraxial administration) can be effective in some circumstances. Examples include occipital nerve blocks for migraine or cervicogenic headache and trigger point injections for myofascial pain. If there is limited compression of a spinal nerve root, the nerve root injections into the epidural space may help settle symptoms and avoid the need for surgical intervention. Neurodestructive procedures can also be employed for intractable pain but are rarely used outside the palliative care setting.

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m

Symptom or clinical feature*

Characteristic

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Nerve blocks and nerve ablation

34.11  Clinical features of neuropathic pain

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Complementary techniques, such as herbal medicines, vitamins, homeopathy and reflexology, have been used for the treatment of chronic pain but with little evidence of efficacy. It should be noted that herbal medications may interact with conventional drugs, causing adverse effects as the result of drug–drug interactions. St John’s wort (Hypericum perforatum) interacts with many drugs, including many antidepressants used in chronic pain, with increased serotonergic effects. Grapefruit may also increase the risk of serotonergic effects with some antidepressants. Ginkgo biloba may interact with paracetamol to increase bleeding time.

oo

fre e. c

Complementary and alternative therapies

e. co m

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m

e. co

1348 • Pain and palliative care

ks oo

eb

m

ks

ks oo

eb

m

co

e.

fre

m

eb

oo

ks

ok s eb o

Death

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Function

oo

eb

m

Low

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Time

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oo

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om m

m co

High

34

ok s

sf

re

e.

SA, Kendall M, Boyd K, et al. Illness trajectories and palliative care. BMJ 2005; 330:7498; reproduced with permission from the BMJ Publishing Group.

ok

ok

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co

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co

Fig. 34.8  Archetypal trajectories of dying. Reproduced from Murray

Chronic widespread pain (CWP) is often associated with other features, such as fatigue and irritable bowel syndrome.

re

Cancer Organ failure Physical and cognitive frailty

e.

ks fre

re

ks f oo

Chronic widespread pain

sf

re e

sf

oo k

eb

m

ks

oo

eb

m

co m

e.

Phantom limb is a common complication of amputation, occurring in up to 70% of patients. It is a form of neuropathic pain but can be particularly distressing, as the pain is felt in the area where the absent limb was previously. Although usually presenting after limb amputation, reports of phantom pain in other body parts have been reported, such as phantom breast pain following mastectomy. It is very often associated with phantom sensations, which are described as non-painful sensations in the absent body part and pain in the stump. Diagnostic nerve blocks may be helpful in directing therapy, with use of anti-neuropathic medications as outlined in Box 34.7. If there is a definite neuroma at the stump site that is interfering with prosthesis use, surgical review may be necessary.

ok

.c

e. co

fre

fre

eb oo ks eb

co m

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m

m

e. co

such as a fracture but is not associated with peripheral nerve damage, and type II CRPS, which is associated with a peripheral nerve lesion. The diagnosis is primarily clinical, based on the features shown in Box 34.12. Imaging with MRI or radionuclide bone scan may provide support for the diagnosis of type I CRPS in showing bone marrow oedema or increased tracer uptake localised to an affected site (p. 1055). Prompt diagnosis and early treatment with physiotherapy may prevent progression of symptoms. Management is as for neuropathic pain, additional approaches including graded motor imagery. Bisphosphonates have been used empirically for treatment but the evidence base for efficacy in controlling pain is weak. If medical management is incompletely effective, consideration should be given to the appropriateness of a spinal cord stimulator.

m

Palliative care is the term used to describe the active total care of patients with incurable disease. It can be distinguished from end-of-life care, which refers to the care of patients with far advanced, rapidly progressive disease that will soon prove fatal. The focus of palliative care is on symptom control alongside supportive care. While palliative care can and should be delivered at any stage of an incurable illness alongside optimal disease control, the focus of end-of-life care is on quality of life rather than prolongation of life or cure. Palliative care encompasses a distinct body of knowledge and skills that all good physicians must possess to allow them to care effectively for patients. Palliative care is traditionally seen as a means of managing distress and symptoms in patients with cancer, when metastatic disease has been diagnosed and death is seen as inevitable. There is, however, a growing recognition that the principles of palliative care and some of the interventions it uses are equally applicable in other conditions. Palliative may therefore be applied to any chronic disease state. For conditions other than cancer, the challenge is recognising when patients have entered the terminal phase of their illness, as there are fewer clear markers and the course of the illness is much more variable. Different chronic disease states progress at different rates, allowing some general trajectories of illness or dying to be defined (Fig. 34.8). These trajectories are useful in decision-making for individual patients and also in planning services.

ks

oo ks

eb

oo

*The diagnosis of CRPS type 1 can be made if a patient has at least one symptom in at least three out of the four categories and at least one sign in two out of the four categories, and no other diagnosis can explain the symptoms.

Phantom limb pain

m

fre e.

Palliative care

fre

Reduced range of motion Motor dysfunction: Weakness Tremor Dystonia Trophic changes: Hair Nails Skin

e. co m

oo

eb

Oedema Sweating change or asymmetry

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m

e. co

ks fre

Motor/trophic

Hypermobility can be associated with chronic musculoskeletal pain that often targets the joints and periarticular tissues. It is thought to be caused by abnormal stresses being placed on the joints and surrounding soft tissues due to ligament laxity, although the mechanisms are poorly understood since many people with hypermobile joints do not suffer pain. It is described in more detail on page 1059.

m

m

Temperature asymmetry Skin colour change and asymmetry Skin colour asymmetry

Oedema/sudomotor

eb

ks

ok s

eb o

oo eb

m

Vasomotor

m

Joint hypermobility syndrome

eb

Allodynia to: Temperature Light touch Deep somatic pressure Movement Hyperalgesia to pin-prick

m

Sensory

m

re

Symptom or sign

ks f

Category

Fibromyalgia is a subtype of CWP in which there are myofascial trigger points, and is often associated with sleep disturbance. Clinical features and management of fibromyalgia are discussed in more detail on page 1018.

fre

fre e. c

om

m e. co

34.12  Criteria for diagnosis of complex regional pain syndrome (CRPS) type 1*

 

Palliative care • 1349

Intermittent, severe, spasmodic, associated with nausea or vomiting

Antispasmodics Hyoscine butylbromide

Liver capsule pain

Right upper quadrant abdominal pain, often associated with tender enlarged liver Responds poorly to opioids

Neuropathic pain

Spontaneous pain Light touch, pressure and temperature changes are painful; increased pain on pin-prick Numbness, tingling or loss of temperature sensation Skin feels abnormal

Anticonvulsants: Gabapentin Pregabalin Antidepressants Amitriptyline Duloxetine Ketamine

Diffuse, severe, aching pain associated with evidence of poor perfusion Responds poorly to opioids

NSAIDs Ketamine

sf

ks

Intermittent short-acting opioids Nerve block

ks

re e

Episodic pain usually related to movement or bowel spasm

Management: pharmacological treatments

eb

eb

oo

oo k

(NSAIDs = non-steroidal anti-inflammatory drugs)

m

m

m

m

Pharmacological treatments are the mainstay of management in cancer-associated pain. A stepwise approach is adopted, following the principles of the World Health Organisation (WHO) analgesic ladder (Fig. 34.9), in which analgesia that is appropriate for the degree of pain is prescribed first. Patients with mild pain should be started on a non-opioid analgesic drug, such as paracetamol (1 g 4 times daily) or an NSAID (step 1). If the patient fails to respond adequately or has moderate pain, a weak opioid, such as codeine (60 mg 4 times daily), should be added (step 2). This can be prescribed separately or in the form of the compound analgesic co-codamol. If pain relief is still not achieved or if the patient has severe pain, a strong opioid should be substituted for the weak opioid (step 3). If the pain is severe at the outset, strong opioids should be prescribed and increased or titrated according to the patient’s response. It is important not to move ‘sideways’ (change from one drug to another of equal potency), which is a common problem during step 2 of the analgesic ladder.

co

e.

eb

oo

ks

fre

ok s

eb o

m

m

m

m

Opioids

Opioid analgesia plays a key role in patients with moderate to severe pain. Its successful use depends on appropriate assessment and a detailed explanation to the patient and carer about the benefits and potential side-effects of therapy. Morphine

ok s

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Incident pain

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ks

co m

fre e.

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Ischaemic pain

fre

ks

Glucocorticoids

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fre

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sf

m

Abdominal colic

oo

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m

co

m

Careful evaluation to identify the likely mechanisms of pain is important so that the most appropriate treatment can be given. Clinical features and suggested management strategies for common types of pain in cancer are shown in Box 34.13. The majority of patients with cancer-associated pain can be effectively managed using a stepwise approach, as outlined below.

ok

oo

Glucocorticoids Radiotherapy Codeine

m

Headache, worse in the morning, associated with vomiting and occasionally delirium

eb

Increased intracranial pressure

NSAIDs Bisphosphonates Radiotherapy

oo

Tender area over bone Possible pain on movement

Management options

eb

Bone pain

eb

eb

m

co m

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ks f

Pain is a common problem in palliative care. It has been estimated that about two-thirds of patients with cancer experience moderate or severe pain, and a quarter have three or more different sites of pain. Many of these are of a mixed aetiology and about half of patients with cancer-associated pain have a neuropathic element.

Clinical assessment

fre

Features

ks

Type of pain

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m

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fre

eb oo ks Pain

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34.13  Common types of pain in cancer

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ks fre

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m

m

Presenting problems in palliative care

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m

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The ‘rapid decline’ trajectory following a gradual decline, as occurs in cancer, is the best-recognised pattern of the need for palliative care, although a similar trajectory may be observed in other conditions, such as motor neuron disease can. Many traditional hospice services are designed to meet the needs of people on this trajectory. Over recent years, improvements in management of malignant disease mean that some types of cancer may follow an erratic or intermittent decline trajectory. Many chronic diseases, such as advanced chronic obstructive pulmonary disease (COPD) and intractable congestive heart failure, carry as high a burden of symptoms as cancer, as well as psychological and family distress. The ‘palliative phase’ of these illnesses may be more difficult to identify because of periods of relative stability interspersed with acute episodes of severe illness. However, it is still possible to recognise those patients who may benefit from a palliative approach to their care. The challenge is that symptom management needs to be delivered at the same time as treatment for acute exacerbations. This leads to difficult decisions as to the balance between symptom relief and aggressive management of the underlying disease. The starting point of need for palliative care in these conditions is the point at which consideration of comfort and individual values becomes important in decision-making, often alongside management of the underlying disease. The third major trajectory is categorised by years of poor function and frailty before a relatively short terminal period; it is exemplified by dementia but is also increasingly true for patients with many different chronic illnesses. As medical advances extend survival, this mode of dying is being experienced by increasing numbers of people. The main challenge lies in providing nursing care and ensuring that plans are agreed for the time when medical intervention is no longer beneficial. In a situation where death is inevitable and foreseeable, palliative care balances the ‘standard textbook’ approach with the wishes and values of the patient and a realistic assessment of the benefits of medical interventions. This often results in a greater focus on comfort, symptom control and support for patient and family, and may enable withdrawal of both futile and burdensome interventions. In cases of prognostic uncertainty, open, honest and gentle communication with the patient and family is important. The most common symptoms in palliative care are discussed in the next section.

e. co m

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m

e. co

1350 • Pain and palliative care

Nausea/vomiting

ks

ks oo

oo

eb

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re e

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ks

sf

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m

m

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co

Opioid-related adverse effects

ks oo

m

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eb

eb o

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fre

e.

Adverse effects are a common problem with opioids, especially on initiating treatment and on increasing the dose. The most common side-effects are nausea, drowsiness, constipation and dry mouth, as summarised in Box 34.14. Nausea and vomiting can occur initially but usually settle after a few days. Drowsiness is usually transient at opioid initiation and dose increase. If it is persistent, an alternative opioid and/or a non-opioid should be considered. In acute dosing, respiratory depression can occur but this is rare in patients on regular opioids or in those starting on small, regular doses with appropriate titration. Tolerance usually develops to nausea, vomiting and drowsiness but not to constipation or dry mouth. All patients should therefore be prescribed a laxative, unless suffering from diarrhoea, and have access to an antiemetic and good mouth care, along with rationalisation of any concomitant medication that might exacerbate drowsiness. Newer developments include the use of preparations in which opioids are combined with opioid

34

ok s

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sf re

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sf

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The regular dose should be increased by adding the total of the breakthrough doses over the previous 24 hours, unless there are significant problems with unacceptable side-effects. When the correct dose has been established, a continuous release (CR) preparation can be prescribed, usually twice daily. Breakthrough analgesia used for movement-related pain is generally not included in background opioid dose titration. Attempts to control movement-related pain with background opioid dose will usually lead to over-medication and opioid-related side-effects. This can be a risk in metastatic bone pain. Some patients may have concerns about using opioids and it is vital for these to be explored. Patients should be reassured

ok

eb

e. co

fre

ks

oo

eb

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co m

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that psychological dependence is rare when opioids are used for cancer pain, unless a pre-existing dependence problem exists. Pharmacological tolerance is not usually a clinically relevant problem; however, physical dependence, which is physiological, as manifest by a physical withdrawal syndrome, can occur if opioids are suddenly discontinued. Nearly all types of cancer pain respond to morphine to some degree but there is a spectrum of response, such that in some patients the dose of opioid required to control neuropathic pain and all elements of metastatic bone pain may be high and associated with unacceptable side-effects. In these situations, other methods of analgesia, both pharmacological and nonpharmacological, should be explored and considered at an early stage. The most effective and appropriate route of morphine administration is oral but transdermal preparations of strong opioids (usually fentanyl) are useful in certain situations, such as in patients with dysphagia or those who are reluctant to take tablets on a regular basis. Diamorphine is a highly soluble strong opioid used for subcutaneous infusions, particularly in the last few days of life, but is only available in certain countries.

m

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is the most commonly prescribed strong opioid, although there are several alternatives, as outlined in Box 34.9. Oral morphine takes about 20 minutes to exert an effect and usually provides pain relief for 4 hours. Most patients with continuous pain should be prescribed oral morphine every 4 hours initially, as this will provide continuous pain relief over the whole 24-hour period. Controlled-release morphine lasts for 12 or 24 hours, depending on the formulation, and if clinical circumstances dictate, a controlled-release formulation can be used to initiate and titrate morphine. The median effective morphine equivalent dose for cancer pain is about 200 mg per 24 hours. In addition to the regular dose of morphine, an extra dose of immediate-release (IR) morphine should be prescribed ‘as required’ for the treatment of breakthrough pain that has not been controlled by the regular prescription. As a rule of thumb, this additional dose should be one-sixth of the total 24-hour dose of opioid. The frequency of breakthrough doses should be dictated by their efficacy and any side-effects, rather than by a fixed time interval. A patient may require breakthrough analgesia as frequently as hourly if pain is severe, but this should lead to early review of the regular prescription. The patient or carer should note the timing of any breakthrough doses and the reason for them. These should be reviewed daily and the regular 4-hourly dose increased for the next 24 hours on the basis of: • the frequency of and reasons for breakthrough analgesia • the degree and acceptability of side-effects.

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Fig. 34.9  The WHO analgesic ladder. From WHO. Cancer pain relief,

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fre e.

Explanation is very important Symptoms usually settle in a few days Avoid other sedating medication where possible Ensure appropriate use of adjuvant analgesics that can have an opioid-sparing effect May require an alternative opioid

fre

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Sedation

2nd edn. Geneva: WHO; 1996.

Oral haloperidol 0.5–1 mg at night, oral metoclopramide 10 mg 3 times daily or oral domperidone 10 mg 3 times daily If constant, haloperidol or levomepromazine may be given parenterally to break the nausea cycle

m

e. co

Pain

Frequent sips of iced water, soft white paraffin to lips, chlorhexidine mouthwashes twice daily, sugar-free gum, water or saliva sprays

co m

e. co m

m

Non ± ad-opioid juva nt

e. co m

Regular laxative Opioid/naloxone oral combination, in resistant constipation

m

or in pers crea istin sing g

fre

Constipation

ks

Management

Dry mouth

m

m

eb

io mod id for mil e d ± norate pain to ± adn-opioid Pain juvant

Side-effect

m

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P in or a e incrp earssinisting g Op

34.14  Opioid side-effects

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F carnecedom f e ro

r pain m Opio to seid for mo v d ± no ere pain erate ± adn-opioid juvan t

Palliative care • 1351

fre e. c

Physiotherapy

ks

ks

Physiotherapy has a key role in the multidisciplinary approach to a wide spectrum of cancer-related symptoms, including the prevention and management of pain, muscle spasm, reduced mobility, muscle wasting and lymphoedema. Rehabilitation in palliative care has expanded and now includes pre-habilitation, which involves the use of proactive focused exercise to maintain muscle mass during cancer chemotherapy and in other chronic conditions such as COPD.

om

ks m

m

eb

eb

As with chronic pain, there is increasing use of psychological techniques in cancer pain management, which train the patient

oo

oo k

Psychological techniques

sf

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fre

ks

oo

eb

oo

m

m

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eb

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Radiotherapy is the treatment of choice for pain from bone metastases (see Box 34.13) and can also be considered for metastatic involvement at other sites. All patients with pain secondary to bone metastases should be considered for palliative radiotherapy, which can usually be given in a single dose.

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co e.

ok s

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Delirium, anxiety, agitation, hypertension

*In old age, all drugs can cause delirium. (NMDA = N-methyl-D-aspartate; NSAIDs = non-steroidal anti-inflammatory drugs)

sf

ks

fre

Severe neuropathic pain (only under specialist supervision)

Sedation, dizziness, delirium, dry mouth, constipation, urinary retention Avoid in cardiac disease Exacerbation of opioid-related side-effects

m

Neuropathic pain of any aetiology

m

m

Mild sedation, tremor, delirium Exacerbation of opioid-related side-effects

e. co

co

Neuropathic pain of any aetiology

ok s

Ketamine

Gastric irritation if used together with NSAID, fluid retention, proximal muscle myopathy, delirium, Cushingoid appearance, candidiasis, hyperglycaemia

eb o

NMDA receptor blockers

Raised intracranial pressure, nerve compression, soft tissue infiltration, liver pain

m

Amitriptyline

co

co

Tricyclic antidepressants

eb

Evidence strongest for: Gabapentin Pregabalin Duloxetine

m

Anticonvulsants

oo

Gastric irritation and bleeding, fluid retention, headache Caution in renal impairment

ks fre

Dexamethasone 8–16 mg per day, titrated to lowest dose that controls pain

oo

ks f

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Glucocorticoids

Side-effects*

m

Bone metastases, soft tissue infiltration, liver pain, inflammatory pain

m

Indications

Diclofenac

co m

Example

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NSAIDs

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co m

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Radiotherapy

34.15  Adjuvant analgesics in cancer pain

Drug

eb

eb

eb

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Neurodestructive techniques have an important role in the management of cancer pain, where life expectancy is limited. They should be used as part of an overall management plan and considered when the response to drug treatment has been inadequate. Intrathecal analgesia, delivered via either an external pump or a fully implanted device, is a good option, particularly where life expectancy is more than 3 months. Coeliac plexus blocks can be helpful for visceral pain, such as in pancreatic cancer. Lateral cordotomy to disrupt the spinothalamic tracts (either open or percutaneous) may be considered for unilateral chest wall pain, such as may occur in mesothelioma, where life expectancy is limited.

m  

fre

ks

Neurodestructive interventions

m

fre

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eb

m

m

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fre

eb oo ks

m

Management: non-pharmacological treatments

e. co m

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oo eb

m

An adjuvant analgesic is a drug that has a primary indication other than pain but which provides analgesia in some painful conditions and may enhance the effect of the primary analgesic. Commonly used adjuvant analgesics in the palliative care setting are shown in Box 34.15. Some adjuvant analgesics may enhance the side-effect profile of the primary analgesic, and dose reductions of opioids may be required when an adjuvant analgesic is added. At each step of the WHO analgesic ladder, an adjuvant

m

analgesic should be considered, the choice depending on the type of pain.

m

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m

m

m

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antagonists, such as naloxone. The naloxone is poorly absorbed and does not antagonise the systemic analgesic effect but rather acts locally to block opioid receptors in the gut, thereby reducing opioid-related constipation. Vivid dreams, visual hallucinations (often consisting of a sense of movement at the periphery of vision), delirium and myoclonus are typical of opioid-related toxicity and, if present, require urgent reassessment of the opioid dose. Biochemistry should also be checked to exclude renal impairment, dehydration, electrolyte disturbance or hypercalcaemia. Since opioid toxicity can occur at any dose, side-effects should be assessed regularly, but particularly after a dose increase. Pain should be reassessed to ensure that appropriate adjuvants are being used. Parenteral rehydration is often helpful to speed up excretion of active metabolites of morphine. The dose of opioid may need to be reduced or the opioid changed to a strong alternative. Different opioids have different side-effect profiles in different people. If a patient develops side-effects, switching to an alternative strong opioid may be helpful. Options include oxycodone, transdermal fentanyl, alfentanil, hydromorphone and occasionally methadone, any of which may produce a better balance of benefit against side-effects. Fentanyl and alfentanil have no renally excreted active metabolites and may be particularly useful in patients with renal failure. It is possible to switch between opioids but great care must be taken when doing so to make sure the dose is correct and to avoid prescribing too much or too little opioid.

Adjuvant analgesics

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1352 • Pain and palliative care

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Histamine1 Acetylcholine

Cyclizine Levomepromazine Hyoscine

Gut distension (vagal stimulation)

Histamine1

Cyclizine

Gut (chemoreceptors)

5-HT

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Levomepromazine

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drugs. Vomiting related to raised intracranial pressure is worse in the morning. Different receptors are activated, depending on the cause or causes of the nausea (Fig. 34.10). For example, dopamine receptors in the chemotactic trigger zone in the fourth ventricle are stimulated by metabolic and drug causes of nausea, whereas gastric irritation stimulates histamine receptors in the vomiting centre via the vagus nerve. Reversible causes, such as hypercalcaemia and constipation, should be treated appropriately. Drug-induced causes should be considered and the offending drugs stopped if possible. As different classes of antiemetic drug act at different receptors, antiemetic therapy should be based on a careful assessment of the probable causes and a rational decision to use a particular class of drug (Box 34.16).

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(5-HT = 5-hydroxytryptamine, serotonin)

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Metoclopramide

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Gut (gastric stasis)

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Haloperidol Metoclopramide

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Drugs

Dopamine2 5-HT

Vomiting centre

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Receptors

Chemotactic trigger zone

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34.16  Receptor site activity of antiemetic drugs

Area

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The presentation of nausea and vomiting differs depending on the underlying cause, of which there are many (p. 780). Large-volume vomiting with little nausea is common in intestinal obstruction, whereas constant nausea with little or no vomiting is often due to metabolic abnormalities or adverse effects of

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Nausea and vomiting

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Chemoreceptors Mechanoreceptors

Fig. 34.10  Mechanisms of nausea. (ACh = acetylcholine; D2 = dopamine; 5-HT = 5-hydroxytryptamine, serotonin; H1 = histamine)

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Persistent unproductive cough can be helped by opioids, which have an antitussive effect. Troublesome respiratory secretions can be treated with hyoscine hydrobromide (400–600 µg every 4–8 hours), although dry mouth is a common adverse effect. As an alternative, glycopyrronium can be useful and is given by subcutaneous infusion (0.6–1.2 mg in 24 hours).

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Vagal afferents

Metabolic toxins

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Cough

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Peripheral circulation

Retroperistalsis Gastric pyloric contraction Abdominal and thoracic wall contraction

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Vomiting centre H1, ACh, 5-HT

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Palliative care patients often seek symptom relief from both complementary and alternative therapies. While the evidence base is poorly developed, individual patients can gain significant benefits from the complementary therapies outlined on page 1348. It is critically important that patients are encouraged to discuss any alternative medicines they are considering, given the potential interactions with other therapies.

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Chemotactic trigger zone D2, 5-HT

Complementary and alternative therapies

Breathlessness is one of the most common symptoms in palliative care and is distressing for both patients and carers. Patients with breathlessness should be fully assessed to determine whether there is a reversible cause, such as a pleural effusion, heart failure or bronchospasm; if so, this should be managed in the normal way. If symptoms persist, additional measures may be necessary. There are many potential causes of dyspnoea in cancer patients and in other chronic diseases; apart from direct involvement of the lungs, muscle loss secondary to cachexia, anxiety and fear can all contribute. A cycle of panic and breathlessness, often associated with fear of dying, can be dominant. Exploration of precipitating factors is important and patient education about breathlessness and effective breathing has been shown to be effective. Non-pharmacological approaches that include using a hand-held fan, pacing, and following a tailored exercise programme can help. There is no evidence to suggest that oxygen therapy reduces the sensation of breathlessness in advanced cancer any better than cool airflow, and oxygen is indicated only if there is significant hypoxia. Opioids, through both their central and their peripheral action, can palliate breathlessness. Both oral and parenteral opioids are effective. A low dose should be used initially and titrated against symptoms, unless opioids are already being prescribed for pain, in which case the existing dose can be increased further. If anxiety is considered to be playing a significant role, a quick-acting benzodiazepine, such as lorazepam (used sublingually for rapid absorption), may also be useful.

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Vestibular input

Acupuncture and TENS are low-risk stimulation therapies that may be useful in palliative care for management of pain and nausea.

Breathlessness

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Higher centres

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Stimulation therapies

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to use coping strategies and behavioural techniques. Other issues related to the specific experience of a cancer diagnosis and cancer treatment may be complex, and individual therapy in addition to group-based approaches can be helpful.

Palliative care • 1353

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There have been dramatic improvements in the medical treatment and care of patients with cancer and other illnesses over recent years but the inescapable fact remains that everyone will die at some time. Planning for death should be actively considered in patients with chronic diseases when the death is considered to be foreseeable or inevitable. Doctors rarely know exactly when a patient will die but are usually aware that an individual is about to die and that medical interventions are unlikely to extend life or improve its quality significantly. Most people wish their doctors to be honest about this situation to allow them time to think ahead, make plans and address practical issues. A few do not wish to discuss future deterioration or death; if this is felt to be the case, avoidance of discussion should be respected. For doctors, it is helpful to understand an individual’s wishes and values about medical interventions at this time, as this can help guide decisions about interventions. It is important to distinguish between interventions that will not provide clinical benefit (a medical decision) and those that do not confer sufficient benefit to be worthwhile (a decision that can only be reached with a patient’s involvement and consent). A common example of this would be decisions about not attempting cardiopulmonary resuscitation.

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Planning for dying

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Death and dying

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Anxiety and depression are common in palliative care but the diagnosis may be difficult, since the physical symptoms of depression are similar to those of advanced cancer. It is therefore important to realise that these symptoms are not inevitable in advanced cancer. Patients should still expect to look forward to things and to enjoy them, within the context of the situation. Simply asking the question ‘Do you think you are depressed?’ can be very useful in deciding with the patient whether antidepressants or psychological interventions may be of benefit (p. 1199). In this regard, psycho-oncology has been evolving rapidly and there is now good evidence for the role of ‘talk therapy’ in palliative care, along with other appropriate management of anxiety and depression. If antidepressants are required, citalopram and mirtazapine are good choices since they are generally well tolerated in patients with advanced disease.

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Deciding whether to give intravenous fluids can be difficult when a patient is very unwell and the prognosis is uncertain. A patient with a major stroke, who is unable to swallow but is expected to survive the event, will develop renal impairment and thirst if not given fluids and should be hydrated. On the other hand, when a patient has been deteriorating and is clearly dying, parenteral hydration needs very careful consideration and it is very important to manage this on an individual basis. Comfort and avoidance of distress in the family are the primary aims. Where a patient and family are happy with meticulous oral hygiene and care to reduce the sensation of dryness in the mouth, this is usually more appropriate and effective at the end of life than parenteral hydration, which by itself will not necessarily improve the sensation of dryness. In some patients, parenteral hydration will simply exacerbate pooling of secretions, causing noisy and distressing breathing. Each decision should be individual and discussed with the patient’s family.

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Anxiety and depression

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Dehydration

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Patients with cancer lose weight for a variety of reasons, including reduced appetite or the effects of drug treatment, or as a consequence of low mood and anxiety. There is, however, a particularly challenging syndrome associated with weight loss, which is known as cancer cachexia. This results from an alteration of metabolism caused by a complex interaction of tumour-related factors and the body’s response to these factors, resulting in muscle loss, along with anorexia. Treatment involves prescribing exercise to maintain muscle mass and strengthen muscles, ensuring that there is an adequate calorie intake and providing nutritional supplements. Anti-inflammatory medication to attenuate systemic inflammation is the subject of research and many patients self-medicate with fish oil. Glucocorticoids can temporarily boost appetite and general well-being but may cause false weight gain by promoting fluid retention. Their benefits need to be weighed against the risk of side-effects, and glucocorticoids should generally be used on a short-term basis only.

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Weight loss

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Many patients become confused or agitated in the last days of life. It is important to identify and treat potentially reversible causes (p. 183), unless the patient is too close to death for this to be feasible. Early diagnosis and effective management of delirium are extremely important. As in other palliative situations, it may not be possible to identify and treat the underlying cause, and the focus of management should be to ensure that the patient is comfortable. It is important to distinguish between behavioural change due to pain and that due to delirium, as opioids will improve one and worsen the other. The management of delirium is detailed on page 209. It is important, even in the care of the actively dying patient, to treat delirium with antipsychotic medicines, such as haloperidol, rather than to regard it as distress or anxiety and use benzodiazepines only.

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Gastrointestinal obstruction is a frequent complication of intra-abdominal cancer. Patients may have multiple levels of obstruction and symptoms may vary greatly in nature and severity. Surgical mortality is high in patients with advanced disease and obstruction should normally be managed without surgery. The key to effective management is to address the presenting symptoms – colic, abdominal pain, nausea, vomiting, intestinal secretions – individually or in combination, using parenteral drugs that do not cause or worsen other symptoms. This can be problematic when a specific treatment worsens another symptom. Cyclizine improves nausea and colic responds well to anticholinergic agents, such as hyoscine butylbromide, but both slow gut motility. Nausea will improve with metoclopramide, although this is usually contraindicated in the presence of colic because of its prokinetic effect. There is some low-level evidence that glucocorticoids (dexamethasone 8 mg) can shorten the length of obstructive episodes. Somatostatin analogues, such as octreotide, will reduce intestinal secretions and therefore large-volume vomits. Occasionally, a nasogastric tube is required to reduce gaseous or fluid distension.

Delirium and agitation

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Gastrointestinal obstruction

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The subcutaneous route is often required initially to overcome gastric stasis and poor absorption of oral medicines.

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1354 • Pain and palliative care

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Patient and family awareness

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for their care. Trust in the whole team will come through a solid lead working with a team who are appropriately informed and in sympathy with the patient’s situation, each having a clear role. Families and other carers are often unprepared for the challenge of caring for a dying person. It can be an exhausting experience, both emotionally and physically, and without a critical number of carers battle fatigue can ensue, resulting in urgent admissions. With much discussion about advance directives, we should not lose sight of the reality of changing circumstances and wishes. Good anticipatory care means not just providing for new physical symptoms, but also planning for any time when care at home becomes no longer possible.

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The wishes of the patient are paramount in Western societies, whereas in other cultures the views of the family are equally important. If a patient is unable to express their view because of communication or cognitive impairment, that person is said to lack ‘capacity’. In order to decide what the patient would have wished, as much information as possible should be gained about any previously expressed wishes, along with the views of relatives and other health professionals. An advance directive is a previously recorded, written document of a patient’s wishes (p. 1307). It should carry the same weight in decisionmaking as a patient’s expressed wishes at that time, but may

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Capacity and advance directives

34

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• Make sure family know what they have to do • Notify other appropriate health professionals

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Care after death

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• Family’s awareness of condition • Management of symptoms • Need for parenteral hydration

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Religious and spiritual needs

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• Make sure you have contact details for family, that you know when they want to be contacted and that they are aware of facilities available to them

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Support for family

• Make sure any particular wishes are identified and followed

The overwhelming force in caring for any patient must be to listen to that patient and family and take their wishes on board. Patients know when health-care professionals are just receiving the information, as opposed to receiving and understanding the information in the context of the patient, their illness and needs, their carers and the socioeconomic context. It is impossible to provide holistic care for a patient without this comprehension. Every patient is unique and it is important to avoid slipping into a tick-box mentality in addressing items that should be covered in patients with advanced, incurable disease. While the key to successful palliative care is effective interdisciplinary working, every patient needs to know who has overall responsibility

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• Ensure availability of parenteral medication for symptom relief

Ongoing assessment

Ethical considerations

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• Complete Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) form • Deactivate implantable defibrillator Symptom control

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Resuscitation

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• Stop non-essential medications that do not contribute to symptom control • Stop inappropriate investigations and interventions, including routine observations

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Medical interventions

When patients with cancer or other conditions become bedbound, semi-comatose, unable to take tablets and only able to take sips of water, with no reversible cause, they are likely to be dying and many will have died within 2 days. Doctors are sometimes poor at recognising this and should be alert to the views of other members of the multidisciplinary team. A clear decision that the patient is dying should be agreed and recorded.

Once the conclusion has been reached that a patient is going to die in days to a few weeks, there is a significant shift in management (Box 34.17). Symptom control, relief of distress and care for the family become the most important elements of care. Medication and investigation are justifiable only if they contribute to these ends. When patients can no longer drink because they are dying, intravenous fluids are usually not necessary and may cause worsening of bronchial secretions; however, this is a decision that can be made only on an individual basis. Management should not be changed without discussion with the patient and/or family. Medicines should always be prescribed for the relief of symptoms. For example, morphine or diamorphine may be used to control pain, levomepromazine to control nausea, haloperidol to treat delirium, diazepam or midazolam to treat distress, and hyoscine hydrobromide to reduce respiratory secretions. Side-effects, such as drowsiness, may be acceptable if the principal aim of relieving distress is achieved. It is important to discuss and agree the aims of care with the patient’s family. Poor communication with families at this time is one of the most common reasons for family distress afterwards and for formal complaints.

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• Assess patient’s and family’s awareness of the situation • Ensure family understands plan of care

Management of dying

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34.17  How to manage a patient who is dying

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Diagnosing dying

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In general, people wish for a dignified and peaceful death and most prefer to die at home. Families also are grateful for the chance to prepare themselves for the death of a relative, by timely and gentle discussion with the doctor or other health professionals. Early discussion and effective planning improve the chances that an individual’s wishes will be achieved. There are two important caveats: firstly, wishes can and do change as the terminal situation evolves, and secondly, planning in general can only be done over time as patients form a relationship with professionals and evolve an understanding of the situation in which they find themselves. Structures for assessment and planning around end-of-life care are for guidance only and the focus should evolve with the individual patient.

Death and dying • 1355

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Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14:162–173. A comprehensive, high-quality review of the current evidence for the pharmacological management of neuropathic pain.

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Journal articles

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breathworks-mindfulness.org.uk An online resource to support learning the use of mindfulness to deal with pain, illness or stress. cuh.org.uk/breathlessness Information and resources from Cambridge University Hospital on managing breathlessness. hospiceuk.org A resource from UK hospices. mdanderson.org Brief Pain Inventory (Short Form) questionnaire. nhmrc.gov.au Australia and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute pain management: scientific evidence, 3rd edn; 2010. npcrc.org Short-form McGill Pain questionnaire. paintoolkit.org Pain toolkit self-help resource for managing pain. palliativecareguidelines.scot.nhs.uk Regularly reviewed, evidence-based clinical guidelines. palliativedrugs.com Practical information about drugs used in palliative care. sign.ac.uk SIGN guideline 136 – Management of chronic pain.

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In the UK and Europe, between 3% and 6% of dying patients will ask a doctor to end their life. Many of these requests are transient; some are associated with poor control of physical symptoms or a depressive illness. All expressions of a wish to die are an opportunity to help the patient discuss and address unresolved issues and problems. Reversible causes, such as pain or depression, should be treated. Sometimes, patients may choose to discontinue life-prolonging treatments, such as diuretics or anticoagulation, following discussion and the provision of adequate alternative symptom control. However, there remain a small number of patients who have a sustained, competent wish to end their lives, despite good control of physical symptoms. Euthanasia is now permitted or legal under certain circumstances in some countries but remains illegal in many others; public, ethical and legal debate over this issue is likely to continue and is often influenced by many complex non-palliative care issues. The European Association for Palliative Care does not see euthanasia or physician-assisted suicide as part of the role of palliative care physicians.

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Euthanasia

Further information

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not be sufficiently specific to be used in a particular clinical situation. The legal framework for decision-making varies in different countries.

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1356 • Pain and palliative care

35 

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Laboratory reference ranges in pregnancy 1364

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Laboratory reference ranges in childhood and adolescence 1363

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Laboratory reference ranges in adults 1358 Urea and electrolytes in venous blood 1358 Analytes in arterial blood 1358 Hormones in venous blood 1359 Other common analytes in venous blood 1360 Common analytes in urine 1361 Analytes in cerebrospinal fluid 1361 Analytes in faeces 1361 Haematological values 1362

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Notes on the international system of units (SI units) 1358

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Laboratory reference ranges

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Non-SI units

Potassium*

3.6–5.0 mmol/L

3.6–5.0 mEq/L

Chloride

95–107 mmol/L

95–107 mEq/L

Urea

2.5–6.6 mmol/L

15–40 mg/dL

64–111 µmol/L 50–98 µmol/L

0.72–1.26 mg/dL 0.57–1.11 mg/dL

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35.2  Analytes in arterial blood

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135–145 mEq/L

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pH 7.35–7.43

4.5–6.0 kPa

34–45 mmHg

12–15 kPa

90–113 mmHg

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> 97%

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Oxygen saturation

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21–29 mEq/L

37–45 nmol/L

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Hydrogen ion PaCO2

Non-SI units

21–29 mmol/L

SI units

Bicarbonate

PaO2

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Reference range

Analysis

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135–145 mmol/L

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SI units

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By convention, blood pressure is excluded from the SI unit system and is measured in mmHg (millimetres of mercury) rather than pascals. Mass concentrations such as g/L and µg/L are used in preference to molar concentrations for all protein measurements and for substances that do not have a sufficiently well-defined composition. Some enzymes and hormones are measured by ‘bioassay’, in which the activity in the sample is compared with the activity (rather than the mass) of a standard sample that is provided from a central source. For these assays, results are given in standardised ‘units’ (U/L), or ‘international units’ (IU/L), which depend on the activity in the standard sample and may not be readily converted to mass units.

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Reference range

Analysis

*Serum values are, on average, 0.3 mmol/L higher than plasma values.

Exceptions to the use of SI units

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35.1  Urea and electrolytes in venous blood

Creatinine Male Female

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Prefix M k d c m µ n p f

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Name megakilodecicentimillimicronanopicofemto-

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Factor 106 103 10−1 10−2 10−3 10−6 10−9 10−12 10−15

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metre (m) kilogram (kg) mole (mol) joule (J) pascal (Pa) The basic SI unit of volume is the cubic metre (1000 litres). For convenience, however, the litre (L) is used as the unit of volume in laboratory work.

Examples of decimal multiples and submultiples of SI units

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Examples of basic SI units Length Mass Amount of substance Energy Pressure Volume

Reference ranges are largely those used in the Departments of Clinical Biochemistry and Haematology, Lothian Health University Hospitals Division, Edinburgh, UK. Values are shown in both SI units and, where appropriate, non-SI units. Many reference ranges vary between laboratories, depending on the assay method used and on other factors; this is especially the case for enzyme assays. The origin of reference ranges and the interpretation of ‘abnormal’ results are discussed on page 3. No details are given here of the collection requirements, which may be critical to obtaining a meaningful result. Unless otherwise stated, reference ranges shown apply to adults; values in children may be different. Many analytes can be measured in either serum (the supernatant of clotted blood) or plasma (the supernatant of anticoagulated blood). A specific requirement for one or the other may depend on a kit manufacturer’s recommendations. In other instances, the distinction is critical. An example is fibrinogen, where plasma is required, since fibrinogen is largely absent from serum. In contrast, serum is required for electrophoresis to detect paraproteins because fibrinogen migrates as a discrete band in the zone of interest.

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Système International (SI) units are a specific subset of the metre–kilogram–second system of units and were agreed on as the everyday currency for commercial and scientific work in 1960, following a series of international conferences organised by the International Bureau of Weights and Measures. SI units have been adopted widely in clinical laboratories but non-SI units are still used in many countries. For that reason, values in both units are given for common measurements throughout this textbook and commonly used non-SI units are shown in this chapter. The SI unit system is, however, recommended.

Laboratory reference ranges in adults

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Notes on the international system of units (SI units)

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1358 • Laboratory reference ranges

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 18 mIU/L

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0.16–0.4 ng/dL

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1. A number of hormones are unstable and collection details are critical to obtaining a meaningful result. Refer to local laboratory handbook. 2. Values in the table are only a guideline; hormone levels can often be meaningfully understood only in relation to factors such as gender, age, time of day, pubertal status, stage of the menstrual cycle, pregnancy and menopausal status. 3. Reference ranges are usually dependent on the method used for analysis and frequently differ between laboratories. Non-SI units also differ; those shown here are amongst those most widely used. Readers are encouraged to consult their local laboratory for non-SI units for individual analytes and their respective reference ranges.

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0.7–1.63 ng/dL

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2.6–6.2 pmol/L

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Triiodothyronine (free), (free T3)

290–1090 ng/dL 10–90 ng/dL

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9–21 pmol/L

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0.2–4.5 mIU/L

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Thyroid-stimulating hormone (TSH) Thyroxine (free), (free T4)

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10–38 nmol/L 0.3–1.9 nmol/L

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Testosterone Male Female

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fre

m

5–40 mIU/L 5–45 mIU/L 16–63 mIU/L

2.8–23.5 ng/mL

m

60–500 mIU/L

om

Prolactin (PRL)

> 9.3 ng/mL 4.7–9.3 ng/mL  30 nmol/L 15–30 nmol/L